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Faculty Participants

The Saint Louis University Drug Discovery and Development Group brings together talented faculty from a variety of disciplines across the university. The faculty currently participating in the program can be found below.

Co-Directors

Jack Kennell
Biology john.kennell@slu.edu

Jack Kennell, Ph.D., is chair of the SLU Department of Biology. His lab is interested in mitochondrial genomics, intracellular communication pathways, mobile genetic elements and evolution in fungi. He primarily study filamentous fungi (Neurospora and Fusarium spp.), but has worked with a variety of both ascomycete and basidiomycete yeasts and are part of Malassezia consortium. He has conducted two projects that involved the assessment of anti-microbial agents: 1) anti-bacterial effectiveness of silver and zinc compounds in polyurethane rubber compounds (such as flooring products), and; 2) mode of action of zinc pyrithione (the active ingredient in many anti-dandruff shampoos). He has developed some relatively simple and reliable assays that can be conducted in micro-titer plates and carried out by undergraduate students, and also has a collection of Neurospora mutants that can provide insight into whether the anti-fungal properties relate to inhibiting mitochondrial function.

Marvin Meyers

Chemistry, Pharmacology and Physiology and Chemistry
marvin.meyers@health.slu.edu

The research in Marvin Meyers' lab is focused the application of medicinal chemistry towards the discovery of potential drug candidates to treat people with rare and neglected diseases. It collaborates with experts in infectious disease biology, including malaria, tuberculosis, infectious diarrhea (cryptosporidiosis), cryptococcal meningitis, hepatitis B virus and herpes simplex virus. The lab also has ongoing collaborations with experts in oncology, FSHD muscular dystrophy and infant short-gut syndrome.

The lab uses synthetic organic chemistry techniques to prepare new compounds, which are analyzed by its collaborators to assess their biological properties. Using medicinal chemistry and structure-based drug design principles, the lab optimizes the potency, pharmacokinetics and safety profiles of compounds with the goals of identification of tool compounds and, ultimately, candidate drug molecules for clinical trials.

Drug-development publications:

  • Nasamu, A.S.; Glushakova, S.; Russo, I.; Vaupel, B.; Oksman, A.; Kim, A.S.; Fremont, D.H.; Tolia, N.; Beck, J.R.; Meyers, M.J.; Niles, J.C.; Zimmerberg, J.; Goldberg, D.E. Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion. Science, 2017, 358, 518-522.
  • Montoya, M.C.; DiDone, L.; Heier, R.F.; Meyers, M.J.; Krysan, D.J. Antifungal Phenothiazines: Optimization, Characterization of Mechanism, and Modulation of Neuroreceptor Activity. ACS Infect Dis. 2017, DOI: 10.1021/acsinfecdis.7b00157 Article ASAP. Publication Date (Web): October 23, 2017.
  • Lee S, Harwood M, Girouard D, Meyers MJ, Campbell MA, Beamer G, Tzipori S. (2017) The therapeutic efficacy of azithromycin and nitazoxanide in the acute pig model of Cryptosporidium hominis. PLOS ONE 12(10): e0185906. https://doi.org/10.1371/journal.pone.0185906
    Welch RD, Guo C, Sengupta M, Carpenter KJ, Stephens NA, Arnett SA, Meyers MJ, Sparks LM, Smith SR, Zhang J, Burris TP, Flaveny CA. Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome. Molecular Metabolism. 2017; 6(7):703-714.
  • Donlin MJ, Zunica A, Lipnicky A, Garimallaprabhakaran AK, Berkowitz AJ, Grigoryan A, Meyers MJ, Tavis JE, Murelli RP. Troponoids Can Inhibit Growth of the Human Fungal Pathogen Cryptococcus neoformans. Antimicrobial Agents and Chemotherapy. 2017; 61(4).
  • Faidallah HM, Panda SS, Serrano JC, Girgis AS, Khan KA, Alamry KA, Therathanakorn T, Meyers MJ, Sverdrup FM, Eickhoff CS, Getchell SG, Katritzky AR. Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates. Bioorganic & Medicinal Chemistry. 2016; 24(16):3527-39.
  • Lu G, Villa JA, Donlin MJ, Edwards TC, Cheng X, Heier RF, Meyers MJ, Tavis JE. Hepatitis B virus genetic diversity has minimal impact on sensitivity of the viral ribonuclease H to inhibitors. Antiviral Research. 2016; 135:24-30.
  • Masaoka T, Zhao H, Hirsch DR, D'Erasmo MP, Meck C, Varnado B, Gupta A, Meyers MJ, Baines J, Beutler JA, et al. Characterization of the C-Terminal Nuclease Domain of Herpes Simplex Virus pUL15 as a Target of Nucleotidyltransferase Inhibitors. Biochemistry 2016, 55, 809-819.
  • Griggs, D.W.; Prinsen, M.J.; Oliva, J.; Campbell, M.A.; Arnett, S.D.; Tajfirouz, D.; Ruminski, P.G.; Yu, Y.; Bond, B.; Ji, Y.; Neckermann, G.; Choy, R.K.M.; de Hostos, E.; Meyers, M.J. Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea. J. Pharm. Exp. Ther. 2016, 357, 423-431.
  • Meyers, M. J.; Anderson, E. J.; McNitt, S. A.; Krenning, T. M.; Singh, M.; Xu, J.; Zeng, W.; Qin, L.; Xu, W.; Zhao, S.; Qin, L.; Eickhoff, C. S.; Oliva, J.; Campbell, M. A.; Arnett, S. D.; Prinsen, M. J.; Griggs, D. W.; Ruminski, P. G.; Goldberg, D. E.; Ding, K.; Liu, X.; Tu, Z.; Tortorella, M. D.; Sverdrup, F. M.; and Chen, X.; Evaluation of Spiropiperidine Hydantoins as a Novel Class of Antimalarial Agents. Bioorg. Med. Chemistry 2015, 23(16):5144-50.
  • Lu, G.; Lomonosova, E.; Cheng, X.; Moran, E.A.; Meyers, M.J.; Le Grice, S.F.J.; Thomas, C.J.; Jiang, J.-K.; Meck, C.; Hirsch, D.R.; D’Erasmo, M.P.; Suyabatmaz, D.M.; Murelli, R.P.; Tavis, J.E. Hydroxylated tropolones inhibit hepatitis B virus replication by blocking viral ribonuclease H activity. Antimicrob Agents Chemother 2015, 59, 1070–1079.
  • Cai, C.W.; Lomonosova, E.; Moran, E.A.; Cheng, X.; Patel, K.B.; Bailly, F.; Cotelle, P.; Meyers, M.J.; and Tavis, J.E. Hepatitis B Virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity. Antiviral Research 2014, 108, 48-55.
  • Meyers, M. J.;* Tortorella, M. D.; Xu, J.; Qin, L.; He, Z.; Lang, X.; Zeng, W.; Xu, W.; Qin, L.; Prinsen, M. J.; Sverdrup, F. M.; Eickhoff, C. S.; Griggs, D. W.; Oliva, J.; Ruminski, P. G.; Jacobsen, E. J.; Campbell, M. A.; Wood, D. C.; Goldberg, D. E.; Liu, X.; Lu, Y.; Lu, X.; Tu, Z.; Lu, X.; Ding, K.; Chen, X.* Evaluation of Aminohydantoins as a Novel Class of Antimalarial Agents. ACS Medicinal Chemistry Letters 2014, 5, 89-93.
  • Panda, S. S., Ibrahim, M. A., Kuecuekbay, H., Meyers, M. J., Sverdrup, F. M., El-Feky, S. A., Katritzky, A. R.* Synthesis and Antimalarial Bioassay of Quinine - Peptide Conjugates. Chemical Biology & Drug Design. 2013, 82, 361-366.
  • Tavis, J.E., Cheng, X., Hu, Y., Totten, M., Cao, F., Michailidis, E., Aurora, R., Meyers M.J., Jacobsen, J., Parniak, M.A., and Sarafianos, S.G. The hepatitis B virus ribonuclease H is sensitive to inhibitors of the human immunodeficiency virus ribonuclease H and integrase enzymes. PLoS Path. 2013, 9(1): e1003125. doi:10.1371/journal.ppat.1003125.
  • Panda, S. S., Bajaj, K., Meyers, M. J., Sverdrup, F. M., and Katritzky, A. R.* Quinine bis-conjugates with quinolone antibiotics and peptides: synthesis and antimalarial bioassay. Org. Biomol. Chem. 2012, 10, 8985-8993.
  • Meyers, M.J. and Goldberg, D.E. Recent Advances in Plasmepsin Medicinal Chemistry and Implications for Future Antimalarial Drug Discovery Efforts. Curr. Top. Med. Chem. 2012, 12, 445-455.
  • Meyers, M.J. Editorial: The Medicinal Chemistry of Novel Approaches for the Treatment of Malaria. Curr. Top. Med. Chem. 2012, 12, 371-372.

Drug-development patent applications:

  • Cao, F., Tavis, J.E., Donlin, M.J., Meyers, M.J., Murelli, R.P., and Orth, C. Provisional US patent 62/507,551. Inhibitors of nucleotidyl transferase superfamily enzymes as antibiotics. 2017
  • Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists in combination with an agent which interacts with a chemokine receptor. PCT patent application filed November 2, 2017. PCT/US2017/059777.
  • Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists. Provisional patent application filed September 13, 2017. Attorney docket USTL.P0094US.P1 Provisional Serial No. 62/558,045.
  • Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists. Provisional patent application filed September 6, 2017. Attorney docket USTL.P0093US.P1
  • Meyers, MJ; Wood, DC; Arnett, SA; Yates, MP; Ruminski, PG. Fatty acid modified epidermal growth factor. Provisional patent application filed July 27, 2017. Attorney docket USTL.P0092US.P1. Provisional Serial No. 62/537,808.
  • Meyers, MJ; Singh, M; Stallings, CL; Weiss, LA; Wildman, S; Arnett, SD. Thieno[2,3-d]pyrimidines and benzofuro[3,2-d]pyrimidines as antimicrobial agents. Provisional patent application filed July 17, 2017. Attorney docket USTL.P0084US.P1. Provisional Serial No. 62/533,403.
  • Dowd, D; Wang, X; Brothers, RC; John, ARO; Edwards, R; Meyers, M; Arnett, S; Couch, R. Methods and compounds for treating malaria. Provisional patent application filed June 27, 2017. Attorney docket 130761.00865. Provisional Serial No. 62/525,616.
  • Donlin, M.J., Tavis, J.E., Murelli, R., and Meyers, M. US patent 62/324,675. Anti-fungal compounds. 2016
  • Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists in combination with an agent which interacts with a chemokine. Provisional patent application filed November 2, 2016. Attorney docket USTL.P0083US.P1.
  • Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists. Provisional patent application filed November 2, 2016. Attorney docket USTL.P0080US.P1. Provisional Serial No. 62/416,530.
  • Tavis, J.E.; Morrison, L.A.; Meyers, M.J. Inhibitors of nucleotidyl transferases and use in herpes and hepatitis viral infections. WO2016/201306, published December 15, 2016.
  • Tavis, J.E.; Morrison, L.A.; Meyers, M.J. Inhibitors of HSV nucleotidyl transferases and uses. WO2015/077774, published May 28, 2015.
  • Blinn, J.R.; Flick, A.C.; Wennerstaal, G.M.; Jones, P.; Kaila, N.; Kiefer, Jr., J.R.; Kurumbail, R.G.; Mente, S.R.; Meyers, M.J.; Schnute, M.E.; Thorarensen, A.; Xing, L.; Zamaratski, E.; Zapf, C.W. Preparation of N-heteroaryl amides as RORC2 inhibitors. WO2015/015378, published Feb 5, 2015.
  • Chen, X.; Ding, K.; Meyers, M.J.; Tortorella, M.D.; Xu, J. Compositions and methods for the treatment of malaria. WO2014/160775, published Oct 2, 2014. Granted as US 9,353,089. May 31, 2016.
John Tavis
Molecular Microbiology and Immunology
john.tavis@health.slu.edu
 
The Tavis lab’s primary focus ins antiviral drug discovery targeting the Hepatitis B Virus ribonuclease H (RNaseH). The lab has developed a suite of biochemical and cell-based assays to evaluate how inhibitors of the RNaseH affect the enzyme and viral replication. Its key resource is a small but chemically diverse set of nuclease inhibitors and their analogs. The lab routinely conducts cytotoxicity assays using MTS (mitochondrial function), neutral red retention (lysosome function), crystal violet retention (DNA accumulation, usually interpreted as cell growth), and LDH release (plasma membrane integrity) to gain a more comprehensive view of how its compound affect the cell. The lab collaborates with medicinal chemists in the United States, France, Greece and China and are actively pushing forward two anti-HBV RNaseH hit-to-lead optimization projects. They work closely with other members of the SLU-DDG, including Feng Cao, Ph.D.; Maureen Donlin, Ph.D.; Lynda Morrison, Ph.D.; and Getahun Abate, Ph.D. Through these collaborations, the lab has demonstrated that the inhibitors in its library can have high selectivity for one virus or cellular organism over the others, opening a pathway to antimicrobial development targeting nucleases.
 

Drug-development publications:

  • Tavis, J.E., Cheng, X., Hu, Y., Totten, M., Cao, F., Michailidis, E., Aurora, R., Meyers M.J., Jacobsen, J., Parniak, M.A., and Sarafianos, S.G. (2013). The hepatitis B virus ribonuclease H is sensitive to inhibitors of the human immunodeficiency virus ribonuclease H and integrase enzymes. PLoS Path., 9:e1003125.
  • Hu, Y., Cheng, X., Cao, F., Huang, A. and Tavis, J.E. (2013). β-Thujaplicinol Inhibits Hepatitis B Virus Replication by Blocking the Viral Ribonuclease H Activity. Antiviral Res, 99:221-229.
  • Cai, C.W., Lomonosova, E., Moran, E.A., Cheng, X. Patel, K.B., Bailly, F., Cotelle, P., Meyers, M.J., and Tavis, J.E. (2014). Hepatitis B Virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity. Antiviral Res. 108:48-55.
  • Tavis, J.E., Wang, H. Tollefson, A.E., Ying, B., Korom, M., Cheng, X. Cao, F., Davis, K.L., Wold, W.S.M, and Morrison, L.A. (2014). Inhibitors of nucleotidyl transferase superfamily enzymes suppress herpes simplex virus replication. Antimicrob. Agents and Chemother. 58:7451-7461.
  • Lu G., Lomonosova E., Cheng X., Moran E.A., Meyers M.J., Le Grice S.F., Thomas C.J., Jiang J.K., Meck C., Hirsch D.R., D'Erasmo M.P., Suyabatmaz D.M., Murelli R.P., Tavis J.E. (2015). Hydroxylated Tropolones Inhibit Hepatitis B Virus Replication by Blocking the Viral Ribonuclease H Activity. Antimicrob. Agents and Chemother. 59:1070-1079.
  • Ireland, P.J., Tavis, J.E., D’Erasmo, M.P., Hirsch, D.R., Murelli, R.P., Cadiz, M.M., Patel, B.S., Gupta, A.K., Edwards, T.C., Korom, M., Moran, E.A., and Morrison, L.A. (2016). Synthetic α-hydroxytropolones inhibit replication of wild-type and acyclovir-resistant herpes simplex viruses. Antimicrob. Agents and Chemother. 60:2140-2149.
  • Lu, G., Villa, J.A., Donlin, M.J., Edwards, T.C., Cheng, X., Heier, R.F., Meyers, M.J. and Tavis, J.E. (2016). Hepatitis B virus genetic diversity has minimal impact on sensitivity of the viral ribonuclease H to inhibitors. Antiviral Research, 135:24-30.
  • Lomonosova, L., Zlotnick, A., and Tavis, J.E. (2016). Synergistic interactions between Hepatitis B Virus ribonuclease H antagonists and other inhibitors. Antimicrob. Agents and Chemother. 61:e02441-16.
  • Donlin, M.J., Zunica, A., Lipnicky, A., Garimallaprabhakaran, A.K., Berkowitz, A.J., Grigoryan, A., Meyers, M.J., Tavis, J.E., and Murelli, R.P. (2017). Troponoids can inhibit growth of the human fungal pathogen Cryptococcus neoformans. Antimicrob. Agents and Chemother. 61:e02574-16.
  • Edwards, T.C., Lomonosova, E., Patel, J.A., Li, Q., Villa, J.A., Gupta, A.K., Morrison, L.A., Bailly, F., Cotelle, P., Giannakopoulou, E., Zoidis, G., and Tavis, J.E. (2017). Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocycles. Antiviral Res. 143:205-217.
  • Lomonosova, E., Daw, J., Garimallaprabhakaran, A.K., Agyemang, N.B., Ashani, Y. Murelli, R.P., and Tavis, J.E. (2017). Efficacy and Cytotoxicity in Cell Culture of Novel α-Hydroxytropolone Inhibitors of Hepatitis B Virus Ribonuclease H. Antiviral Res. 144:164-172.
  • Hirsch, D., Schiavone, D.V., Berkowitz, A., Morrison, L.A., Masaoka, T., Wilson, J., Lomonosova, E., Zhao, H., Patel, B., Dalta, S., Hoft, S., Majidi, S., Pal, R., Gallicchio, E., Tang, L., Tavis, J.E., Le Grice, S., Beutler, J., and Murelli, R.P. (2017). Synthesis and Biological Assessment of 3,7 Dihydroxytropolones. Org. Biomol. Chem. In Press.
  • Long, K.R.*, Lomonosova, E.*, Li, Q., Ponzar, L., Villa, J.A., Touchette, E., Rapp, S. Liley, R.M. Murelli, R.P., Grigoryan, A., Buller, R.M., Wilson, L., Bial, J., Sagartz, J.E., and Tavis, J.E. (2017). In vivo efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice. Antiviral Res. 149:41-47.

Drug-development patent applications:

  • 2012 Tavis, J.E. and Hu, Y. US 14/647,331. HBV RNAseH Purification and Enzyme Inhibitors. Pending.
  • 2013 Tavis, J.E. and Morrison, L.A. PCT/US2014/067407. Inhibitors of HSV nucleotidyl transferases and uses therefore. Pending.
  • 2014 Mosa, A. Abouhaidar, M., Feld, J., and Tavis, J.E. US Patent 62/102,596. Pan-Valent HCV Vaccine. Pending.
  • 2015 Tavis, J.E., Morrison, L.A. and Meyers, M. US Patent 61/174,385. Inhibitors of nucleotidyl transferases and uses in herpes and hepatitis viral infections thererfor. Pending.
  • 2015 Tavis, J.E., Murelli, R.P., and Morrison, L.A. US Patent 62/174,350. Hydroxylated tropolone inhibitors of nucleotidyl transferases in herpesviruses and hepatitis B and uses therefore. Pending.
  • 2016 Tavis, J.E., Cotelle, P., and Bailly, F. US patent 62/309,332. N-Hydroxyisoquinolinedione inhibitors of HBV replication. Pending.
  • 2016 Donlin, M.J., Tavis, J.E., Murelli, R., and Meyers, M. US patent 62/324,675. Anti-fungal compounds. Pending.
  • 2017 Cao, F., Tavis, J.E., Donlin, M.J., Meyers, M.J., Murelli, R.P., and Orth, C. Provisional US patent 62/507,551. Inhibitors of nucleotidyl transferase superfamily enzymes as antibiotics. Pending.
Graeme Thomas

Research Innovation Group
graeme.thomas@slu.edu

Graeme Thomas is executive director of Saint Louis University’s Research Innovation Group. In this role, he is responsible for commercializing the products of SLU research including all aspects of IP protection, contracts management and industry collaboration.

Thomas has led the spin-out and support of numerous startup businesses based on SLU research and development. They include startups engaged in the development of drugs for the treatment of fibrotic disease, (Indalo Therapeutics, Inc.,) for non-opioid pain relief (BioIntervene Inc.,) and for HSV and fungal infections and hepatitis B (Casterbridge Pharmaceuticals, Inc.). He has also been engaged in the commercialization of drugs developed for use in treatment of rare diseases including MPS VII enzyme deficiencies and FSHD muscular dystrophies, both licensed to Ultragenyx Pharmaceutical Inc., an established, publicly listed, strategic licensee dedicated to the treatment of ultra-rare diseases.

Thomas has led additional initiatives within SLU including the spin-out of a joint-venture CRO focused on PK/PD studies (Gateway Laboratories) in partnership with an executive of the former Center for World Health & Medicine (CWHM). He later led the repositioning within SLU of ongoing drug development programs formerly conducted within CWHM.

He is also responsible for the promotion and expansion of the university’s sponsored research initiative, for the formation and management of a series of funded research innovation initiatives and for the direction and oversight of MEDLaunch, SLU’s student-led, student-driven biomedical incubator.

Prior to joining SLU, Graeme Thomas was founder of, and held C-level roles in, four early-stage businesses including private equity financed medical device acquisitions, low voltage implantable devices for cardiac arrhythmias and the use of stabilized enzymes from biofuel cells to carbon capture and separation. He had previously held senior management positions with international and global medical device and pharmaceutical companies. He has served as an advisor and director for several private companies, also as board member and committee chair for a NASDAQ -listed ophthalmic device company. Thomas is also active in the support and encouragement of early-stage businesses within the St. Louis innovation and entrepreneurial ecosystem.

Biology

Getahun Abate

Infectious Diseases
getahun.abate@health.slu.edu

Development of new drugs against mycobacterial diseases is one of Getahun Abate’s key research interests. His lab works closely with the Hoft lab, and has the following capacities: screening new drugs against bacillus Calmitte Guerin (the attenuated TB vaccine) using a rapid growth inhibition assay, testing drugs on reference strains of Mycobacterium tuberculosis and M. avium, studying anti-mycobacterial activities against intracellular mycobacteria using human macrophages from healthy donors, testing interactions of new drugs with first-line anti-TB drugs against extracellular and intracellular mycobacteria, studying the effects of new drugs on mycobacterium-specific immunity and testing the cytotoxicity of new drugs on THP-1 (human) and J774.A1 (murine) macrophage cell lines. His lab also has a protocol to test the anti-TB activities of new drugs in murine TB model.

Drug-development publications:

  • Abate G, Hoffner SE. Synergistic antimycobacterial activity between ethambutol and the beta-lactam drug cefepime. Diagn Microbiol Infect Dis. 1997; 28:119-22.
  • Abate G, Miörner H. Susceptibility of multidrug-resistant strains of Mycobacterium tuberculosis to amoxycillin in combination with clavulanic acid and ethambutol. J Antimicrob Chemother. 1998; 42:735-40.
  • Abate G, Koivula T, Hoffner SE. In vitro activity of thiacetazone on mycobacterial species belonging to the Mycobacterium tuberculosis complex. Int J Tuberc Lung Dis. 2002; 6:933-5.
  • Abate G, Ruminiski PG, Kumar M, Singh K, Hamzabegovic F, Hoft DF, Eickhoff CS, Selimovic A, Campbell M, Chibale K. New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells. Antimicrob Agents Chemother. 2015; 60:1216-25.
  • Kumar M, Singh K, Naran K, Hamzabegovic F, Hoft DF, Warner DF, Ruminski P, Abate G, Chibale K. Design, Synthesis, and Evaluation of Novel Hybrid Efflux Pump Inhibitors for Use against Mycobacterium tuberculosis. ACS Infect Dis. 2016; 2: 714-725.
  • Reversed Isoniazids: Design, synthesis and evaluation against Mycobacterium tuberculosis Kumar M, Singh K, Ngwane AH, Hamzabegovicc F, Abate G, Baker B, Wiid I, Hoft DF, Ruminski PG, Chibale K. Submitted (BMC).
Rajeev Aurora
Molecular Microbiology and Immunology

rajeev.aurora@health.slu.edu

The Aurora laboratory has developed a treatment that promotes the crosstalk between the immune and skeletal systems to restore homeostasis. It has been recognized that cytokines produced by proinflammatory T-cells leads to activation of osteoclasts, cells that resorb bone. Persistent exposure to the cytokines leads to erosion of the bone in a number of diseases including postmenopausal osteoporosis, rheumatoid arthritis and periodontitis. The laboratory discovered that osteoclasts, in addition to their bone resorbing activity also are antigen presenting cells. Antigen presentation by osteoclasts leads to induction of regulatory CD8 T-cells (TcREG) that express FoxP3, CD25, CTLA-4, IL-10, IL-6 and IFN-γ. TcREG are immune-suppressive, but also directly suppress osteoclast differentiation and mature osteoclasts, forming a negative feedback loop. The lab demonstrated that treating mice with low-dose RANKL induced TcREG. It has used several mouse disease models to test the effectiveness of TcREG in suppressing bone loss and inflammation. These models include: ovariectomy as a model of postmenopausal osteoporosis. In ovariectomized mice adoptive transfer or pulsed low-dose RANKL, not only suppressed bone loss but was bone regenerative allowing bone mass to be restored. The lab also have test the role of TcREG in two models of rheumatoid arthritis (RA): the serum transfer and collagen induced arthritis. Although, TcREG were not effective at suppressing inflammation in these two models, they promoted restoration of joint Finally, they have in collaboration with Joan Marini, Ph.D., (NIH) a mouse model of Osteogenesis imperfecta (OI) called the BRTL/+ mouse. Based on the lab's current studies pulsed low-dose RANKL can be used to treat a number of inflammatory bone erosion diseases. Lastly, the lab also has several compounds that act like low-dose RANKL but may be given orally to induce TcREG.

Drug-development publications:

  • Cline-Smith A, Gibbs J, Shashkova E, Buchwald ZS, Novack DV, Aurora R. (2016) Pulsed low-dose RANKL as a potential therapeutic for postmenopausal osteoporosis. JCI Insight. 1(13).
  • Shashkova EV, Trivedi J, Cline-Smith AB, Ferris C, Buchwald ZS, Gibbs J, Novack DV, Aurora R. Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-γ To Regulate Bone Resorption. (2016) J Immunol. 197(3):726-35.
  • Buchwald ZS, Yang C, Nellore S, Shashkova EV, Davis JL, Cline A, Ko J, Novack DV, DiPaolo R, Aurora R. A Bone Anabolic Effect of RANKL in a Murine Model of Osteoporosis Mediated Through FoxP3+ CD8 T Cells. (2015) J Bone Miner Res. 30(8):1508-22.
  • Buchwald ZS, Kiesel JR, Yang C, DiPaolo R, Novack DV, Aurora R. (2013) Osteoclast-induced Foxp3+ CD8 T-cells limit bone loss in mice. Bone. 56(1):163-73.
  • Buchwald ZS, Aurora R. (2013) Osteoclasts and CD8 T cells form a negative feedback loop that contributes to homeostasis of both the skeletal and immune systems. Clin Dev Immunol. 2013:429373.
  • Buchwald ZS, Kiesel JR, DiPaolo R, Pagadala MS, Aurora R. (2012) Osteoclast activated FoxP3+ CD8+ T-cells suppress bone resorption in vitro. PLoS One. 7(6):e38199.
  • Kiesel JR, Buchwald ZS, Aurora R. (2009) Cross-presentation by osteoclasts induces FoxP3 in CD8+ T cells. J Immunol. 182(9):5477-87.
  • Kiesel J, Miller C, Abu-Amer Y, Aurora R. (2007) Systems level analysis of osteoclastogenesis reveals intrinsic and extrinsic regulatory interactions. Dev Dyn. 236(8):2181-97.

Patent applications:

  • 2017 Rajeev Aurora, Zachary Buchwald, Jennifer Kiesel US 15/052,793 Suppression of bone loss by introducing FoxP3+ CD8 T-cells (TcREG). Patent Allowed.
James Brien
Molecular Microbiology and Immunology

james.brien@health.slu.edu

The Pinto and Brien labs work closely together. The labs have established a pipeline to evaluate anti-viral therapeutics for a wide range of viral pathogens, including highly pathogenic flaviviruses that broadly represent current and potential threats to public health. They evaluate toxicity and efficacy of anti-viral therapeutics against viruses that represent a range of emerging infectious diseases that affect animals and humans. Therapeutics that can be evaluated range from small-molecule compounds to biologics that target either the virus or the host. Their screening methods to evaluate therapeutics are highly scalable with the ability to evaluate toxicity and efficacy of compounds over a wide range on conditions. They have established small-molecule compounds and/or biologics as tools to mechanistically evaluate host pathogen interactions with the ability to detect and define escape mutants to improve compound design and targeting.

Drug-development publications:

  • Pinto AK*, Brien JD*, Chia-Ying KL, Johnson S, Chiang C, Hiscott J, Sarathy VV, Barett AD, Shresta S, Diamond MS. 2015. Defining New Therapeutics Using a More Immunocompetent Mouse Model of Antibody-Enhanced Dengue Virus Infection. MBio. 2015 September 15;6(5) (*co-first author)
  • Lazear HM*, Daniels BP*, Pinto AK, Albert Huang A, Vick SC, Gale M., Klein RS, and Diamond MS. Interferon lambda restricts West Nile virus neuroinvasion by enhancing integrity of the blood-brain barrier. Science Translational Medicine 2015 Apr 22;7(284). (*co-first author)
  • Kim, S*, Pinto, AK*, Myers, NB, Weidanz, JA, Hildebrand, WH, Diamond, MS, and Hansen, TH, Use of a novel T cell receptor mimic to define cells that cross-present an immunodominant West Nile virus epitope in mice. European Journal of Immunology 2014 Jul;44(7):1936-46. (*co-first author)
  • Pinto AK, Richner J, Poore E, Patil P, Amanna I, Slifka M, and Diamond MS A hydrogen peroxide-inactivated virus vaccine elicits humoral and cellular immunity and protects against lethal West Nile virus infection in aged mice. Journal of Virology 2013 February; 87(4):1926-36.
  • Lazear HM, Pinto AK, Vogt MR, Gale M Jr, Diamond MS. Interferon-{beta} controls West Nile virus infection and pathogenesis in mice. Journal of Virology. 2011 May 4;85(14):7186-94.
  • Smith, S., L. Sliva, J. Fox, A. Flyak, N. Kose, G. Sapparapu, S. Khomadiak, A. Ashbrook, K. Kahle, R. Fong, S. Swayne, B. Doranz, C. McGee, M. Heise, P. Pal, J.D. Brien, K. Austin, M.S. Diamond, T. Dermody, J.E. Crowe. Jr. 2015. Broad and ultrapotent human monoclonal antibodies with therapeutic activity against chikungunya virus. Cell Host & Microbe. 2015 Jul 8;18(1):86-95.
  • Sukupolvi-Petty, S., J. D. Brien, S. K. Austin, B. Shrestha, S. Swayne, K. Kahle, B. J. Doranz, S. Johnson, T. C. Pierson, D. H. Fremont, and M. S. Diamond. 2013. Functional Analysis of Antibodies against Dengue Virus Type 4 Reveals Strain-Dependent Epitope Exposure That Impacts Neutralization and Protection. Journal of Virology 87:8826-8842.
  • Brien, J. D., S. Sukupolvi-Petty, K.L. Williams, C. K. Lam, M. A. Schmid, S. Johnson, E. Harris, and M. S. Diamond. 2013. Protection by Fc-Dual Affinity Re-Targeting Antibodies against Dengue Virus. Journal of Virology 87:7747-7753.
  • Uhrlaub, J. L., J. D. Brien, D. G. Widman, P. W. Mason, and J. Nikolich-Zugich. 2011. Repeated in vivo stimulation of T and B cell responses in old mice generates protective immunity against lethal West Nile virus encephalitis. Journal of Immunology 186:3882-3891
  • Shrestha, B., J. D. Brien, S. Sukupolvi-Petty, S. K. Austin, M. A. Edeling, T. Kim, K. M. O'Brien, C. A. Nelson, S. Johnson, D. H. Fremont, and M. S. Diamond. 2010. The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1. PLoS Pathogens 6:e1000823.
  • Sukupolvi-Petty, S., S. K. Austin, M. Engle, J. D. Brien, K. A. Dowd, K. L. Williams, S. Johnson, R. Rico-Hesse, E. Harris, T. C. Pierson, D. H. Fremont, and M. S. Diamond. 2010. Structure and function analysis of therapeutic monoclonal antibodies against dengue virus type 2. Journal of Virology 84:9227-9239.
  • Brien, J. D., S. K. Austin, S. Sukupolvi-Petty, K. M. O'Brien, S. Johnson, D. H. Fremont, and M. S. Diamond. 2010. Genotype-specific neutralization and protection by antibodies against dengue virus type 3. Journal of Virology 84:10630-10643.
Feng Cao

St. Louis Veteran's Administration Hospital
Feng.Cao@va.gov

Feng Cao, Ph.D., is an adjunct assistant professor at SLU. Her primary duties are as a clinical microbiologist for the VA hospital. She has assembled a large set of pathogenic bacteria from VA patients that have well-characterized drug resistance patterns and has established rapid, standardized screening assays for each of these bacterial species. She collaborates with the Tavis lab to screen his collection of nuclease inhibitors against this spectrum of bacteria. She is focusing on the top five bacteria of critical interest to the WHO (below).

  • Acinetobacter baumannii
  • Pseudomonas aeruginosa
  • Enterobacteriaceae (E. coli, Klebsiella pneumonia, Citrobacter koseri, Enterobacter cloacae complex, Morganella morganii and Proteus mirabilis)
  • Staphylococcus aureus (also Coagulase-negative Staphylococcus including S. saprophyticus, S. epidermidis, S. lugdunensis and S. hominis)
  • Enterococcus faecium

Cao also performs indirect screening on the multi-drug resistant Gram-negative bacteria to search for the antibiotic adjuvants, i.e. resistance breakers (such as efflux pump inhibitors, uptake enhancers). The location of her research lab in the John Cochran VA hospital campus, next to VA clinical microbiology lab, provides convenient access to clinical specimens from veterans. She welcomes collaborative research, especially projects on infectious diseases of military importance.

Drug-development publications:

  • Feng Cao, Cari Orth, Maureen J. Donlin, Marvin J. Meyers, Ryan P. Murelli, Patrick Adegboyega, and John E. Tavis. Troponoids as a novel antibacterial agents. Manuscript in preparation.

Drug-development applications

  • 2017 Cao, F., Tavis, J.E., Donlin, M.J., Meyers, M.J., Murelli, R.P., and Orth, C. Provisional US patent 62/507,551. Inhibitors of nucleotidyl transferase superfamily enzymes as antibiotics. Pending.
Yie-Hwa Chang

Biochemistry and Molecular Biology
yiehwa.chang@health.slu.edu

Yie-Hwa Chang has been interested in developing anti-cancer drugs and antibiotics for the past 15 years. His lab has discovered and characterized two types of methionine aminopeptidases (MetAPs). The type-2 MetAP plays a key role in angiogenesis, and has been identified as a potential target for developing anti-cancer and anti-obesity drugs. The lab's discovery was licensed to 11 major pharmaceutical companies for their drug discovery projects. The lab has worked with David Griggs and Eric Jacobsen. Together, they have identified promising leading compounds as potential anti-TB drugs via inhibition of the MetAPs. In addition, Chang has been collaborating with Tomasz Heyduk, and have developed a series of novel homogeneous assays that have been used by many pharmaceutical companies for high-throughput drug screening projects. For example, they developed the first homogeneous assay for cAMP, S-adenosylmethionine (SAMe) and L-tryptophan. The cAMP assay has been used for developing drugs targeting GPCRs. The SAMe assay has been used for developing drugs for targeting methyltransferases. Finally, the L-tryptophan assay has been used for developing drugs targeting Indoleamine 2,3-dioxygenase (IDO1/IDO2). IDO1 is an important immunotherapy target for cancer treatment.

Drug-discovery publications:

  • Zuo SL, Guo Q, Chang YH. A protease assay via pre-column derivatization and high pressure liquid chromatography. Analytical Biochemistry 1994, 222:514-516.
  • Li X, Chang YH. Amino-terminal protein processing in Saccharomyces cerevisiae is an essential function that requires two distinct methionine aminopeptidases. Proc. Natl. Sci. Acad. USA 1995, 92:12357-12361.
  • Griffith EC, Su Z, Turk B, Chen S, Chang YH, Wu Z, Biemann K, Liu JO. Methionine aminopeptidase (Type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin. Chemistry and Biology, 1997, 4:461-471.
  • Griffith EC, Su, Z, Niwayama S, Ramsay CA, Chang YH. Molecular recognition of angiogenesis inhibitors fumagillin and ovalicin by methionine aminopeptidase 2. Proc. Natl. Acad. Sci. USA 1998, 95:15183-15188.
  • Turk BE, Griffith EC, Wolf S, Bieman K, Chang YH, Liu JO. Selective inhibition of N-terminal processing by TNP-470 and Ovalicin in endothelial cells. Chemistry and Biology 1999, 6:823-833.
  • Udagawa T, Yuan J, Panigrahy D, Chang YH, Shah J, D'Amato RJ. Cytochalasin E, an epoxide containing Aspergillus-derived fungal metabolite, inhibits angiogenesis and tumor growth. J. Pharmacol. Exp. Ther. 2000, 294:421-427.
  • Kwon JY, Jeong HW, Kim HK, Kang KH, Chang YH, Bae KS, Choi JD, Lee UC, Son KH, Kwon BM cis-Fumagillin, a new methionine aminopeptidase (type 2) inhibitor produced by Penicillium sp. F2757. J. Antibiotics. 2000, 53:799-80.
  • Asami, Y.; Kakeya, H.; Onose, R.; Chang, Y.-H.; Toi, M.; Osada, H. RK-805, an endothelial-cell-growth inhibitor produced by Neosartorya sp., and a docking model with methionine aminopepidase-2. Tetrahedron, 2004, 60:7085-7091.
  • Heyduk E, Dummitt B, Chang YH, Heyduk T. Molecular pincers: antibody- based homogeneous protein sensors. Anal Chem. 2008, 80:5152-5159.
  • Tian L, Wang RE, Fei Y, Chang YH. A homogeneous fluorescent assay for cAMP-phosphodiesterase enzyme activity. J Biomol Screen. 2011, 17:409-414.
  • Chang YH. Common therapeutic target for both cancer and obesity. World journal of biological chemistry. 2017, 8:102-107.

Drug-development patent applications:

  • Chang YH. Patent No. 5,888,796. (1999) Clone of a Nucleotide Sequence Encoding a Protein Having Two Functions.
  • Chang YH. Patent No. 6,593,454. (2001) Methods for Identifying Inhibitors of Methionine Aminopeptidases.
  • Ray R, Ray R, Basu A and Chang YH. Patent No. 7232893. (2007) Method of manufacturing a stellate cell death factor.
  • Heyduk T, Tian L, Wang RE and Chang YH. Patent No. 8,956,857, (2015) Three-component biosensors for detecting macromolecules and other analytes.
  • Heyduk T, Tian L, Wang RE and Chang YH. Patent No. 9,618,505, (2017) Biosensors for detecting macromolecules and other analytes.
  • Chang YH, Tian L, Heyduk T. Patent No. 9,797,892 (2017) Molecular biosensors capable of signal amplification.
Maureen Donlin

Biochemistry and Molecular Biology
maureen.donlin@health.slu.edu

Maureen Donlin's lab is interested in developing new anti-fungal drugs, with an immediate focus on compounds that can inhibit Cryptococcus neoformans, a pathogen affecting immune-suppressed patients. She is a bioinformatician with extensive experience in biochemistry, molecular genetics, biostatistics and computer programming who has provided bioinformatics and biostatistical support to the Departments of Biochemistry and Microbiology at Saint Louis University for 17 years. She is well versed in the SPSS statistical package, and programming skills include PERL, MySQL, PHP, HTML and the statistical language R. She has conducted the primary analysis of microarray, RNAseq and proteomics data from several difference species in collaboration with many different groups. She is applying these skills to identify the target(s) of the highly effective inhibitors of C. neoformans that she has identified through her screening efforts. She is also the director of the SLU master’s program in Bioinformatics and Computational Biology and can help identify potential interns for higher order data analysis needs of the SLU-DDG.

Drug-development publications:

  • Cannon, N.A., Donlin, M.J., Mayes, L.M., Castro, A.L., Di Bisceglie, A.M., and Tavis, J.E. (2009). Evidence for action of ribavirin through the hepatitis C virus RNA polymerase. J. Viral Hep., 16:595-604.
  • Lu, G., Villa, J.A., Donlin, M.J., Edwards, T.C., Cheng, X., Heier, R.F., Meyers, M.J. and Tavis, J.E. (2016). Hepatitis B virus genetic diversity has minimal impact on sensitivity of the viral ribonuclease H to inhibitors. Antiviral Research, 135:24-30.
  • Donlin, M.J., Zunica, A., Lipnicky, A., Garimallaprabhakaran, A.K., Berkowitz, A.J., Grigoryan, A., Meyers, M.J., Tavis, J.E., and Murelli, R.P. (2017). Troponoids can inhibit growth of the human fungal pathogen Cryptococcus neoformans. Antimicrob. Agents and Chemother. 61:e02574-16.

Drug-development patent applications:

  • 2016 Donlin, M.J., Tavis, J.E., Murelli, R., and Meyers, M. US patent 62/324,675. Anti-fungal compounds. Pending.
  • 2017 Cao, F., Tavis, J.E., Donlin, M.J., Meyers, M.J., Murelli, R.P., and Orth, C. Provisional US patent 62/507,551. Inhibitors of nucleotidyl transferase superfamily enzymes as antibiotics. Pending.
Susana Gonzalo
Biochemistry and Molecular Biology
susana.gonzalohervas@health.slu.edu
 

Susana Gonzalo's long-term research interest is to understand the molecular mechanisms that contribute to the genomic instability that drives aging and cancer, with the ultimate goal of targeting these mechanisms therapeutically. The spatial and temporal organization of the genome has emerged as an additional level of regulation of genome function and integrity. Nuclear lamins orchestrate genome organization, forming a scaffold for tethering chromatin and protein complexes regulating many nuclear functions. Lamins dysfunction impacts nuclear architecture, chromatin structure, as well as DNA transcription, replication and repair. These data, and the association of lamins dysfunction with dozen of degenerative disorders, premature aging, and cancer, provide evidence for these proteins operating as “caretakers of the genome." Gonzalo's research focuses on identifying mechanisms whereby lamins regulate genome stability and function, as these mechanisms are key to identify therapies that ameliorate the progression of laminopathies in patients. In addition, she is interested in the genomic instability that drives breast cancers with the poorest prognosis, such as BRCA-mutated and triple negative (TNBC). Intriguingly, they found similar alterations in cells from these aggressive cancers and in cells from laminopathies, including deficiencies in DNA repair and in the vitamin D/vitamin D receptor (VDR) axis. Importantly, she has have shown that calcitriol, the most bioactive vitamin D metabolite, ameliorates genomic instability phenotypes in breast cancer cells and in lamins-deficient cells. These findings suggest that targeting the vitamin D/VDR axis could have beneficial effects in subsets of TNBC patients, as well as in some laminopathy patients.

Recent publications:

  • Kreienkamp R*, Graziano S*, Coll-Bonfill N*, Bedia-Diaz G, Cybulla E, Vindigni A, Dorsett D, Kubben N, Batista LFZ, Gonzalo S. “A cell intrinsic interferon-like response links replication stress to cellular aging”. Cell Reports. In press.
  • Zhang Y, Lai J, Du Z, Gao J, Yang S, Gorityala S, Xiong X, Deng O, Ma Z, Yan C, Gonzalo S, Xu Y, Zhang J. “Targeting radioresistance breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress”. Oncotarget 2016 Jun 7;7(23):34688-702. PMID: 2716719.
  • Kreienkamp R, Croke M, Neumann MA, Bedia-Diaz G, Graziano S, Dusso A, Dorsett D, Carlberg C and Gonzalo S. “Vitamin D receptor signaling improves Hutchinson-Gilford progeria syndrome cellular phenotypes”. Oncotarget 2016. May 24;7(21):30018-31. PMID: 27145372
  • Graziano S, Johnston R, Deng O, Zhang J, Gonzalo S. “Vitamin D/vitamin D receptor axis regulates DNA repair during oncogene-induced senescence”. Oncogene 2016 Oct 13;35(41):5362-5376. PMID: 27041576
  • Bronshthein I, Kepten E, Berezin S, Kanter I, Lindner M, Redwood AB, Mai S, Gonzalo S, Foisner R, Shav-Tal Y, Garini Y. “Loss of lamin A function increases chromatin dynamics in the nuclear interior”. Nat Commun. 2015 Aug 24;6:8044. PMID: 26299252
David Griggs
Molecular Microbiology and Immunology

david.griggs@health.slu.edu

David Griggs' laboratory specializes in drug discovery and the translation of basic discoveries to therapeutic application. It performs assay development and optimization for high-throughput screening of compounds, assessment of target potency and selectivity for lead characterization, and in vitro and in vivo assessment of compound pharmacokinetics and metabolism (ADME). A major interest of Griggs for many years, both at SLU and in prior research performed while working at global pharmaceutical companies (Searle/Pharmacia/Pfizer), has been the roles of integrins in physiology and disease. The lab has recently discovered and characterized new small molecule compounds that are making exciting progress toward development of an effective treatment to reduce or reverse the destructive organ fibrosis that occurs in many disease conditions. The lab is also currently applying its molecular, cellular and pharmacology expertise in sponsored research programs to develop new medicines for treatment of tuberculosis, cryptosporidiosis and bone disorders. The lab maintains diverse and productive collaborations with companies, foundations, and researchers at SLU and around the world, all of which aim to advance new and better treatments for patients.

Drug-development publications:

  • Henderson, N.C., T.D. Arnold, Y. Katamura, M.M. Giacomini, J.D. Rodriquez, J.H. McCarty, A. Pellicoro, A.C. Mackinnon, P.G. Ruminski, D.W. Griggs, M.J. Prinsen, J.J. Maher, J.P. Iredale, A. Lacy-hulbert, R.H. Adams, and D. Sheppard. 2013. Targeting av integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nature Medicine. 19:1617-1624
  • Meyers, M.J., M.D. Tortorella, J. Xu, L. Qin, Z. He, X. Lang, W. Zeng, W. Xu, L. Qin, M.J. Prinsen, F.M. Sverdrup, C.S. Eickhoff, D.W. Griggs, J. Oliva, P.G. Ruminski, E.J. Jacobsen, M.A. Campbell, D.C. Wood, D.E. Goldberg, X. Liu, Y. Chen, Z. Tu, X. Lu, K. Ding, and X. Chen. 2013. Evaluation of aminohydantoins as a novel class of antimalarial agents. 2014. ACS Med. Chem. Lett. 5:89-93.
  • Meyers, M.J., E.J. Anderson, S.A. McNitt, T.M. Krenning, M. Singh, J. Xu, W. Zeng, L. Qin, C.S.. Eickhoff, J. Oliva, M.A. Campbell, S.D. Arnett, M.J. Prinsen, D.W. Griggs, P.G. Ruminski, D.E. Goldberg, K. Ding, X. Liu, Z. Tu, M.D. Tortorella, F. M, Sverdrup, and X. Chen. Evaluation of spiropiperadine hydantoins as a novel class of antimalarial agents. 2015. Bioorg Med Chem 23:5144-5150.
  • Ulmasov, B., B.A. Neuschwander-Tetri, J. Lai, V. Monastyrskiy, T. Bhat, M. Yates, J. Oliva, M.J. Prinsen, P. Ruminski, D.W. Griggs. Targeted pharmacologic inhibition of RGD-binding integrins suppresses pancreatic fibrosis in mice. 2016. Cell Mol Gastroenterol Hepatol 2:499-518.
  • Griggs, D.W. M.J. Prinsen, J. Oliva, M.A. Campbell, S.D. Arnett, D. Tajfirouz, P.G. Ruminski, Y. Yu, B.R. Bond, Y. Ji, G. Neckermann, R.K.M Choy, E. de Hostos, M.J. Meyers. 2016. Pharmacologic comparison of clinical neutral endopeptidase inhibitors in a rat model of acute secretory diarrhea. J Pharmacol Exp Ther 367:423-431.
  • Murray, I.R., Z.N. Gonzalez, J. Baily, R. Dobie, R.J. Wallace, A.C. Mackinnon, J.R. Smith, S.N. Greenhaigh, A.I. Thompson, K.P. Conroy, D.W. Griggs, P.G. Ruminski, G.A. Gray, M. Singh, M.A. Campbell, T.J. Kendall, J. Dai, Y. Li, J.P Iredale, H. Simpson, J. Huard, B. Peault, N.C. Henderson. 2017. Alpha v integrins on mesenchymal cells critically regulate skeletal and cardiac muscle fibrosis. Nature Communications 8(1):1118.
  • Stebbins, E., R.S. Jumani, C. Klopfer, J. Barlow, P. Miller, M.A. Campbell, M.J. Meyers, D.W. Griggs, and C.D. Huston. 2018. Clinical and microbiologic efficacy of the piperazine-based drug lead MMV665917 in the dairy calf cryptosporidiosis model. PLOS Neglected Trop. Dis. In press.

Drug-development patent applications:

  • 2013 Griggs DW, and Ruminski, P.G., Beta amino acid derivatives as integrin antagonists. Granted US patent 9085606.
  • 2013 Griggs DW, and Ruminski, P. G., 3,5 phenyl-substituted beta amino acid derivatives as integrin antagonists. Granted US Patent 8716226.
  • 2016 Griggs DW, and Ruminski, P.G., Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists. WO 2017117538. Pending.
  • 2017 Griggs DW, and Ruminski, P.G., αVβ1 integrin antagonists. Provisional US patent 62/471,882. Pending.
Daniel Hoft

Infectious Diseases
daniel.hoft@health.slu.edu

Daniel Hoft is the chief of the SLU Division of Infectious Diseases, Allergy and Immunology. He has three drug-development projects in his lab.

  1. Tuberculosis: Hoft's group has been supporting the study of new drugs for TB. Abate is the leader of these efforts in the Infectious Diseases division. They have the capacity to study the effects of new drugs against extracellular Mycobacterium tuberculosis (Mtb), intracellular Mtb in human primary monocytes and cell lines, in vivo studies in murine models and human trials. This recent work has already resulted in 2 published papers. In addition, they recently received a VTEU award (~$6 million in total funding) to conduct a multi-drug resistant (MDR)-TB treatment trial in South Africa and Uganda with the goal of comparing the current standard of care treatment (involving 1-2 years of total treatment including an injectable agent daily for at least the first 6 months) with a new all oral drug regimen (replacing the injectable with delamanid, a newly approved oral TB drug).
  2. Chagas disease: Hoft has studied infections with Trypanosoma cruzi in mice for 30 years. Most of his work has focused on basic immunology and vaccine development. However, the Hoft lab has developed high throughput assays for screening new compounds for inhibitory effects against extracellular life stages of the parasite, low-moderate throughput assays for screening for intracellular effects of drugs on parasites infecting human primary monocytes and/or cell lines, and has in vivo murine models for testing protective effects of new drugs.
  3. Influenza: Hoft's lab has been developing a T cell targeting universal vaccine for influenza A, and has been engaged in multiple clinical trials of currently licensed and experimental influenza vaccines. This work has led to in vitro assays capable of measure immune and/or drug effects against intracellular development of viral progeny in primary human monocytes. In addition, Hoft is developing a human influenza challenge unit for testing the efficacy of new drugs and/or vaccines.
Jack Kennell

Biology
john.kennell@slu.edu

Jack Kennell is chair of the SLU Department of Biology. His lab is interested in mitochondrial genomics, intracellular communication pathways, mobile genetic elements and evolution in fungi. He primarily study filamentous fungi (Neurospora and Fusarium spp.), but has worked with a variety of both ascomycete and basidiomycete yeasts and are part of Malassezia consortium. He has conducted two projects that involved the assessment of anti-microbial agents: 1) anti-bacterial effectiveness of silver and zinc compounds in polyurethane rubber compounds (such as flooring products), and; 2) mode of action of zinc pyrithione (the active ingredient in many anti-dandruff shampoos). He has developed some relatively simple and reliable assays that can be conducted in micro-titer plates and carried out by undergraduate students, and also has a collection of Neurospora mutants that can provide insight into whether the anti-fungal properties relate to inhibiting mitochondrial function.

Sergey Korolev
E.A. Doisy Department of Biochemistry and Molecular Biology
sergey.korolev@health.slu.edu
 

The Korolev lab studies mechanism of protein function using X-ray crystallography combined with biophysical and biochemical methods. They are deciphering an atomic resolution structures to understand mechanism of protein function under normal conditions, the effect of disease-related mutations and the mechanism of protein interactions with ligands, cofactors and inhibitors. They are developing high throughput inhibitor screening assays for DNA binding and peptide interacting proteins. Systems of interest include 1) recombination mediator proteins (RMPs) important for genome maintenance, DNA repair and implicated in cancer and other diseases; 2) DNA helicases involved in DNA replication and repair; 3) calcium-independent phospholipase critical for inflammation, calcium homeostasis and implicated in a wide spectrum of diseases from ischemia to neurodegeneration. The work closely with other members of the SLU-DDG, including John Tavis, Duane Grandgenett and David Griggs.

Drug-development and protein ligand interaction publications:

  • Li, Y., Korolev, S. and Waksman, G., Crystal structure of open and closed forms of binary and ternary complexes of the large fragment of Thermus aquaticus DNA polymerase I: structural basis for nucleotide incorporation. EMBO J. 1998, 17:7514-7525. PMCID: PMC1171095
  • Li, Y., Kong. M., Korolev, S. and Waksman, G. Crystal structures of the Klenow Fragment of Thermus aquaticus DNA Polymerase I Complexed with Deoxyribonucleoside Triphosphates. Protein Science 1998, 7:1116-1123. PMCID: PMC2144016
  • Bhantgar, R.S., Futterer, K., Farazi, T.A., Korolev, S., Murray, C.L., Jackson-Machelski, E., Gokel, G.W., Gordon, J.I. and Waksman, G., Structure of N-myristoyltransferase with bound myristoylCoA and peptide substrate analogs. Nature Str. Biol. 1998, 5:1091-1097.
  • Lu, D., Futterer, K., Korolev, S., Zheng, X., Tan, K., Waksman, G., Sadler, J.E. Crystal structure of enteropeptidase light chain complexed with an analog of the trypsinogen activation peptide. J. Mol. Biol.1999, 292:361-73.
  • Korolev S, Ikeguchi Y, Skarina T, Beasley S, Arrowsmith C, Edwards A, Joachimiak A, Pegg AE, Li, Y., Savchenko A. The crystal structure of spermidine synthase with a multisubstrate adduct inhibitor. Nat. Struct. Biol. 2002, 9(1):27-31.
  • Pandey KK, Bera S, Korolev S, Campbell M, Yin Z, Aihara H, Grandgenett DP. (2014) Rous sarcoma virus synaptic complex capable of concerted integration is kinetically trapped by human immunodeficiency virus integrase strand transfer inhibitors. J. Biol. Chem. 2014; 289(28):19648-58.
  • Lu X, Malley KR, Brenner CC, Koroleva O, Korolev S*, Downes BP. A MUB E2 structure reveals E1 selectivity between cognate ubiquitin E2s in eukaryotes. Nat. Commun. 2016, 7:12580
  • Malley K.R., Olga Koroleva O., Miller I., Sanishvili R., Jenkins C.M., Gross R.M. Korolev S. A novel dimeric active site and regulation mechanism revealed by the crystal structure of iPLA2β. BIORXIV/2017/196097

Drug-development patent applications:

  • Brian Downs, Sergey Korolev, Xiaolong Lu. “MUB Motif is an inhibitor of e2-ubiquitin thioester formation”. PATENT USTL.P0061US.P1
Lynda Morrison
Molecular Microbiology and Immunology

lynda.morrison@health.slu.edu

The Morrison lab focuses primarily on developing new chemotherapy for herpes simplex viruses, and possibly other herpesviruses. The lab has identified several new chemotypes with anti-herpes activity from among compounds in the Tavis lab compound library. They have the capacity to screen compounds in a higher throughput 96-well format (colorimetric or luminescence assay), assess genome load by qPCR and inhibition of virus replication by plaque assay. Cytotoxicity of compounds is routinely assessed by MTS, LDH and neutral red assays. Its collaborators carry out biochemical assays for inhibition of enzymatic activity. In addition, they are adept with mouse models of HSV-1 eye disease, HSV-1/HSV-2 genital disease (vaginal mucosa), and are developing a mouse model of HSV-1 skin infection.

Drug-development publications:

  • Tavis, J.E., Wang, H. Tollefson, A.E., Ying, B., Korom, M., Cheng, X. Cao, F., Davis, K.L., Wold, W.S.M, and Morrison, L.A. (2014). Inhibitors of nucleotidyl transferase superfamily enzymes suppress herpes simplex virus replication. Antimicrob. Agents and Chemother. 58:7451-7461. PMCID: PMC4249532.
  • Ireland, P.J., Tavis, J.E., D’Erasmo, M.P., Hirsch, D.R., Murelli, R.P., Cadiz, M.M., Patel, B.S., Gupta, A.K., Edwards, T.C., Korom, M., Moran, E.A., and Morrison, L.A. (2016). Synthetic α-hydroxytropolones inhibit replication of wild-type and acyclovir-resistant herpes simplex viruses. Antimicrob. Agents and Chemother. 60:2140-2149. PMCID: PMC4808205.
  • Edwards, T.C., Lomonosova, E., Patel, J.A., Li, Q., Villa, J.A., Gupta, A.K., Morrison, L.A., Bailly, F., Cotelle, P., Giannakopoulou, E., Zoidis, G., and Tavis, J.E. (2017). Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocycles. Antiviral Res. 143:205-217.
  • Hirsch, D., Schiavone, D.V., Berkowitz, A., Morrison, L.A., Masaoka, T., Wilson, J., Lomonosova, E., Zhao, H., Patel, B., Dalta, S., Hoft, S., Majidi, S., Pal, R., Gallicchio, E., Tang, L., Tavis, J.E., Le Grice, S., Beutler, J., and Murelli, R.P. (2017). Synthesis and Biological Assessment of 3,7 Dihydroxytropolones. Org. Biomol. Chem. In press.

Drug-development patent applications:

  • 2013 Tavis, J.E. and Morrison, L.A. PCT/US2014/067407. Inhibitors of HSV nucleotidyl transferases and uses therefore. Pending.
  • 2015 Tavis, J.E., Morrison, L.A. and Meyers, M. US Patent 61/174,385. Inhibitors of nucleotidyl transferases and uses in herpes and hepatitis viral infections thererfor. Pending.
  • 2015 Tavis, J.E., Murelli, R.P., and Morrison, L.A. US Patent 62/174,350. Hydroxylated tropolone inhibitors of nucleotidyl transferases in herpesviruses and hepatitis B and uses therefore. Pending.
Judith Mosinger Ogilvie
Department of Biology
judith.ogilvie@slu.edu
 

A major focus of the Ogilvie lab is on retinal degenerative diseases. They have a well-characterized in vitro mouse model of early onset retinitis pigmentosa using the rd1 mouse retina grown in organ culture for four weeks. This system allows for environmental and drug manipulations. In addition, they are currently collaborating with Nader Sheibani at University of Wisconsin to develop and characterize a rapid onset mouse model of diabetic retinopathy. Research progress on this disease has been slowed by the very gradual onset and development of symptoms in animal models that are currently available. Previous work has included an intravitreal gene therapy approach to treatment of retinal and brain degeneration due to inherited mucopolysaccharidosis defects.

Drug-development publications:

  • Mosinger Ogilvie, J., J.D. Speck, J.M. Lett, and T.T. Fleming (1999). A reliable method for organ culture of neonatal mouse retina with long-term survival. J. Neurosci. Meth. 87:57-65.
  • Ogilvie, J.M., J.D. Speck, and J.L. Lett (2000). Growth Factors In Combination, But Not Individually, Rescue rd Mouse Photoreceptors in Organ Culture. Exp. Neurol. 161:676-685.
  • Ogilvie, J.M. (2001). Photoreceptor Rescue in an Organotypic Model of Retinal Degeneration. Prog. Brain Res. 131:641-648.
  • Ogilvie, J.M. and J.D. Speck (2002). Dopamine has a critical role in photoreceptor degeneration in the rd mouse. Neurobiol. Dis. 10:33-40.Hennig, A.K., B. Levy, J.M. Ogilvie, C.A. Vogler, N. Galvin, S. Bassnett, and M.S. Sands (2003). Intra-vitreal gene therapy reduces lysosomal storage in the brains of mucopolysaccharidosis VII mice. J. Neurosci. 23:3302-3307.
  • Hennig, A.K., J.M. Ogilvie, K.K. Ohlemiller, A.M. Timmers, W.W. Hauswirth, and M.S. Sands (2004). AAV-Mediated intravitreal gene therapy reduces lysosomal storage in the retinal pigmented epithelium and improves retinal function in adult MPS VII mice. Mol. Ther. 10:106-116.
  • Liu, Y., L. Xu, A.K. Hennig, A. Kovacs, A. Fu, S. Chung, D. Lee, B. Wang, J.M. Ogilive, S.-R. Cai, and K.P. Ponder (2005). Liver-directed Neonatal Gene Therapy Prevents Cardiac, Bone, Ear, and Eye Disease in Mucopolysaccharidosis I Mice. Mol. Ther. 11:35-47.
  • Griffey, M., S.L. Macauley, J.M. Ogilvie, M.S. Sands. (2005) AAV2-mediated ocular gene therapy for infantile neuronal ceroid lipofuscinosis (INCLs). Mol. Ther. 12:413-21.
  • Ogilvie, J.M., K.K. Ohlemiller, G.N. Shah, B. Ulmasov, T.A. Becker, A. Waheed, A.K. Hennig, P.D. Lukasiewicz, W.S. Sly (2007). Carbonic anhydrase XIV deficiency produces a functional defect in the retinal light response. Proc. Nat. Acad. Sci. 104:8514-8519.
  • Heldermon, C.D., A.K. Hennig, K.K. Ohlemiller, J.M. Ogilvie, E.D. Herzog, A, Breidenbach, C. Vogler, D.F. Wozniak, M.S. Sands (2007). Development of sensory, motor and behavioral deficits in the murine model of Sanfilippo syndrome type B. PLoS ONE. 2(8): e772. doi:10.1371/journal.pone.0000772
  • Ogilvie, J.M., A.M. Hakenewerth, R.R. Gardner, J.G. Martak, V.M. Maggio (2009) Dopamine receptor loss of function is not protective of rd1 rod photoreceptors in vivo. Mol. Vision. 15:2868-2878. www.molvis.org/molvis/v15/a303/
  • Zhang, J., A.M. Richmond, J.M. Ogilvie (2014) Inhibition of dopamine signaling suppresses cGMP accumulation in rd1 retinal organ cultures. NeuroReport. 25:601-606. DOI: 10.1097/WNR.0000000000000145. PMID: 24614363.
Amelia Pinto
Molecular Microbiology and Immunology

amelia.pinto@health.slu.edu

The Pinto and Brien labs work closely together. They have established a pipeline to evaluate anti-viral therapeutics for a wide range of viral pathogens, including highly pathogenic flaviviruses that broadly represent current and potential threats to public health. They evaluate toxicity and efficacy of anti-viral therapeutics against viruses that represent a range of emerging infectious diseases that affect animals and humans. Therapeutics that can be evaluated range from small-molecule compounds to biologics that target either the virus or the host. Their screening methods to evaluate therapeutics are highly scalable with the ability to evaluate toxicity and efficacy of compounds over a wide range on conditions. They have established small-molecule compounds and/or biologics as tools to mechanistically evaluate host pathogen interactions with the ability to detect and define escape mutants to improve compound design and targeting.

Drug-development publications:

  • Pinto AK*, Brien JD*, Chia-Ying KL, Johnson S, Chiang C, Hiscott J, Sarathy VV, Barett AD, Shresta S, Diamond MS. 2015. Defining New Therapeutics Using a More Immunocompetent Mouse Model of Antibody-Enhanced Dengue Virus Infection. MBio. 2015 September 15;6(5) (*co-first author)
  • Lazear HM*, Daniels BP*, Pinto AK, Albert Huang A, Vick SC, Gale M., Klein RS, and Diamond MS. Interferon lambda restricts West Nile virus neuroinvasion by enhancing integrity of the blood-brain barrier. Science Translational Medicine 2015 Apr 22;7(284). (*co-first author)
  • Kim, S*, Pinto, AK*, Myers, NB, Weidanz, JA, Hildebrand, WH, Diamond, MS, and Hansen, TH, Use of a novel T cell receptor mimic to define cells that cross-present an immunodominant West Nile virus epitope in mice. European Journal of Immunology 2014 Jul;44(7):1936-46. (*co-first author)
  • Pinto AK, Richner J, Poore E, Patil P, Amanna I, Slifka M, and Diamond MS A hydrogen peroxide-inactivated virus vaccine elicits humoral and cellular immunity and protects against lethal West Nile virus infection in aged mice. Journal of Virology 2013 February; 87(4):1926-36.
  • Lazear HM, Pinto AK, Vogt MR, Gale M Jr, Diamond MS. Interferon-{beta} controls West Nile virus infection and pathogenesis in mice. Journal of Virology. 2011 May 4;85(14):7186-94.
  • Smith, S., L. Sliva, J. Fox, A. Flyak, N. Kose, G. Sapparapu, S. Khomadiak, A. Ashbrook, K. Kahle, R. Fong, S. Swayne, B. Doranz, C. McGee, M. Heise, P. Pal, J.D. Brien, K. Austin, M.S. Diamond, T. Dermody, J.E. Crowe. Jr. 2015. Broad and ultrapotent human monoclonal antibodies with therapeutic activity against chikungunya virus. Cell Host & Microbe. 2015 Jul 8;18(1):86-95.
  • Sukupolvi-Petty, S., J. D. Brien, S. K. Austin, B. Shrestha, S. Swayne, K. Kahle, B. J. Doranz, S. Johnson, T. C. Pierson, D. H. Fremont, and M. S. Diamond. 2013. Functional Analysis of Antibodies against Dengue Virus Type 4 Reveals Strain-Dependent Epitope Exposure That Impacts Neutralization and Protection. Journal of Virology 87:8826-8842.
  • Brien, J. D., S. Sukupolvi-Petty, K.L. Williams, C. K. Lam, M. A. Schmid, S. Johnson, E. Harris, and M. S. Diamond. 2013. Protection by Fc-Dual Affinity Re-Targeting Antibodies against Dengue Virus. Journal of Virology 87:7747-7753.
  • Uhrlaub, J. L., J. D. Brien, D. G. Widman, P. W. Mason, and J. Nikolich-Zugich. 2011. Repeated in vivo stimulation of T and B cell responses in old mice generates protective immunity against lethal West Nile virus encephalitis. Journal of Immunology 186:3882-3891
  • Shrestha, B., J. D. Brien, S. Sukupolvi-Petty, S. K. Austin, M. A. Edeling, T. Kim, K. M. O'Brien, C. A. Nelson, S. Johnson, D. H. Fremont, and M. S. Diamond. 2010. The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1. PLoS Pathogens 6:e1000823.
  • Sukupolvi-Petty, S., S. K. Austin, M. Engle, J. D. Brien, K. A. Dowd, K. L. Williams, S. Johnson, R. Rico-Hesse, E. Harris, T. C. Pierson, D. H. Fremont, and M. S. Diamond. 2010. Structure and function analysis of therapeutic monoclonal antibodies against dengue virus type 2. Journal of Virology 84:9227-9239.
  • Brien, J. D., S. K. Austin, S. Sukupolvi-Petty, K. M. O'Brien, S. Johnson, D. H. Fremont, and M. S. Diamond. 2010. Genotype-specific neutralization and protection by antibodies against dengue virus type 3. Journal of Virology 84:10630-10643.
Nicola Pozzi
Biochemistry and Molecular Biology
nicola.pozzi@health.slu.edu
 

Pathological activation of the complement and clotting cascades leads to thrombosis and chronic inflammation, and is linked to the onset and progression of autoimmune disorders. In Pozzi's laboratory, they study the unknown biology of complement and clotting factors, investigate their structure-function relationships, identify new ligands and define their mechanisms of recognition. Finally, they engineer novel constructs with the desired functional properties to correct the disease state. To achieve their goals, they routinely express recombinant proteins from bacteria and mammalian cells for biophysical (single molecule fluorescence, DLS, analytical centrifugation, calorimetry) and structural analysis (X-ray crystallography and SAXS). They develop and perform kinetic and binding assays based on absorbance, fluorescence and luminescence spectroscopy, and surface plasmon resonance. The recent development of a novel family of anticoagulant fusion proteins to ameliorate the outcome of patients suffering from thrombosis in acute clinical settings such as sepsis and stroke is a representative example of their work.

Drug-development publications:

  • Barranco-Medina S, Murphy M, Pelc L, Chen Z, Di Cera E, Pozzi N. Rational Design of Protein C Activators. Sci Rep. 2017 Mar 15;7:44596.
  • Acquasaliente L, Peterle D, Tescari S, Pozzi N, Pengo V, De Filippis V. Molecular mapping of α-thrombin (αT)/β2-glycoprotein I (β2GpI) interaction reveals how β2GpI affects αT functions. Biochem J. 2016 Dec 15;473(24):4629-4650.
  • Pozzi N, Bystranowska D, Zuo X, Di Cera E. Structural Architecture of Prothrombin in Solution Revealed by Single Molecule Spectroscopy. J Biol Chem. 2016 Aug 26;291(35):18107-16.
  • Pozzi N, Zerbetto M, Acquasaliente L, Tescari S, Frezzato D, Polimeno A, Gohara DW, Di Cera E, De Filippis V. Loop Electrostatics Asymmetry Modulates the Preexisting Conformational Equilibrium in Thrombin. Biochemistry. 2016 Jul 19;55(28):3984-94.
  • Wood DC, Pelc LA, Pozzi N, Wallisch M, Verbout NG, Tucker EI, Gruber A, Di Cera E. WEDGE: an anticoagulant thrombin mutant produced by autoactivation. J Thromb Haemost. 2015 Jan;13(1):111-4.
  • Pozzi N, Chen Z, Zapata F, Niu W, Barranco-Medina S, Pelc LA, Di Cera E. Autoactivation of thrombin precursors. J Biol Chem. 2013 Apr 19;288(16):11601-10.
  • Banzato A, Pozzi N, Frasson R, De Filippis V, Ruffatti A, Bison E, Padayattil SJ, Denas G, Pengo V. Antibodies to Domain I of β(2)Glycoprotein I are in close relation to patients risk categories in Antiphospholipid Syndrome (APS). Thromb Res. 2011 Dec;128(6):583-6.
  • Pozzi N, Banzato A, Bettin S, Bison E, Pengo V, De Filippis V. Chemical synthesis and characterization of wild-type and biotinylated N-terminal domain 1-64 of beta2-glycoprotein I. Protein Sci. 2010 May;19(5):1065-78.

Drug-development patent applications:

  • 2011 Di Cera E., Gruber A., Gandhi P., Pelc L., Pozzi N., Wood D.C. Expression of thrombin variants. US8940297B2. Granted
  • 2012 Pozzi N., Di Cera E., Barranco-Medina S. Recombinant auto-activating protease precursors. US15004280. Pending.
  • 2017 Barranco-Medina S., Di Cera E., Pozzi N. WO2017189943A1. Thrombin-thrombomodulin fusion proteins as a powerful anticoagulant. Application
  • 2017 Barranco-Medina S., Di Cera E., Pozzi N. WO2016176440A9. Thrombin-thrombomodulin fusion
Ratna Ray
Pathology
Ratna.ray@health.slu.edu

Ratna Ray's laboratory in focused on studying chemopreventive and therapeutic effect on several solid tumors in preclinical models using a natural product, Bitter Melon (Momordica charantia). They have excellent results from Their preclinical studies. Currently, they are identifying the active component(s) of bitter melon in collaboration with Bahaa Elgendy. Their initial experiments suggested few interesting components they need to be investigated.

Drug-discovery publications:

  • Sur S, Steele R, Aurora R, Varvares M, Schwetye KE, Ray RB. Bitter Melon Prevents the Development of 4-NQO-Induced Oral Squamous Cell Carcinoma in an Immunocompetent Mouse Model by Modulating Immune Signaling. Cancer Prev Res (Phila). 2017 Oct 23. doi: 10.1158/1940-6207.CAPR-17-0237. [Epub ahead of print]
  • Muhammad N, Steele R, Isbell TS, Philips N, Ray RB. Bitter melon extract inhibits breast cancer growth in preclinical model by inducing autophagic cell death. Oncotarget. 2017 Aug 3;8(39):66226-66236. doi: 10.18632/oncotarget.19887. eCollection 2017 Sep 12.
  • Bhattacharya S, Muhammad N, Steele R, Kornbluth J, Ray RB. Bitter Melon Enhances Natural Killer-Mediated Toxicity against Head and Neck Cancer Cells. Cancer Prev Res (Phila). 2017 Jun;10(6):337-344. doi: 10.1158/1940-6207.CAPR-17-0046. Epub 2017 May 2.
  • Bhattacharya S, Muhammad N, Steele R, Peng G, Ray RB. Immunomodulatory role of bitter melon extract in inhibition of head and neck squamous cell carcinoma growth. Oncotarget. 2016 May 31;7(22):33202-9. doi: 10.18632/oncotarget.8898.
  • Rajamoorthi A, Shrivastava S, Steele R, Nerurkar P, Gonzalez JG, Crawford S, Varvares M, Ray RB. Bitter melon reduces head and neck squamous cell carcinoma growth by targeting c-Met signaling. PLoS One. 2013 Oct 17;8(10):e78006. doi: 10.1371/journal.pone.0078006. eCollection 2013.
  • Ru P, Steele R, Nerurkar PV, Phillips N, Ray RB. Bitter melon extract impairs prostate cancer cell-cycle progression and delays prostatic intraepithelial neoplasia in TRAMP model. Cancer Prev Res (Phila). 2011 Dec;4(12):2122-30. doi: 10.1158/1940-6207.CAPR-11-0376. Epub 2011 Sep 12.
  • Ray RB, Raychoudhuri A, Steele R, Nerurkar P. Bitter melon (Momordica charantia) extract inhibits breast cancer cell proliferation by modulating cell cycle regulatory genes and promotes apoptosis. Cancer Res. 2010 Mar 1;70(5):1925-31. doi: 10.1158/0008-5472.CAN-09-3438. Epub 2010 Feb 23.
Fran Sverdrup

Biochemistry and Molecular Biology
fran.sverdrup@health.slu.edu

Fran Sverdrup's lab is focused on drug discovery in human genetic diseases as well as infectious diseases. They perform target identification and validation, drug screening and preclinical evaluation of drug candidates. Their major current project targets facioscapulohumeral muscular dystrophy (FSHD), one of the most common forms of muscular dystrophy for which there is no treatment. Their goals are to identify druggable pathways that modulate expression of the toxic DUX4 gene that is responsible for FSHD and translate those finding into potential therapies. Their approach is to perform high throughput screening of chemical libraries to identify compounds intended to epigenetically suppress the DUX4 gene. They are currently advancing three exciting classes of drugs that turn off DUX4 expression including a robust lead optimization program that involves close collaboration with Their medicinal chemistry colleagues. They evaluate new compounds by using biochemical and cell based assays. They are now moving these compounds into animal model testing and have established a key collaboration with a pharmaceutical partner to eventually advance one of these into human clinical trials. A second interest is in anti-infectives research with recent programs targeting malaria, lymphatic filariasis and African sleeping sickness. To accomplish these activities, they maintain a network of collaborations with disease experts, medicinal chemists, pharmaceutical/biotech companies and foundations.

Drug-development publications:

  • Campbell AE, Oliva J, Yates MP, Zhong JW, Shadle SC, Snider L, Singh N, Tai S, Hiramuki Y, Tawil R, van der Maarel SM, Tapscott SJ, Sverdrup FM. 2017. BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells. Skelet Muscle. 7(1):16.
  • Faidallah HM, Panda SS, Serrano JC, Girgis AS, Khan KA, Alamry KA, Therathanakorn T, Meyers MJ, Sverdrup FM, Eickhoff CS, Getchell SG, Katritzky AR. 2016. Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates. Bioorganic & Medicinal Chemistry. 24(16):3527-39.
  • Meyers MJ, Anderson EJ, McNitt SA, Krenning TM, Singh M, Xu J, Zeng W, Qin L, Xu W, Zhao S, Qin L, Eickhoff CS, Oliva J, Campbell MA, Arnett SD, Prinsen MJ, Griggs DW, Ruminski PG, Goldberg DE, Ding K, Liu X, Tu Z, Tortorella MD, Sverdrup FM, Chen X. 2015. Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents. Bioorganic & Medicinal Chemistry. 23(16):5144-50.
  • Gillan V, O'Neill K, Maitland K, Sverdrup FM, Devaney E. 2015. A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes. PLoS Neglected Tropical Diseases. 8(2):e2699.
  • Meyers MJ, Tortorella MD, Xu J, Qin L, He Z, Lang X, Zeng W, Xu W, Qin L, Prinsen MJ, Sverdrup FM, Eickhoff CS, Griggs DW, Oliva J, Ruminski PG, Jacobsen EJ, Campbell MA, Wood DC, Goldberg DE, Liu X, Lu Y, Lu X, Tu Z, Lu X, Ding K, Chen X. 2014. Evaluation of aminohydantoins as a novel class of antimalarial agents. ACS Medicinal Chemistry Letters. 5(1):89-93.
  • Panda SS, Ibrahim MA, Küçükbay H, Meyers MJ, Sverdrup FM, El-Feky SA, Katritzky AR. 2013. Synthesis and antimalarial bioassay of quinine - peptide conjugates. Chemical Biology & Drug Design. 82(4):361-6.
  • Panda SS, Bajaj K, Meyers MJ, Sverdrup FM, Katritzky AR. 2012. Quinine bis-conjugates with quinolone antibiotics and peptides: synthesis and antimalarial bioassay. Organic & Biomolecular Chemistry. 10(45):8985-93.
  • Madsen SH, Andreassen KV, Christensen ST, Karsdal MA, Sverdrup FM, Bay-Jensen AC, Henriksen K. 2011. Glucocorticoids exert context-dependent effects on cells of the joint in vitro. Steroids. 76(13):1474 82.
  • Sverdrup FM, Yates MP, Vickery LE, Klover JA, Song LR, Anglin CP, Misko TP. 2010. Protein geranylgeranylation controls collagenase expression in osteoarthritic cartilage. Osteoarthritis and Cartilage. 18(7):948-55.
  • Yates MP, Settle SL, Yocum SA, Aggarwal P, Vickery LE, Aguiar DJ, Skepner AP, Kellner D, Weinrich SL, Sverdrup FM. 2010. IGFBP-5 Metabolism Is Disrupted in the Rat Medial Meniscal Tear Model of Osteoarthritis. Cartilage. 1(1):43-54.
  • Busby WH Jr, Yocum SA, Rowland M, Kellner D, Lazerwith S, Sverdrup F, Yates M, Radabaugh M, Clemmons DR. 2009. Complement 1s is the serine protease that cleaves IGFBP-5 in human osteoarthritic joint fluid. Osteoarthritis and Cartilage. 17(4):547-55.

Drug-development patent applications:

  • 2002 Schmidt, B.F., Allen, M.L., Sverdrup, F., and Carmichael, D.F. US Patent 09/292,036. Connective tissue growth factor (CTGF) and methods of use.
  • 2005 Fisher, C., Bashkin, J.K., Crowley, K., Sverdrup, F.M., Garner-Hamrick, P.A., and Phillion, D.P. WO2005033282. Polyamide compositions and therapeutic methods for treatment of human papilloma virus.
  • 2017 Sverdrup, F.M. and Tapscott, S.J. US Patent 14/491,599. Inhibition of DUX4 expression using bromodomain and extra-terminal domain protein inhibitors (BETi).
  • 2017 Sverdrup, F.M., Tapscott, S.J., Oliva, J., Campbell, A.E. and Meyers, M.J. Provisional US patent 62/589,225. Compositions for modulating DUX4 expression in FSHD. Pending.
John Tavis
Molecular Microbiology and Immunology

john.tavis@health.slu.edu

The Tavis lab’s primary focus is in antiviral drug discovery targeting the Hepatitis B Virus ribonuclease H (RNaseH). They have developed a suite of biochemical and cell-based assays to evaluate how inhibitors of the RNaseH affect the enzyme and viral replication. Their key resource is a small but chemically diverse set of nuclease inhibitors and their analogs. They routinely conduct cytotoxicity assays using MTS (mitochondrial function), neutral red retention (lysosome function), crystal violet retention (DNA accumulation, usually interpreted as cell growth), and LDH release (plasma membrane integrity) to gain a more comprehensive view of how their compound affect the cell. They collaborate with medicinal chemists in the United States, France, Greece and China and are actively pushing forward two anti-HBV RNaseH hit-to-lead optimization projects. They work closely with other members of the SLU-DDG, including Feng Cao, Maureen Donlin, Lynda Morrison and Getahun Abate. Through these collaborations, they have demonstrated that the inhibitors in their library can have high selectivity for one virus or cellular organism over the others, opening a pathway to antimicrobial development targeting nucleases.

Drug-development publications:

  • Tavis, J.E., Cheng, X., Hu, Y., Totten, M., Cao, F., Michailidis, E., Aurora, R., Meyers M.J., Jacobsen, J., Parniak, M.A., and Sarafianos, S.G. (2013). The hepatitis B virus ribonuclease H is sensitive to inhibitors of the human immunodeficiency virus ribonuclease H and integrase enzymes. PLoS Path., 9:e1003125.
  • Hu, Y., Cheng, X., Cao, F., Huang, A. and Tavis, J.E. (2013). β-Thujaplicinol Inhibits Hepatitis B Virus Replication by Blocking the Viral Ribonuclease H Activity. Antiviral Res, 99:221-229.
  • Cai, C.W., Lomonosova, E., Moran, E.A., Cheng, X. Patel, K.B., Bailly, F., Cotelle, P., Meyers, M.J., and Tavis, J.E. (2014). Hepatitis B Virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity. Antiviral Res. 108:48-55.
  • Tavis, J.E., Wang, H. Tollefson, A.E., Ying, B., Korom, M., Cheng, X. Cao, F., Davis, K.L., Wold, W.S.M, and Morrison, L.A. (2014). Inhibitors of nucleotidyl transferase superfamily enzymes suppress herpes simplex virus replication. Antimicrob. Agents and Chemother. 58:7451-7461.
  • Lu G., Lomonosova E., Cheng X., Moran E.A., Meyers M.J., Le Grice S.F., Thomas C.J., Jiang J.K., Meck C., Hirsch D.R., D'Erasmo M.P., Suyabatmaz D.M., Murelli R.P., Tavis J.E. (2015). Hydroxylated Tropolones Inhibit Hepatitis B Virus Replication by Blocking the Viral Ribonuclease H Activity. Antimicrob. Agents and Chemother. 59:1070-1079.
  • Ireland, P.J., Tavis, J.E., D’Erasmo, M.P., Hirsch, D.R., Murelli, R.P., Cadiz, M.M., Patel, B.S., Gupta, A.K., Edwards, T.C., Korom, M., Moran, E.A., and Morrison, L.A. (2016). Synthetic α-hydroxytropolones inhibit replication of wild-type and acyclovir-resistant herpes simplex viruses. Antimicrob. Agents and Chemother. 60:2140-2149.
  • Lu, G., Villa, J.A., Donlin, M.J., Edwards, T.C., Cheng, X., Heier, R.F., Meyers, M.J. and Tavis, J.E. (2016). Hepatitis B virus genetic diversity has minimal impact on sensitivity of the viral ribonuclease H to inhibitors. Antiviral Research, 135:24-30.
  • Lomonosova, L., Zlotnick, A., and Tavis, J.E. (2016). Synergistic interactions between Hepatitis B Virus ribonuclease H antagonists and other inhibitors. Antimicrob. Agents and Chemother. 61:e02441-16.
  • Donlin, M.J., Zunica, A., Lipnicky, A., Garimallaprabhakaran, A.K., Berkowitz, A.J., Grigoryan, A., Meyers, M.J., Tavis, J.E., and Murelli, R.P. (2017). Troponoids can inhibit growth of the human fungal pathogen Cryptococcus neoformans. Antimicrob. Agents and Chemother. 61:e02574-16.
  • Edwards, T.C., Lomonosova, E., Patel, J.A., Li, Q., Villa, J.A., Gupta, A.K., Morrison, L.A., Bailly, F., Cotelle, P., Giannakopoulou, E., Zoidis, G., and Tavis, J.E. (2017). Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocycles. Antiviral Res. 143:205-217.
  • Lomonosova, E., Daw, J., Garimallaprabhakaran, A.K., Agyemang, N.B., Ashani, Y. Murelli, R.P., and Tavis, J.E. (2017). Efficacy and Cytotoxicity in Cell Culture of Novel α-Hydroxytropolone Inhibitors of Hepatitis B Virus Ribonuclease H. Antiviral Res. 144:164-172.
  • Hirsch, D., Schiavone, D.V., Berkowitz, A., Morrison, L.A., Masaoka, T., Wilson, J., Lomonosova, E., Zhao, H., Patel, B., Dalta, S., Hoft, S., Majidi, S., Pal, R., Gallicchio, E., Tang, L., Tavis, J.E., Le Grice, S., Beutler, J., and Murelli, R.P. (2017). Synthesis and Biological Assessment of 3,7 Dihydroxytropolones. Org. Biomol. Chem. In Press.
  • Long, K.R.*, Lomonosova, E.*, Li, Q., Ponzar, L., Villa, J.A., Touchette, E., Rapp, S. Liley, R.M. Murelli, R.P., Grigoryan, A., Buller, R.M., Wilson, L., Bial, J., Sagartz, J.E., and Tavis, J.E. (2017). In vivo efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice. Antiviral Res. 149:41-47.

Drug-development patent applications:

  • 2012 Tavis, J.E. and Hu, Y. US 14/647,331. HBV RNAseH Purification and Enzyme Inhibitors. Pending.
  • 2013 Tavis, J.E. and Morrison, L.A. PCT/US2014/067407. Inhibitors of HSV nucleotidyl transferases and uses therefore. Pending.
  • 2014 Mosa, A. Abouhaidar, M., Feld, J., and Tavis, J.E. US Patent 62/102,596. Pan-Valent HCV Vaccine. Pending.
  • 2015 Tavis, J.E., Morrison, L.A. and Meyers, M. US Patent 61/174,385. Inhibitors of nucleotidyl transferases and uses in herpes and hepatitis viral infections thererfor. Pending.
  • 2015 Tavis, J.E., Murelli, R.P., and Morrison, L.A. US Patent 62/174,350. Hydroxylated tropolone inhibitors of nucleotidyl transferases in herpesviruses and hepatitis B and uses therefore. Pending.
  • 2016 Tavis, J.E., Cotelle, P., and Bailly, F. US patent 62/309,332. N-Hydroxyisoquinolinedione inhibitors of HBV replication. Pending.
  • 2016 Donlin, M.J., Tavis, J.E., Murelli, R., and Meyers, M. US patent 62/324,675. Anti-fungal compounds. Pending.
  • 2017 Cao, F., Tavis, J.E., Donlin, M.J., Meyers, M.J., Murelli, R.P., and Orth, C. Provisional US patent 62/507,551. Inhibitors of nucleotidyl transferase superfamily enzymes as antibiotics. Pending.
Ryan M. Teague
Molecular Microbiology and Immunology
ryan.teague@health.slu.edu
 

Immunotherapy relies on tumor-specific T cells to target and eradicate cancer cells, and this potential has motivated immunologists and oncologists for many decades. Despite tremendous recent success, translating immunotherapy into a reliable treatment option for most cancer patients is still not a reality. One of the major challenges to successful immunotherapy is the induction of T cell tolerance within patients. Tolerance is multifaceted, involving both the death of tumor-reactive T cells and the induction of anergy, which renders any surviving T cells inert. Research in our lab aims to identify and therapeutically target the molecular mechanisms that regulate T cell tolerance as a means to boost anti-tumor immunity, and ultimately to inform translational efforts to provide enhanced immunotherapy for patients with cancer.

One of two research projects on immunotherapy is to explore the targeting mechanisms of T cell dysfunction for immunotherapy. We have demonstrated that T cell tolerance can be overcome to elicit durable immunotherapy in mice with disseminated leukemia by administrating antibodies that block T cell co-inhibitory checkpoint molecules such as PD-1, CTLA-4 and LAG-3. Similar “checkpoint blockade” approaches are now being tested in human clinical trials, but the molecular mechanisms required to rescue T cell function have not been clearly identified. This hampers efforts to improve outcomes in a broader range of cancer patients. We recently discovered that activation of the transcription factor T-bet is required to reinvigorate tumor-infiltrating CD8+ T cells for successful checkpoint blockade immunotherapy. Our ongoing studies are aimed at identifying the genes targeted by T-bet during this complex process, and uncovering additional cellular and molecular mechanisms involved.

A second research project is to understand how obesity as an obstacle to cancer immunotherapy. Nearly 35% of Americans are obese, and this is expected to rise in the next decade. The link between obesity and increased prevalence of cancer has been established in humans and likely stems in part from loss of vigilant innate and adaptive immune surveillance. However, the mechanisms that undermine tumor immunity in obese patients are largely unknown. Recent studies in our lab have revealed poor anti-tumor immunity in obese mice treated with checkpoint blockade immunotherapy. Our ongoing research is aimed at determining how poor diet and obesity influence cell-mediated immunity toward cancer, and to identify translational strategies to overcome the challenges of obesity for enhanced immunotherapy and better outcomes in a larger number of patients.

Recent Drug-development publications:

  • Teaching old CAR-T cells new tricks. Lindsey M Kuehm and Ryan M. Teague, Journal of Leukocyte Biology (102):188-190 (2017) Pubmed Abstract Link: 28765509
  • Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes.
  • Lauryn E. Klevorn, Melissa M. Berrien-Elliott, Jinyun Yuan, Lindsey M. Kuehm, Gregory D. Felock, Sean A. Crowe, and Ryan M. Teague. Cancer Immunology Research, 2016 (12):1016-26. Pubmed Abstract Link: 27803062
  • BTLA and HVEM govern induction of extrathymic regulatory T cells and tolerance by dendritic cells. Andrew Jones, Jessica Bourque, Lindsey Kuehm, Adeleye Opejin, Ryan M. Teague, Cindy Gross and Daniel Hawiger. Immunity, 2016 (5):1066-1077. Pubmed Abstract Link: 27793593
  • Adapting Cancer Immunotherapy Models for the Real World. Lauryn E. Klevorn and Ryan M. Teague. Trends in Immunology, 2016 37(6):354-363. Pubmed Abstract Link: 27105824
  • Checkpoint Blockade Immunotherapy Relies on T-bet but Not Eomes to Induce Effector Function in Tumor-Infiltrating CD8+ T Cells. Berrien-Elliott MM, Yuan J, Swier LE, Jackson SR, Chen CL, Donlin MJ, Teague RM. Cancer Immunology Research, 2015 3(2):116-124. Pubmed Abstract Link: 25516478
  • Neuropilin-1 Expression Is Induced on Tolerant Self-Reactive CD8+ T Cells but Is Dispensable for the Tolerant Phenotype. Jackson SR, Berrien-Elliott M, Yuan J, Hsueh EC, Teague RM.
  • PLoS One, 2014 Oct 24;9(10):e110707. Pubmed Abstract Link: 25343644
  • Targeting CD8(+) T-cell tolerance for cancer immunotherapy. Jackson SR, Yuan J, Teague RM.
  • Immunotherapy, 2014 Jul;6(7):833-52. Pubmed Abstract Link: 25290416
Ann Tollefson
Molecular Microbiology and Immunology
ann.tollefson@health.slu.edu
 
Karoly Toth
Molecular Microbiology and Immunology

karoly.toth@health.slu.edu

Karoly Toth’s primary focus is the testing of anti-adenoviral drugs. Toth's lab's main area of expertise is in vivo drug testing; they developed the Syrian hamster model to study human adenovirus infections. Syrian hamsters (unlike mice and rats) are permissive for human adenoviruses, and develop pathology similar to that in humans. Presently, this is the only practical animal model to model human adenovirus infections. They can use this model to evaluate the efficacy of compounds against both disseminated (intravenous challenge) and respiratory (intranasal challenge) adenovirus infection. For the past seven years, they held a contract from the NIH to test drug candidates submitted to the Animal Models for Infectious Diseases program. In this capacity, they conducted over 60 experiments with 17 drug candidates and formed collaborations with scientists from both academic and industrial laboratories in the USA and Europe. To test compounds in vitro, they developed cell-based assays to evaluate how drugs affect viral replication; these assays measure cell survival using neutral red retention.

Besides adenovirus, they also have been developing an animal model of enteric norovirus infection. The model is based on mouse norovirus infections of AG129 (IFNa/b and IFNg receptor deficient) mice; these animals develop severe illness after oral infection with mouse norovirus. In collaboration with a pharmaceutical company, they are in the process of testing if this system can be used to test the efficacy of anti-noroviral compounds.

Drug-development publications:

  • Toth K, Tollefson AE, Spencer JF, Ying B, Wold WSM. (2017) Combination therapy with brincidofovir and valganciclovir against species C adenovirus infection in the immunosuppressed Syrian hamster model allows for substantial reduction of dose for both compounds. Antiviral Res 146:121-129
  • Toth K, Spencer JF, Ying B, Tollefson AE, Wold WSM. (2017) HAdV-C6 Is a More Relevant Challenge Virus than HAdV-C5 for Testing Antiviral Drugs with the Immunosuppressed Syrian Hamster Model. Viruses 9.
  • Schaar K, Geisler A, Kraus M, Pinkert S, Pryshliak M, Spencer JF, Tollefson AE, Ying B, Kurreck J, Wold WS, Klopfleisch R, Toth K, Fechner H. Anti-adenoviral Artificial MicroRNAs Expressed from AAV9 Vectors Inhibit Human Adenovirus Infection in Immunosuppressed Syrian Hamsters. (2017) Molecular Therapy - Nucleic Acids 8:300-316.
  • Toth, K, Ying, B, Tollefson, AE, Spencer, JF, Balakrishnan, L, Sagartz JE, Buller, RML and Wold, WSM (2015) Valganciclovir Inhibits Human Adenovirus Replication and Pathology in Permissive Immunosuppressed Female and Male Syrian Hamsters Viruses 7(3), 1409-1428
  • Ying B, Tollefson AE, Spencer JF, Balakrishnan L, Dewhurst S, Capella C, Buller RM, Toth K†, Wold WS. (2014). Ganciclovir Inhibits Human Adenovirus Replication and Pathogenicity in Permissive Immunosuppressed Syrian Hamsters. Antimicrob. Agents Chemother. 58, 7171-81
  • Tollefson AE, Spencer JF, Ying B, Buller RML, Wold WSM, Toth K†. (2014). Cidofovir and brincidofovir reduce the pathology caused by systemic infection with human type 5 adenovirus in immunosuppressed Syrian hamsters, while ribavirin is largely ineffective in this model. Antiviral Res. 112, 38-46
  • Toth K., Spencer J.F., Dhar D., Sagartz J.E., Buller R.M.L., Painter G.R., and Wold W.S.M. (2008). Hexadecyloxypropyl-Cidofovir Prevents Adenovirus-Induced Mortality in a New, Permissive, Immunosuppressed Animal Model. Proc Natl Acad Sci U S A, 105(20):7293-7, (Selected as an “In This Issue” article of particular interest)
Alessandro Vindigni
Biochemistry & Molecular Biology
alessandro.vindigni@health.slu.edu
 

Our laboratory focuses on the mechanisms of DNA replication and repair, and on the possible strategies to target these mechanisms for cancer treatment. Aberrant DNA replication is one of the leading causes of mutations and chromosome rearrangements associated with several cancer related pathologies. At the same time, agents that stall or damage DNA replication forks are widely used for chemotherapy, in the attempt to selectively target highly proliferating cancer cells. Our work provides a new rationale to design novel molecularly-guided treatments targeting the pathways of replication stress response to cancer chemotherapeutics.

Recent drug-development publications:

  • Quinet A, Lemaçon D, Vindigni A. Replication Fork Reversal: Players and Guardians. Mol Cell. 2017 68:830-83. Review. PubMed PMID: 29220651.
  • Pasero P, Vindigni A. Nucleases Acting at Stalled Forks: How to Reboot the Replication Program with a Few Shortcuts. Annu Rev Genet. 2017 51:477-499. PubMed PMID: 29178820.
  • Lemaçon D, Jackson J, Quinet A, Brickner JR, Li S, Yazinski S, You Z, Ira G,
  • Zou L, Mosammaparast N, Vindigni A. MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells. Nat Commun. 2017 8:860. PubMed PMID: 29038425
  • Quinet A, Carvajal-Maldonado D, Lemacon D, Vindigni A. DNA Fiber Analysis: Mind the Gap! Methods Enzymol. 2017 591:55-82. PubMed PMID: 28645379.
  • Vindigni A. Special issue: "At the Intersection of DNA Replication and Genome Maintenance: from Mechanisms to Therapy". Biophys Chem. 2017 225:1-2. PubMed PMID: 28641746.
  • Vindigni A, Lopes M. Combining electron microscopy with single molecule DNA fiber approaches to study DNA replication dynamics. Biophys Chem. 2017 225:3-9.PubMed PMID: 27939387
  • Saratz N, Zanin DA, Ramsperger U, Cannas S, Pescia D, Vindigni A. Critical exponents and scaling invariance in the absence of a critical point. Nat Commun. 2016 7:13611. PubMed PMID: 27917865
  • Kenig S, Faoro V, Bourkoula E, Podergajs N, Ius T, Vindigni M, Skrap M, Lah T, Cesselli D, Storici P, Vindigni A. Topoisomerase IIβ mediates the resistance of glioblastoma stem cells to replication stress-inducing drugs. Cancer Cell Int. 2016 Jul 26;16:58. PubMed PMID: 27462186
  • Berti M, Vindigni A. Replication stress: getting back on track. Nat Struct Mol Biol. 2016 23:103-9. Review. PubMed PMID: 26840898
William Wold

Molecular Microbiology and Immunology
bill.wold@health.slu.edu

Their main expertise lies with the design, execution, and analysis of animal experiments. Most of their experience is with adenoviruses and noroviruses, but the techniques they use can be extended to other pathogens as well. They have worked with various infection models using mice, Syrian hamsters, cotton rats and Guinea pigs. They can investigate the natural history of an infection in a given model (pathogenesis, replication of the pathogen in target organs), they can test the efficacy (effect on pathogenesis and pathogen burden) of an anti-infective, they can perform the in-life portion of toxicology and pharmacokinetics experiments and collect samples for analysis. They have collaborated with numerous pharmaceutical companies, and executed large scale, in-the-spirit-of GLP studies that formed the basis of a successful IND submission.

Besides animal experiments, they have extensive experience with in vitro experiments with adenoviruses, and to a lesser extent, noroviruses. They have the capacity to produce large scale purified stocks of these viruses, quantify them using both physical and biological assays, and perform molecular biology-type studies.

They have a Beckman Coulter BioMek 2000 robot (base unit plus side extensions) with various tools. This robot can be used to automate basic liquid handling procedures in the 96-well format.

Fenglian Xu

Biology and Neurosceicne
fenglian.xu@slu.edu

The Xu lab seeks to help optimize drugs that promote nervous system development and neural regeneration by investigating their physiological roles and cellular mechanisms, as well as evaluating their potential neurotoxicity. To do this, the lab utilizes multiple state-of-the-art approaches. These include in vitro cell culture of primary neurons, PC-12 cells, and HEK 293 cells, electrophysiology, calcium imaging, immunocytochemistry, confocal microscopy, pharmacological and molecular biological techniques. Currently, the Xu lab is actively collaborating with Arnatt (SLU Chemistry) to develop specific and effective agonists and antagonists for G-protein coupled estrogen receptors (GPER) and investigate the physiology role and the underlying mechanisms of GPER in neural growth and synapse formation. The lab is also collaborating with Zustiak (SLU Biomedical engineering) and Kuljanishvili (SLU Physics) to develop 3D nanoparticle-hydrogel composites for nerve repair.

Drug-development publications:

  • Getz, A.M., Xu, F., Visser, F., Person, R., Syed, N.I. (2017) Tumor suppressor menin is required for subunit-specific nAChR α5 transcription and nAChR-dependent presynaptic facilitation in cultured mouse hippocampal neurons. Scientific Reports, 7(1):1768, doi:10.1038/s41598-017-01825-x
  • Getz, A.M., Visser, F., Bell, E.M., Xu, F., Flynn, N.M., Zaidi, W., Syed, N.I. (2016) Two proteolytic fragments of menin coordinate the nuclear transcription and postsynaptic clustering of neurotransmitter receptors during synaptogenesis between Lymnaea neurons. Scientific Reports, 19;6:31779. doi: 10.1038/srep31779
  • Xu, F., Armstrong, R., Urrego, D., Qazzaz, M., Pehar, M., Armstrong, J.N., Shutt, T., Syed, N.I. (2016) The mitochondrial division inhibitor Mdivi-1 rescues mammalian neurons from anesthetic-induced cytotoxicity. Molecular Brain, 9(1): 35.
  • Armstrong, R., Xu, F., Rasic, N., Syed, N.I. (2016) General anesthetics and cytotoxicity: possible implications for brain health. Drug and Chemical Toxicology, 2:1-9.
  • Janes, T.A., Xu, F., Syed. N.I (2015) Graded hypoxia acts through a network of distributed peripheral oxygen chemoreceptors to produce changes in respiratory behavior and plasticity. European Journal of Neuroscience, 42 (2): 1858-71
  • Ghazavi, A., Westwich, D., Xu, F., Wijdenes, P., Syed, N.I., Dalton, C. (2015) A circular, planar electrode serves as a better substrate for neuronal stimulation than sinusoidal and spiral electrodes. Journal of Neuroscience Methods, 248: 51-58.
  • Singh, B., Krishnan, A., Micu, I., Koshy, K., Singh, V., Martinez, J.A., Koshy, D., Xu, F., Chandrasekhar, A., Dalton, C., Syed, N., Stys P.K., Zochodne, D. W. (2015) Peripheral neuron plasticity is enhanced by brief electrical stimulation and overrides attenuated regrowth in experimental diabetes. Neurobiology of Disease, 83: 134-151
  • Xu, F., Luk, C., Wiermsa-Meems, R., Baehre, K., Herman, C., Zaidi, W., Wong, N., and Syed, N.I. (2014) Neuronal somata and extrasomal compartments play distinct roles during synapse formation between Lymnaea neurons. Journal of Neuroscience, 34(34): 11304-15
  • Chen, P., Jiang, H., Wen, B., Ren, S., Chen, Y., Ji, W., Hu, B., Zhang, J., Xu, F., Zhu, Z. (2014) Gastrodin suppresses amyloid β–induced increase of spontaneous discharges in entorhinal cortex of rats. Neural Plasticity (2014:320937. doi: 10.1155, Epub)
  • Chen, S., Chen, P., Jiang, H., Mi, Z., Xu, F. *, Hu, B., Zhang, J., Zhu., Z. (2014) Persistent sodium currents contribute to Aβ1-42-induced hyperexcitation of hippocampal CA1 pyramidal neurons. Neuroscience Letters, 580: 62-67
  • Zhu, Z., Xu, F., Ji, W., Ren, S., Chen, F., Chen, P., Jiang, H., Mi, Z., Hu, B., Zhang, J., Xiong, Y. (2014) Synaptic mechanisms underlying thalamic activation-induced plasticity in the rat auditory cortex. Journal of Neurophysiology, 111(9): 1746-58.
  • Ren, S., Shao, H., Ji, W., Xu, F., Chen, P., Jiang, H., Mi, Z., Wen, Bo., Zhu, G., Zhu, Z. (2014) Riluzole prevents soluble Aβ1-42 oligomers-induced perturbation of spontaneous discharges in the hippocampal CA1 region of rats. Amyloid, 4:1-9.
  • Zhu, Z., Xu, F., Wu, J., Ren, S., Zhang, Y., Hu, B., Zhang, J., Han, L., Xiong, Y. (2013) Frequency-specific plasticity of the auditory cortex elicited by thalamic stimulation in the rat. Neuroscience Letters, 555: 30-35
  • Xu, F., Piett, C., Farkas, S., Qazzaz, M.., and Syed, N.I. (2013) Silver nanoparticles (AgNPs) cause degeneration of cytoskeleton and disrupt synaptic machinery of cultured cortical neurons. Molecular Brain, 6(1): 29.
  • Xu, F., Farkas, S., Kortbeek, S., Zhang, F.X., Chen, L., Zamponi, G.W., and Syed, N.I. (2012) Mercury-induced toxicity of rat cortical neurons is mediated through NMDA receptors. Molecular Brain, 5(1): 30.
  • Getz, A, Xu, F. and Syed N.I. (2012) Antidepressant Pharmacotherapy – Do the Benefits Outweigh the Risks? InTech book chapter – Mental Illness (ISBN: 978-953-307-779-6)
  • Getz, A., Xu, F., Zaidi, W., Syed, N.I. (2011) The antidepressant Fluoxetine but not Citalopram suppresses synapse formation and synaptic transmission between Lymnaea neurons by perturbing pre- and postsynaptic machinery. European Journal of Neuroscience, 34(2): 221-234
  • Xu, F., Proft J., Gibbs, S., Winkfein, B., Johnson, J.N., Syed, N.I., and Braun J.E.A. (2010) Quercetin causes cysteine string protein dimerization and impairs synaptic transmission. PLoS ONE, 5 (6): e11045.
  • Xu, F., Luk, C., Richard, M.P, Zaidi, W., Svetlana, F., Getz, A., Lee, A., van Minnen, J., and Syed, N.I. (2010) Antidepressant Fluoxetine suppresses neuronal growth and perturbs synapse formation between cholinergic neurons. European Journal of Neuroscience, 31(6): 994-1005.
  • Xu, F., Hennessy, D.A., Lee, T., and Syed, N.I. (2009) Trophic factor-induced intracellular calcium oscillations are required for the expression of postsynaptic acetylcholine receptors during synapse formation between Lymnaea neurons. Journal of Neuroscience 29 (7): 2167-2176.
  • Xu, F., Tse, F.W., and Tse, A.. (2008) Stimulatory actions of pituitary adenylate cyclase-activating polypeptide (PACAP) in rat carotid glomus cells. Advanced Experimental Medical Biology 605:69-74.
  • Xu, F., Tse, F.W. and Tse, A. (2007) Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates the oxygen sensing type I (glomus) cells of rat carotid bodies via reduction of a background TASK-like K+ current. Journal of Neurochemistry 101(5):1284-93.
  • Xu, F., Xu, J., Tse, F.W. and Tse, A. (2006) Adenosine stimulates depolarization and rise in cytoplasmic Ca2+ concentration in type I cells of rat carotid bodies. American Journal of Physiology– Cell Physiology 290(6):C1592-8.
  • Xu, J., Xu, F., Tse, F.W. and Tse, A. (2005) ATP inhibits the hypoxia response in type I cells of rat carotid bodies. Journal of Neurochemistry 92:1419-1430.
Silviya Petrova Zustiak
Biomedical Engineering

silviya.zustiak@slu.edu

Zustiak’s laboratory focuses on hydrogel biomaterials and soft tissue engineering, with emphasis on developing novel biomaterials as cell scaffolds, drug screening platforms and protein delivery devices.

A major challenge of tissue engineering is to build three-dimensional (3D) in vitro models for studying tissue physiology and pathology. 3D in vitro models are the bridge between conventional two-dimensional (2D) tissue culture, which does not capture the complexity of human tissue, and animal models, which are costly, time-consuming and raise ethical concerns. One area in which 3D models are underrepresented but where they can have an immediate impact is the development of platforms for toxicology screening. Such in vitro models have the potential to address the growing concerns of drug failures in clinical trials due to lack of efficacy or unexpected side effects. Further, they can play a role in preventive medicine by answering the urgent need for efficient platforms enabling the screening of the plethora of environmental hazards linked to incidences of diseases such as cancer. Zustiak applies her expertise in the design and characterization of synthetic biomaterials, to provide a complete toolbox for building 3D in vitro models as platforms for toxicology screening and for the study of disease progression. Her current focus is on solid tumors in soft tissues.

Zustiak’s laboratory also develops injectable and biodegradable hydrogel formulations for sustained localized protein release. These technologies enable novel and effective protein-based therapeutic strategies by: i) providing sustained protein release and hence increased protein residence time in vivo, ii) preserving the proteins’ bioactivity prior to release, iii) decreasing protein immunogenicity, and iv) localizing protein release to reduce protein dosage needed for a therapeutic effect and reduce systemic side effects.

Drug-development publications:

  • E. Jain, S. Sheth, A. Dunn, *S. P. Zustiak, *S. Sell, “Sustained release of multicomponent platelet-rich plasma proteins from hydrolytically degradable PEG hydrogels”, Journal of Biomedical Materials Research: Part A, In Press; (IF: 3.076)
  • S. Sheth, E. Jain, K. Polito, *S. Sell, *S. P. Zustiak, “Storage stability of biodegradable polyethylene glycol microspheres”, Materials Research Express, In Press; (IF: 1.068)
  • A. S. Qayyum, E. Jain, G. Kolar, Y. Kim, S. Sell, *S. P. Zustiak, “Design of electrohydrodynamic sprayed polyethylene glycol hydrogel miscrospheres for cell encapsulation”, Biofabrication, 2017, 9(2), 025019; (IF: 5.240)
  • E. Jain, L. Hill, E. Canning, *S. Sell, *S. P. Zustiak, “Control of gelation, degradation and physical properties of polyethylene glycol hydrogels through the chemical and physical identity of the crosslinker”, Journal of Materials Chemistry B, 2017, 5, 2679-2691; (IF: 4.543)
  • F. Ordikhani, S. Sheth, *S. P. Zustiak, “Polymeric particle-mediated therapies to treat spinal cord injury”, International Journal of Pharmaceutics, 2017, 516(1-2), 71-81; (IF: 3.649)
  • F. Ordikhani, *S. P. Zustiak, *A. Simchi, “Surface modifications of titanium implants by multilayer bioactive coatings with drug delivery potential: antimicrobial, biological, and drug release studies”, Journal of the Minerals, Metals, and Materials Society (JOMJ), 2016, 68(4), 1100-1108; (IF: 1.860)
  • S. P. Zustiak, C. Medina, S. Dadhwal, S. Steczina, Y. Chehreghanianzabi, A. Ashraf, P. Asuri, “Three-dimensional matrix stiffness and adhesive ligands affect cancer cell response to toxins”, Biotechnology & Bioengineering, 2016, 113(2), 443-452; (IF: 4.481)
  • E. Jain, K. Scott, *S. P. Zustiak, *S. Sell, “Fabrication of polyethylene glycol-based hydrogel microspheres through electrospraying”, Macromolecular Materials and Engineering, 2015, 300(8), 823-835; (IF: 2.834)
  • *S. P. Zustiak, “The role of matrix compliance on cell responses to drugs and toxins: towards predictive drug screening platforms”, Macromolecular Bioscience, 2015, 15(5), 589-599; (IF: 3.850)
  • *S. P. Zustiak, R. Nossal, D. Sackett, “Multiwell stiffness assay for the study of cell responsiveness to cytotoxic drugs”, Biotechnology & Bioengineering, 2014, 111(2), 396-403; (IF:4.481)
  • S. P. Zustiak, *J. B. Leach, “Characterization of Protein Release from Hydrolytically Degradable Poly(ethylene glycol) Hydrogels”, Biotechnology & Bioengineering, 2011, 108, 197-206; (IF: 4.481)
  • S. P. Zustiak, *J. B. Leach, “Hydrolytically Degradable Poly(ethylene glycol) Hydrogel Scaffolds with Tunable Degradation and Mechanical Properties”, Biomacromolecules, 2010, 11, 1348-1357; (IF: 5.246)

Drug-development patent applications:

  • Provisional patent: A. Montano, E. Jain, S. P. Zustiak, “Delivering enzyme using an injectable hydrogel depot”, U.S. Patent Application Serial No. 62/580,699; SLU Ref No: 17-008, November 2017
  • Provisional patent: E. Jain, *S. P. Zustiak, *S. A. Sell, “Fabrication of hydrogel microsphere delivery vehicles through electrospraying and timed gelation”, U.S. Patent Application Serial No. 62/136,089; SLU Ref No: 14-013, March 2015

Medicinal Chemistry

Christopher Arnatt
Department of Chemistry
chris.arnatt@slu.edu
 

The core theme of research in the Arnatt Lab revolves around utilizing organic chemistry to decipher cellular processes and disease states. Specifically, they are developing novel small molecule chemical probes and fluorescent probes to study biological systems. Much of their current research is focused on deciphering the protein-ligand interactions of the G Protein-Coupled Estrogen Receptor (GPER, GPR30). Very little is known about how this non-traditional estrogen receptor interacts with estrogen and modulates hormonal signaling inside of cells. thereforee, the goal of their research is to design ligands that bind to GPER, identify selective agonists and antagonists, characterize their interactions with the receptor, analyze those interactions to develop ligands which can modulate receptor function in cells, and determine their therapeutic potential. Their laboratory performs both the medicinal chemistry and pharmacology research for this project and has developed the first ever high-throughput assays for this receptor. Through collaborations with biologists, pharmacologists, and geneticists at SLU and the Albert Einstein School of Medicine, they have begun to reveal GPER plays a role in neurological development and gallstone formation.

Drug-development publications:

  • Arnatt, C. K.; Falls, B. A.; Yuan, Y.; Raborg, T. J.; Masvekar, R. R.; El-Hage, N.; Selley, D. E.; Nicola, A. V.; Knapp, P. E.; Hauser, K. F.; Zhang, Y. Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization. Bioorganic & Medicinal Chemistry 2016, 24, 5969-5987.
  • Yuan, Y.; Li, X.; Zaidi, S. A.; Arnatt, C. K.; Yu, X.; Guo, C.; Wang, X. Y.; Zhang, Y. Small molecule inhibits activity of scavenger receptor A: Lead identification and preliminary studies. Bioorganic & Medicinal Chemistry Letters 2015, 25, 3179-3183.
  • Arnatt, C. K.; Zhang, Y. Bivalent ligands targeting chemokine receptor dimerization: Molecular design and functional studies. Current Topics in Medicinal Chemistry 2014, 14, 1606.
  • Arnatt, C. K.; Adams, J. L.; Zhang, Z.; Haney, K. M.; Guo, Li, Zhang, Y. Design, synthesis, and characterization of piperazine based chemokine receptor CCR5 antagonists as anti prostate cancer agents. Bioorganic & Medicinal Chemistry Letters 2014, 24, 2319-2323.
  • Zaidi, S. A.; Arnatt, C. K.; He, H.; Selley, D. E.; Mosier, P. E.; Kellogg, G. E.; Zhang, Y. Binding mode characterization of 6α- and 6β-N-heterocyclic substituted naltrexamine derivatives via docking in opioid receptor crystal structures and site-directed mutagenesis studies: Application of the ‘message-address’ concept in development of mu opioid receptor selective antagonists. Bioorganic & Medicinal Chemistry, 2013, 21, 6405-6413.
  • Arnatt, C. K.; Zaidi, S. A.; Zhang, Z.; Li, G.; Richardson, A. C.; Ware, J. L.; Zhang, Y. Design, synthesis, and characterization of pharmacophore based chemokine receptor CCR5 antagonists as anti prostate cancer agents. European Journal of Medicinal Chemistry, 2013, 69, 647-658.
  • El-Hage, N.; Dever, S. M.; Podhaizer, E. M.; Arnatt, C. K.; Zhang, Y.; Hauser, K. F. A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-µ-opioid receptor interactions between human astroglia and microglia. AIDS 2013, 27, 2181-2190.
  • Arnatt, C. K.; Zhang, Y. G protein-coupled estrogen receptor (GPER) agonist dual binding mode analyses toward understanding of its activation mechanism: a comparative homology modeling approach. Molecular Informatics 2013, 32, 647-658.
  • Yuan, Y.; Arnatt, C. K.; El-Hage, N.; Dever, S.; Jacob, J.; Selley, D.; Hauser, K.; Zhang, Y. A bivalent ligand targeting the putative mu opioid receptor and chemokine receptor CCR5 heterodimers: binding affinity versus functional activities. Med. Chem. Comm. 2013, 4, 847-851.
  • Zhang, F.; Arnatt, C. K.; Haney, K. M.; Fang, H. C.; Bajacan, J. E.; Richardson, A. C.; Ware, J. L.; Zhang, Y. Structure activity relationship studies of natural product chemokine receptor CCR5 antagonist anibamine toward the development of novel anti prostate cancer agents. European Journal of Medicinal Chemistry 2012, 55, 395-408.
  • Zhang, Y.; Arnatt, C. K.; Zhang, F.; Wang, J.; Haney, K. M.; Fang, X. The potential role of anibamine, a natural product CCR5 antagonist, and its analogues as leads toward development of anti-ovarian cancer agents. Bioorganic & Medicinal Chemistry Letters 2012, 22, 5093-5097.
  • Yuan, Y.; Arnatt, C. K.; Li, G.; Haney, K. M.; Ding, D.; Jacob, J. C.; Selley, D. E.; Zhang, Y. Design and synthesis of a ligand to explore the putative heterodimerization of the mu opioid receptor and the chemokine receptor CCR5. Organic & Biomolecular Chemistry 2012, 10, 2633-2646.
  • Arnatt, C. K.; Zhang, Y. Facile synthesis of 2,3,5,6-tetrabromo-4-methyl-nitrocyclohexa- 2,5-dien-1-one, a mild nitration reagent. Tetrahedron Letters 2012, 53, 1592-1594.
  • Haney, K. M.; Zhang, F.; Arnatt, C. K.; Yuan, Y.; Li, G.; Ware, J. L.; Gerwirtz, D. A.; Zhang, Y. The natural product CCR5 antagonist anibamine and its analogs as antiprostate cancer agents. Bioorganic & Medicinal Chemistry Letters 2011, 21, 5159-63.

Drug-development patent applications:

  • 2017 Arnatt, C. K. and Elliot, J. US20170121599A1. Process for making an asymmetric fluorophore. Patent.
  • 2017 Arnatt, C. K. and O’Dea, A. USTL.P090US.P1. Compounds and methods targeting GPER in cancer. Provisional.
  • 2017 Arnatt, C. K. and Deleon, C. USTL.P089US.P1. Compound and methods targeting GPER in calcium. Provisional.
  • 2017 Arnatt, C. K., McCulla, R. Ansor, A. Atomic oxygen in photodynamic therapies for cancer. Provisional.
Bahaa El-Gendy
Pharmacology and Physiology

bahaaeldien.elgendy@health.slu.edu

The main focus of El-Gendy’s research group is medicinal chemistry with a broad goal of drug design and optimization. Most of the work in his lab concentrates on developing small molecules modulators for different targets. For example, he designs and synthesize modulators of nuclear hormone receptors for the therapeutic treatment of cancer and fatty liver diseases. Also, he develops small molecules that can act as anti-viral agents against HCV, ZIKV, and other microbes. He has a wide international collaboration with scientists from United Kingdom, United Arab Emerates and Egypt. El-Gendy incorporates computational methods such as quantitative structure activity relationships, pharmacophore modeling, and virtual screening in his drug discovery pipeline to accelerate the process of drug discovery and optimization.

Piotr Mak
Biophysics

piotr.mak@slu.edu

The primary research focus in their lab is structure-function relationships of heme proteins that play important roles in human physiology. More specifically, they focus on understanding the structural features that control heme enzyme activities, including active site environments, substrate-assisted catalysis, drug-drug interactions, suicide inhibition and protein environmental conditions, such as the nature of the interactions with redox partners and cofactors. While resonance Raman (rR) spectroscopy is the primary tool used in their work, these studies are complemented, if needed, by application of other spectroscopic techniques, that is electronic absorption, EPR and NMR spectroscopies. They also use cryoradiolysis method to generate and trap unstable enzymatic intermediates. An innovative combination of this method with rR spectroscopy allows effective interrogation of previously inaccessible catalytic intermediates. Altogether, these studies can provide valuable guidelines towards design of new selective and efficient drugs and protein inhibitors.

The current research subjects are human heme oxygenase, a promising therapeutic target for atherosclerotic, inflammation, allergy and anticancer treatments as well as cytochromes P450 involved in physiology and virulence of human pathogen Mycobacterium tuberculosis.

Drug-development publications:

  • Mak, P. J., Zhang, H., Hollenberg, P. F., Kincaid, J. R. (2010). Defining the Structural Consequences of Mechanism-Based Inactivation of Mammalian Cytochrome P450 2B4 Using Resonance Raman Spectroscopy. J. Am. Chem. Soc. 13:1494-1495.
  • Mak, P. J., Denisov, I.G., Grinkova, Y. V., Sligar, S. G., Kincaid, J. R. (2011). Defining CYP3A4 Structural Responses to Substrate Binding. Raman Spectroscopic Studies of a Nanodisc-Incorporated Mammalian Cytochrome P450. J. Am. Chem. Soc. 133:1357-1366.
  • Mak, P. J., Yang, Y., Im, S.-C., Waskell, L. A., Kincaid, J. R. (2012). Experimental Documentation of the Structural Consequences of Hydrogen-Bonding Interactions to the Proximal Cysteine of a Cytochrome P450. Angew. Chem. Int. Ed. 51:10403-10407.
  • Gregory, M., Mak, P. J., Sligar, S. G., Kincaid, J. R. (2013) Differential Hydrogen Bonding in Human CYP17 Dictates Hydroxylation versus Lyase Chemistry. Angew. Chem. Int. Ed. 52:5342-5345.
  • Mak, P. J., Gregory, M. C., Sligar, S. G., Kincaid, J. R. (2014) Resonance Raman spectroscopy reveals that substrate structure selectively impacts the heme-bound diatomic ligands of CYP17. Biochemistry, 53:90-100.
  • Mak, P. J., Luthra, A., Sligar, S. G., Kincaid, J. R. (2014) Resonance Raman spectroscopy of the oxygenated intermediates of CYP19 implicates a Compound I intermediate in the final lyase step. J. Am. Chem. Soc. 136:4825-4828.
  • Mak, P. J., Thammawichai, W., Wiedenhoeft, D., Kincaid, J. R. (2015) Resonance Raman spectroscopy reveals pH-dependent active site structural changes of Lactoperoxidase Compound 0 and its ferryl heme O-O bond cleavage products. J. Am. Chem. Soc. 137:349-361.
  • Mak, P. J., Gregory, M. C., Denisov, I. G., Sligar, S. G., Kincaid, J. R. (2015) Unveiling the crucial intermediates in androgen production. Proc. Natl. Acad. Sci. USA 112:15856-15861.
  • Mak, P. J. (2016) Resonance Raman spectroscopy as a structural probe of cytochrome P450 enzymatic cycle", Handbook of Porphyrin Science, Kadish, K. M.; Smith, K.; Guilard, R. Eds., World Scientific Publishing Co., Singapore, 42:1-120.
Marvin Meyers

Chemistry
Pharmacology and Physiology and Chemistry
marvin.meyers@health.slu.edu

The research in Meyer's lab is focused the application of medicinal chemistry towards the discovery of potential drug candidates to treat people with rare and neglected diseases. They collaborate with experts in infectious disease biology, including malaria, tuberculosis, infectious diarrhea (cryptosporidiosis), cryptococcal meningitis, hepatitis B virus, and herpes simplex virus. They also have ongoing collaborations with experts in oncology, FSHD muscular dystrophy, and infant short-gut syndrome.

They use synthetic organic chemistry techniques to prepare new compounds, which are analyzed by their collaborators to assess their biological properties. Using medicinal chemistry and structure-based drug design principles, they optimize the potency, pharmacokinetics, and safety profiles of compounds with the goals of identification of tool compounds and, ultimately, candidate drug molecules for clinical trials.

Drug-development publications:

  • Nasamu, A.S.; Glushakova, S.; Russo, I.; Vaupel, B.; Oksman, A.; Kim, A.S.; Fremont, D.H.; Tolia, N.; Beck, J.R.; Meyers, M.J.; Niles, J.C.; Zimmerberg, J.; Goldberg, D.E. Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion. Science, 2017, 358, 518-522.
  • Montoya, M.C.; DiDone, L.; Heier, R.F.; Meyers, M.J.; Krysan, D.J. Antifungal Phenothiazines: Optimization, Characterization of Mechanism, and Modulation of Neuroreceptor Activity. ACS Infect Dis. 2017, DOI: 10.1021/acsinfecdis.7b00157 Article ASAP. Publication Date (Web): October 23, 2017.
  • Lee S, Harwood M, Girouard D, Meyers MJ, Campbell MA, Beamer G, Tzipori S. (2017) The therapeutic efficacy of azithromycin and nitazoxanide in the acute pig model of Cryptosporidium hominis. PLOS ONE 12(10): e0185906. https://doi.org/10.1371/journal.pone.0185906
  • Welch RD, Guo C, Sengupta M, Carpenter KJ, Stephens NA, Arnett SA, Meyers MJ, Sparks LM, Smith SR, Zhang J, Burris TP, Flaveny CA. Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome. Molecular Metabolism. 2017; 6(7):703-714.
  • Donlin MJ, Zunica A, Lipnicky A, Garimallaprabhakaran AK, Berkowitz AJ, Grigoryan A, Meyers MJ, Tavis JE, Murelli RP. Troponoids Can Inhibit Growth of the Human Fungal Pathogen. Cryptococcus neoformans. Antimicrobial Agents and Chemotherapy. 2017; 61(4).
    Faidallah HM, Panda SS, Serrano JC, Girgis AS, Khan KA, Alamry KA, Therathanakorn T, Meyers MJ, Sverdrup FM, Eickhoff CS, Getchell SG, Katritzky AR. Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates. Bioorganic & Medicinal Chemistry. 2016; 24(16):3527-39.
  • Lu G, Villa JA, Donlin MJ, Edwards TC, Cheng X, Heier RF, Meyers MJ, Tavis JE. Hepatitis B virus genetic diversity has minimal impact on sensitivity of the viral ribonuclease H to inhibitors. Antiviral Research. 2016; 135:24-30.
  • Masaoka T, Zhao H, Hirsch DR, D'Erasmo MP, Meck C, Varnado B, Gupta A, Meyers MJ, Baines J, Beutler JA, et al. Characterization of the C-Terminal Nuclease Domain of Herpes Simplex Virus pUL15 as a Target of Nucleotidyltransferase Inhibitors. Biochemistry 2016, 55, 809-819.
  • Griggs, D.W.; Prinsen, M.J.; Oliva, J.; Campbell, M.A.; Arnett, S.D.; Tajfirouz, D.; Ruminski, P.G.; Yu, Y.; Bond, B.; Ji, Y.; Neckermann, G.; Choy, R.K.M.; de Hostos, E.; Meyers, M.J. Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea. J. Pharm. Exp. Ther. 2016, 357, 423-431.
  • Meyers, M. J.; Anderson, E. J.; McNitt, S. A.; Krenning, T. M.; Singh, M.; Xu, J.; Zeng, W.; Qin, L.; Xu, W.; Zhao, S.; Qin, L.; Eickhoff, C. S.; Oliva, J.; Campbell, M. A.; Arnett, S. D.; Prinsen, M. J.; Griggs, D. W.; Ruminski, P. G.; Goldberg, D. E.; Ding, K.; Liu, X.; Tu, Z.; Tortorella, M. D.; Sverdrup, F. M.; and Chen, X.; Evaluation of Spiropiperidine Hydantoins as a Novel Class of Antimalarial Agents. Bioorg. Med. Chemistry 2015, 23(16):5144-50.
  • Lu, G.; Lomonosova, E.; Cheng, X.; Moran, E.A.; Meyers, M.J.; Le Grice, S.F.J.; Thomas, C.J.; Jiang, J.-K.; Meck, C.; Hirsch, D.R.; D’Erasmo, M.P.; Suyabatmaz, D.M.; Murelli, R.P.; Tavis, J.E. Hydroxylated tropolones inhibit hepatitis B virus replication by blocking viral ribonuclease H activity. Antimicrob Agents Chemother 2015, 59, 1070–1079.
  • Cai, C.W.; Lomonosova, E.; Moran, E.A.; Cheng, X.; Patel, K.B.; Bailly, F.; Cotelle, P.; Meyers, M.J.; and Tavis, J.E. Hepatitis B Virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity. Antiviral Research 2014, 108, 48-55.
  • Meyers, M. J.;* Tortorella, M. D.; Xu, J.; Qin, L.; He, Z.; Lang, X.; Zeng, W.; Xu, W.; Qin, L.; Prinsen, M. J.; Sverdrup, F. M.; Eickhoff, C. S.; Griggs, D. W.; Oliva, J.; Ruminski, P. G.; Jacobsen, E. J.; Campbell, M. A.; Wood, D. C.; Goldberg, D. E.; Liu, X.; Lu, Y.; Lu, X.; Tu, Z.; Lu, X.; Ding, K.; Chen, X.* Evaluation of Aminohydantoins as a Novel Class of Antimalarial Agents. ACS Medicinal Chemistry Letters 2014, 5, 89-93.
  • Panda, S. S., Ibrahim, M. A., Kuecuekbay, H., Meyers, M. J., Sverdrup, F. M., El-Feky, S. A., Katritzky, A. R.* Synthesis and Antimalarial Bioassay of Quinine - Peptide Conjugates. Chemical Biology & Drug Design. 2013, 82, 361-366.
  • Tavis, J.E., Cheng, X., Hu, Y., Totten, M., Cao, F., Michailidis, E., Aurora, R., Meyers M.J., Jacobsen, J., Parniak, M.A., and Sarafianos, S.G. The hepatitis B virus ribonuclease H is sensitive to inhibitors of the human immunodeficiency virus ribonuclease H and integrase enzymes. PLoS Path. 2013, 9(1): e1003125. doi:10.1371/journal.ppat.1003125.
  • Panda, S. S., Bajaj, K., Meyers, M. J., Sverdrup, F. M., and Katritzky, A. R.* Quinine bis-conjugates with quinolone antibiotics and peptides: synthesis and antimalarial bioassay. Org. Biomol. Chem. 2012, 10, 8985-8993.
  • Meyers, M.J. and Goldberg, D.E. Recent Advances in Plasmepsin Medicinal Chemistry and Implications for Future Antimalarial Drug Discovery Efforts. Curr. Top. Med. Chem. 2012, 12, 445-455.
  • Meyers, M.J. Editorial: The Medicinal Chemistry of Novel Approaches for the Treatment of Malaria. Curr. Top. Med. Chem. 2012, 12, 371-372.

Drug-development patent applications:

  • Cao, F., Tavis, J.E., Donlin, M.J., Meyers, M.J., Murelli, R.P., and Orth, C. Provisional US patent 62/507,551. Inhibitors of nucleotidyl transferase superfamily enzymes as antibiotics. 2017
    Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists in combination with an agent which interacts with a chemokine receptor. PCT patent application filed November 2, 2017. PCT/US2017/059777.
  • Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists. Provisional patent application filed September 13, 2017. Attorney docket USTL.P0094US.P1 Provisional Serial No. 62/558,045.
  • Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists. Provisional patent application filed September 6, 2017. Attorney docket USTL.P0093US.P1
    Meyers, MJ; Wood, DC; Arnett, SA; Yates, MP; Ruminski, PG. Fatty acid modified epidermal growth factor. Provisional patent application filed July 27, 2017. Attorney docket USTL.P0092US.P1. Provisional Serial No. 62/537,808.
  • Meyers, MJ; Singh, M; Stallings, CL; Weiss, LA; Wildman, S; Arnett, SD. Thieno[2,3-d]pyrimidines and benzofuro[3,2-d]pyrimidines as antimicrobial agents. Provisional patent application filed July 17, 2017. Attorney docket USTL.P0084US.P1. Provisional Serial No. 62/533,403.
  • Dowd, D; Wang, X; Brothers, RC; John, ARO; Edwards, R; Meyers, M; Arnett, S; Couch, R. Methods and compounds for treating malaria. Provisional patent application filed June 27, 2017. Attorney docket 130761.00865. Provisional Serial No. 62/525,616.
  • Donlin, M.J., Tavis, J.E., Murelli, R., and Meyers, M. US patent 62/324,675. Anti-fungal compounds. 2016
  • Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists in combination with an agent which interacts with a chemokine. Provisional patent application filed November 2, 2016. Attorney docket USTL.P0083US.P1.
  • Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists. Provisional patent application filed November 2, 2016. Attorney docket USTL.P0080US.P1. Provisional Serial No. 62/416,530.
  • Tavis, J.E.; Morrison, L.A.; Meyers, M.J. Inhibitors of nucleotidyl transferases and use in herpes and hepatitis viral infections. WO2016/201306, published December 15, 2016.
    Tavis, J.E.; Morrison, L.A.; Meyers, M.J. Inhibitors of HSV nucleotidyl transferases and uses. WO2015/077774, published May 28, 2015.
  • Blinn, J.R.; Flick, A.C.; Wennerstaal, G.M.; Jones, P.; Kaila, N.; Kiefer, Jr., J.R.; Kurumbail, R.G.; Mente, S.R.; Meyers, M.J.; Schnute, M.E.; Thorarensen, A.; Xing, L.; Zamaratski, E.; Zapf, C.W. Preparation of N-heteroaryl amides as RORC2 inhibitors. WO2015/015378, published Feb 5, 2015.
  • Chen, X.; Ding, K.; Meyers, M.J.; Tortorella, M.D.; Xu, J. Compositions and methods for the treatment of malaria. WO2014/160775, published Oct 2, 2014. Granted as US 9,353,089. May 31, 2016.
John Walker
Pharmacology and Physiology

john.walker@health.slu.edu

Research in the Walker lab focuses mainly on synthetic and medicinal chemistry to develop tool compounds or novel therapeutic agents against a variety of biological targets and therapeutic indications. The lab is actively involved in multiple research collaborations partnering with investigators both at SLU and other Universities. They use modern synthesis techniques and also a number of in silico approaches to design and synthesize new target molecules.

A major area of research focus and collaboration for their group is developing strategies and molecules to target antibacterial resistance as part of their long-standing collaboration with the Zgurskaya and Rybenkov labs at the University of Oklahoma. They are working to develop molecules that can penetrate the outer membrane of Gram-negative pathogens and inhibit efflux pumps, which contribute both to the intrinsic and acquired resistance of many pathogens to antibiotics. They recently demonstrated that novel ligands they prepared can potentiate the activity of the antibiotics novobiocin and erythromycin in E. coli.

Brent M. Znosko
Chemistry

brent.znosko@slu.edu

Research in the Znosko laboratory focuses on the thermodynamics and structural features of RNA motifs. While sequences of many important RNAs have been determined, little is known about structure-function relationships of RNA. One reason for this lack of information is that there is little definitive secondary and tertiary structural information about RNA. X-ray crystallography and NMR methods are providing an increasing number of RNA structures, but it is unlikely that these methods will keep pace with the rate at which interesting sequences are being discovered. Thus, there is a need for reliable, rapid methods to predict secondary and tertiary structures of RNA. Being able to predict secondary and tertiary structures of RNA provides a foundation for determining structure-function relationships for RNA and for targeting RNA with therapeutics. thereforee, one broad, long-term objective of the laboratory is to improve RNA secondary and tertiary structure prediction from sequence.

Nucleic acids are attractive target molecules for therapeutics as they direct replication, transcription, and translation. The ability to rationally design drugs that target nucleic acids, thereforee, is important in developing pharmaceuticals to combat cancer, tumor growth, etc. Naphthalimides are DNA intercalating agents that are useful as therapeutic agents due to their conjugated pi system and ability for moiety attachment. Due to the success of the originally studied 1,8-naphthalimides, different analogues continue to be investigated for therapeutic activity. With the ongoing study of naphthalimide intercalators and their derivatives, there is still a need to understand these molecules and their ability to interact with DNA. While most studies focus on developing new intercalating compounds, few studies focus on the effects of small changes to a core intercalator structure. Also, most studies of naphthalimide derivatives use either calf thymus or salmon testes DNA as the target nucleic acid. By using such large DNA, it is difficult to understand DNA-intercalator interactions that are a result of the specific DNA sequence. Our team has recognized the need to understand intercalator interactions with short oligonucleotides. To evaluate the interactions important in DNA-intercalator complexes, they are performing systematic studies with mono- and di-substituted naphthalimides. The results of this work will provide a framework for more detailed studies of other known intercalators, as well as aid in the rational design of novel intercalators that may serve as therapeutic agents.

Structural Biology and Drug-development publications:

  • Jolley, E. A. and Znosko, B. M. (2017) “The loss of a hydrogen bond: Thermodynamic contributions of a non-standard nucleotide,” Nucleic Acids Res. 45, 1479-1487.
  • Richardson, K. E. and Znosko, B. M. (2016) “Nearest-neighbor parameters for 7-deaza-adenosine·uridine base pairs in RNA duplexes,” RNA 22, 934-942.
  • Liu, B., Childs-Disney, J. L., Znosko, B. M., Wang, D., Fallahi, M., Gallo, S. M., and Disney, M. D. (2016) “Analysis of secondary structural elements in human microRNA hairpin precursors,” BMC Bioinformatics 17, 112.
  • Jolley, E. A., Lewis, M., and Znosko, B. M. (2015) “A computational model for predicting experimental RNA nearest-neighbor free energy rankings: Inosine-uridine pairs,” Chem. Phys. Lett. 639, 157-160.
  • Tomcho, J. C., Tillman, M. R., and Znosko, B. M. (2015) “Improved model for predicting the free energy contribution of dinucleotide bulges to RNA duplex stability,” Biochemistry 54, 5290-5296.
  • Johnson, C. A., Hudson, G. A., Hardebeck, L. K. E., Jolley, E. A., Ren, Y., Lewis, M., and Znosko, B. M. (2015) “Effect of intercalator substituent and nucleotide sequence on the stability of DNA- and RNA-naphthalimide complexes,” Bioorg. Med. Chem. 23, 3586-3591.
  • Murray, M. H., Hard, J. A., and Znosko, B. M. (2014) "Improved model to predict the free energy contribution of trinucleotide bulges to RNA duplex stability," Biochemistry 53, 3502-3508.
  • Hardebeck, L. K. E., Johnson, C. A., Hudson, G. A., Ren, Y., Watt, M., Kirkpatrick, C. C., Znosko, B. M., and Lewis M. (2013) Predicting DNA-intercalator binding: The development of an arene-arene stacking parameter from SAPT analysis of benzene-substituted benzene complexes, J. Phys. Org. Chem. 26, 879-884.
  • Hudson, G. A., Bloomingdale, R. J., and Znosko, B. M. (2013) Thermodynamic contribution and nearest neighbor parameters of pseudouridine-adenosine base pairs in oligoribonucleotides, RNA 19, 1474-1482.
  • Chen, Z. and Znosko, B. M. (2013) Effect of sodium ions on RNA duplex stability, Biochemistry 52, 7477-7485.
  • Grohman, J. K., Gorelick, R. J., Lickwar, C. R., Lieb, J. D., Bower, B. D., Znosko, B. M., and Weeks, K. M. (2013) A guanosine-centric mechanism for RNA chaperone function, Science 340, 190-195.
  • Johnson, C. A., Bloomingdale, R. J., Ponnusamy, V. E., Tillinghast, C. A., Znosko, B. M., and Lewis, M. (2012) Reply to “Comment on “Computational model for predicting experimental RNA and DNA nearest-neighbor free energy rankings,’” J. Phys. Chem. B 116, 8333-8334.
  • Hausmann, N. Z. and Znosko, B. M. (2012) Thermodynamic characterization of RNA 2x3 nucleotide internal loops, Biochemistry 51, 5359-5368.
  • Vanegas, P. L., Horwitz, T. S., and Znosko, B. M. (2012) Effects of non-nearest neighbors on the thermodynamic stability of RNA GNRA hairpin tetraloops, Biochemistry 51, 2192-2198.
  • Levengood, J. D., Rollins, C., Mishler, C. H., Johnson, C. A., Miner, G., Rajan, P., Znosko, B. M., and Tolbert, B. S. (2012) Solution structure of the HIV-1 exon splicing silencer 3, J. Mol. Biol. 415, 680-698.
  • Vanegas, P. L., Hudson, G. A., Davis, A. R., Kelly, S. C., Kirkpatrick, C. C., and Znosko, B. M. (2012) RNA CoSSMos: Characterization of secondary structure motifs - A searchable database of secondary structure motifs in RNA three-dimensional structures, Nucleic Acids Res. 40, D439-D444.
  • Johnson, C. A., Bloomingdale, R. J., Ponnusamy, V. E., Tillinghast, C. A., Znosko, B. M., and Lewis, M. (2011) Computational model for predicting experimental RNA and DNA nearest-neighbor free energy rankings, J. Phys. Chem. B 115, 9244-9251.
  • Davis, A. R., Kirkpatrick, C. C., and Znosko, B. M. (2011) Structural characterization of naturally occurring RNA single mismatches, Nucleic Acids Res. 39, 1081-1094.
  • Thulasi, P., Pandya, L. K., and Znosko, B. M. (2010) Thermodynamic characterization of RNA triloops, Biochemistry 49, 9058-9062.
  • Davis, A. R. and Znosko, B. M. (2010) Positional and neighboring base pair effects on the thermodynamic stability of RNA single mismatches, Biochemistry 49, 8669-8679.
  • Sheehy, J. P., Davis, A. R., and Znosko, B. M. (2010) Thermodynamic characterization of naturally occurring RNA tetraloops, RNA 16, 417-429.
  • Christiansen, M. E. and Znosko, B. M. (2009) Thermodynamic characterization of tandem mismatches in naturally occurring RNA, Nucleic Acids Res. 37, 4696-4706.
  • Davis, A. R. and Znosko, B. M. (2008) Thermodynamic characterization of naturally occurring RNA single mismatches with G-U nearest neighbors, Biochemistry 47, 10178-10187.
  • Christiansen, M. E. and Znosko, B. M. (2008) Thermodynamic characterization of the complete set of sequence symmetric tandem mismatches in RNA and an improved model for predicting the free energy contribution of sequence asymmetric tandem mismatches, Biochemistry 47, 4329-4336.
  • Badhwar, J., Karri, S., Cass, C. K., Wunderlich, E. L., and Znosko, B. M. (2007) Thermodynamic characterization of RNA duplexes containing naturally occurring 1x2 nucleotide internal loops, Biochemistry 46, 14715-14724.
  • Davis, A. R. and Znosko, B. M. (2007) Thermodynamic characterization of single mismatches found in naturally occurring RNA, Biochemistry 46, 13425-13436.
  • Wright, D. J., Rice, J. L., Yanker, D. M., and Znosko, B. M. (2007) Nearest neighbor parameters for inosine-uridine pairs in RNA duplexes, Biochemistry 46, 4625-4634.
  • Chen, G., Znosko, B. M., Kennedy, S. D., Krugh, T. R., and Turner, D. H. (2005) Solution structure of an RNA internal loop with three consecutive sheared GA pairs, Biochemistry 44, 2845-2856.
  • Znosko, B. M., Kennedy, S. D., Wille, P. C., Krugh, T. R., and Turner, D. H. (2004) Structural features and thermodynamics of the J4/5 loop from the Candida albicans and Candida dubliniensis group I introns, Biochemistry 43, 15822-15837.
  • Chen, G., Znosko, B. M., Jiao, X., and Turner, D. H. (2004) Factors affecting thermodynamic stabilities of RNA 3x3 internal loops, Biochemistry 43, 12865-12876.
  • Znosko, B. M., Barnes T. W., Krugh T. R., and Turner, D. H. NMR studies of DNA single strands and DNA:RNA hybrids with and without 1-propynylation at C5 of oligopyrimidines. (2003) J. Am. Chem. Soc. 125, 6090-6097.
  • Znosko, B. M., Burkard, M. E., Krugh, T. R., and Turner, D. H. (2002) Molecular recognition in purine-rich internal loops: Thermodynamic, structural, and dynamic consequences of purine for adenine substitutions in 5’(rGGCAAGCCU)2, Biochemistry 41, 14978-14987.
  • Znosko, B. M., Burkard, M. E., Schroeder, S. J., Krugh, T. R., and Turner, D. H. (2002) Sheared Aanti×Aanti base pairs in a destabilizing 2x2 internal loop: The NMR structure of 5’(rGGCAAGCCU)2, Biochemistry 41, 14969-14977.
  • Znosko, B. M., Silvestri, S. B., Volkman, H., Boswell, B., and Serra, M. J. (2002) Thermodynamic parameters for an expanded nearest-neighbor model for the formation of RNA duplexes with single nucleotide bulges, Biochemistry 41, 10406-10417

Pharmacology

Ian Mitchelle de Vera

Pharmacology and Physiology
ian.devera@health.slu.edu

The de Vera lab focuses on drug discovery efforts targeting orphan nuclear receptors (NRs). They have developed and utilized an array of biophysical methods for high-throughput screening of compounds binding the Germ Cell Nuclear Factor (GCNF), which holds great promise to the future of stem cell therapy and the development of anti-sterility drugs for men. Their goal is to identify the endogenous metabolite of orphan nuclear receptors using in-silico molecular docking of compound libraries to orphan NR targets, in tandem with a liquid chromatography-mass spectrometry (LC-MS) metabolomics platform. The deorphanization of NRs could provide crucial clues to the structure of synthetic compounds that would fit the binding pocket. They will use X-ray crystallography to structurally confirm specific binding of drugs and endogenous metabolites to NRs, and NMR spectroscopy techniques to characterize the interaction dynamics. The invaluable structural and dynamics information will aid structure optimization of synthetic compounds for better drug potency and efficacy. They will be working closely with other members of the SLU-DDG, including John Tavis, Marvin Meyers, Feng Cao, Maureen Donlin, Lynda Morrison and Getahun Abate on drug discovery efforts.

Drug-development publications:

  • de Vera, I. M. S., Zheng, J., Novick, S., Shang, J., Hughes, T. S., Brust, R., Munoz-Tello, P., Gardner, Jr. W. J., Marciano, D. P., Kong, X., Griffin, P. R. and Kojetin, D. J., “Synergistic regulation of coregulator/nuclear receptor interaction by ligand and DNA.” Structure, 25, 10, 1506-1518.e4, 2017. 

  • Weikum, E., de Vera, I. M. S., Nwachukwu, J.C., Hudson, W. H., Nettles, K. W., Kojetin, D. J., and Ortlund, E. “Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes.” Nucleic Acids Research, 45, 14, 8596-8608, 2017. 

  • de Vera, I. M. S., Giri, P., Munoz-Tello, P., Brust, R., Fuhrmann, J., Matta- Camacho, E., Shang, J., Campbell, S., Wilson, H. D., Granados, J., Gardner, W. J., Creamer, T. P., Solt, L. A. and Kojetin, D. J., “Identification of a binding site for unsaturated fatty acids in the orphan nuclear receptor Nurr1.” ACS Chem Biol, 11, 7, 1795-1799, 2016. 

  • Thenin-Houssier, S., de Vera, I. M. S., Pedro-Rosa, L., Brady, A., Richard, A., Konnick, B., Opp, S., Buffone, C., Fuhrmann, J., Kota, S., Billack, B., Pietka-Ottlik, M., Tellinghuisen, T., Choe, H., Spicer, T., Scampavia, L., Diaz-Griffero, F., Kojetin, D. J. and Valente, S. T., “Ebselen, a small molecule capsid-inhibitor of HIV replication.” Antimicrob Agents Chemother, 60, 4, 2195-2208, 2016. 

  • Hughes, T. S., Shang, J., Brust, R., de Vera, I. M. S., Fuhrmann, J., Ruiz, C., Cameron, M. D., Kamenecka, T. M. and Kojetin, D. J., “Probing the complex binding modes of the PPARg partial agonist 2-Chloro-N-(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4 (trifluoromethyl)benzene sulfonamide (T2384) to orthosteric and allosteric sites with NMR spectroscopy, J Med Chem, 59, 22, 10335-10341, 2016.
  • Hudson, W. H., Kossmann*, B. R., de Vera, I. M. S.*, Chuo, S., Weikum, E. R., Eick, G. N., Thornton, J. W., Ivanov, I. N., Kojetin, D. J. and Ortlund, E. A., “Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformation space.” Proc Natl Acad Sci, USA, 113, 2, 326-331, 2016. *contributed equally
  • Liu, Z., Casey, T. M., Blackburn, M. E., Huang, X., Pham, L., de Vera, I. M. S., Carter, J. D., Kear-Scott, J. L., Veloro, A. M., Galiano, L. and Fanucci, G. E., “Pulsed EPR characterization of HIV-1 protease conformational sampling and inhibitor-induced population shifts.” Phys Chem Chem Phys, 18, 8, 5819-5831, 2015.
  • Hughes, T. S., Giri, P. K., de Vera, I. M. S., Marciano, D. P., Kuruvilla, D. S., Shin, Y., Blayo, A. L., Kamenecka, T. M., Burris, T. P., Griffin, P. R., and Kojetin, D. J. “An alternate binding site for PPARγ ligands.” Nature Communications, 5, 3571, 2014.
  • Hudson, W. H., Pickard, M., de Vera, I. M. S. , Kuiper, E., Mourtada-Maarabouni, M., Conn, G., Kojetin, D., Williams, G. and Ortlund, E., “Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate.” Nature Communications, 5, 5395, 2014.
  • Carter, J. D., Gonzales, E. G. Huang, X., Smith, A. N., de Vera, I. M. S., D’Amore, P. D. Rocca, J. R. Goodenow, M., Dunn, B. M. and Fanucci, G. E. “Effects of PRE and POST therapy drug-pressure selected mutations on HIV-1 protease conformational sampling.” FEBS Lett., 588, 17, 3123-3128, 2014.
  • de Vera, I. M. S., Smith, A. N., Dancel, M. C., Huang, X., Dunn, B. M. and Fanucci, G. E. “Elucidating a relationship between conformational sampling and drug resistance in HIV-1 protease.” Biochemistry, 52, 3278–3288, 2013. 

  • de Vera, I. M. S., Blackburn, M.E. and Fanucci, G.E. “Correlating conformational shift induction with altered inhibitor potency in a multidrug resistant HIV-1 protease variant.” Biochemistry, 51, 7813-7815, 2012. 

  • Huang, X., de Vera, I. M. S., Veloro, A., Blackburn, M. E., Kear, J. L., Carter, J., Rocca, J.R., Simmerling, C., Dunn, B.M. and Fanucci, G.E. “Inhibitor-induced conformational shifts and ligand exchange dynamics for HIV-1 protease by pulsed EPR and NMR spectroscopy.” J. Phy. Chem. B, 116, 14235–14244, 2012.
Bahaa El-Gendy

Pharmacology and Physiology
bahaaeldien.elgendy@health.slu.edu

The main focus of El-Gendy’s research group is medicinal chemistry with a broad goal of drug design and optimization. Most of the work in his lab concentrates on developing small molecules modulators for different targets. For example, he designs and synthesize modulators of nuclear hormone receptors for the therapeutic treatment of cancer and fatty liver diseases. Also, he develops small molecules that can act as anti-viral agents against HCV, ZIKV, and other microbes. He has a wide international collaboration with scientists from United Kingdom, United Arab Emerates and Egypt. El-Gendy incorporates computational methods such as quantitative structure activity relationships, pharmacophore modeling, and virtual screening in his drug discovery pipeline to accelerate the process of drug discovery and optimization.

David Griggs
Molecular Microbiology and Immunology

david.griggs@health.slu.edu

Griggs' laboratory specializes in drug discovery and the translation of basic discoveries to therapeutic application. The lab performs assay development and optimization for high-throughput screening of compounds, assessment of target potency and selectivity for lead characterization, and in vitro and in vivo assessment of compound pharmacokinetics and metabolism (ADME). A major interest of his for many years, both at SLU and in prior research performed while working at global pharmaceutical companies (Searle/Pharmacia/Pfizer), has been the roles of integrins in physiology and disease. The lab has recently discovered and characterized new small molecule compounds which are making exciting progress toward development of an effective treatment to reduce or reverse the destructive organ fibrosis that occurs in many disease conditions. They are also currently applying their molecular, cellular, and pharmacology expertise in sponsored research programs to develop new medicines for treatment of tuberculosis, cryptosporidiosis, and bone disorders. Grigg's lab maintains diverse and productive collaborations with companies, foundations, and researchers at SLU and around the world, all of which aim to advance new and better treatments for patients.

Drug-development publications:

  • Henderson, N.C., T.D. Arnold, Y. Katamura, M.M. Giacomini, J.D. Rodriquez, J.H. McCarty, A. Pellicoro, A.C. Mackinnon, P.G. Ruminski, D.W. Griggs, M.J. Prinsen, J.J. Maher, J.P. Iredale, A. Lacy-hulbert, R.H. Adams, and D. Sheppard. 2013. Targeting av integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nature Medicine. 19:1617-1624
  • Meyers, M.J., M.D. Tortorella, J. Xu, L. Qin, Z. He, X. Lang, W. Zeng, W. Xu, L. Qin, M.J. Prinsen, F.M. Sverdrup, C.S. Eickhoff, D.W. Griggs, J. Oliva, P.G. Ruminski, E.J. Jacobsen, M.A. Campbell, D.C. Wood, D.E. Goldberg, X. Liu, Y. Chen, Z. Tu, X. Lu, K. Ding, and X. Chen. 2013. Evaluation of aminohydantoins as a novel class of antimalarial agents. 2014. ACS Med. Chem. Lett. 5:89-93.
  • Meyers, M.J., E.J. Anderson, S.A. McNitt, T.M. Krenning, M. Singh, J. Xu, W. Zeng, L. Qin, C.S.. Eickhoff, J. Oliva, M.A. Campbell, S.D. Arnett, M.J. Prinsen, D.W. Griggs, P.G. Ruminski, D.E. Goldberg, K. Ding, X. Liu, Z. Tu, M.D. Tortorella, F. M, Sverdrup, and X. Chen. Evaluation of spiropiperadine hydantoins as a novel class of antimalarial agents. 2015. Bioorg Med Chem 23:5144-5150.
  • Ulmasov, B., B.A. Neuschwander-Tetri, J. Lai, V. Monastyrskiy, T. Bhat, M. Yates, J. Oliva, M.J. Prinsen, P. Ruminski, D.W. Griggs. Targeted pharmacologic inhibition of RGD-binding integrins suppresses pancreatic fibrosis in mice. 2016. Cell Mol Gastroenterol Hepatol 2:499-518.
  • Griggs, D.W. M.J. Prinsen, J. Oliva, M.A. Campbell, S.D. Arnett, D. Tajfirouz, P.G. Ruminski, Y. Yu, B.R. Bond, Y. Ji, G. Neckermann, R.K.M Choy, E. de Hostos, M.J. Meyers. 2016. Pharmacologic comparison of clinical neutral endopeptidase inhibitors in a rat model of acute secretory diarrhea. J Pharmacol Exp Ther 367:423-431.
  • Murray, I.R., Z.N. Gonzalez, J. Baily, R. Dobie, R.J. Wallace, A.C. Mackinnon, J.R. Smith, S.N. Greenhaigh, A.I. Thompson, K.P. Conroy, D.W. Griggs, P.G. Ruminski, G.A. Gray, M. Singh, M.A. Campbell, T.J. Kendall, J. Dai, Y. Li, J.P Iredale, H. Simpson, J. Huard, B. Peault, N.C. Henderson. 2017. Alpha v integrins on mesenchymal cells critically regulate skeletal and cardiac muscle fibrosis. Nature Communications 8(1):1118.
  • Stebbins, E., R.S. Jumani, C. Klopfer, J. Barlow, P. Miller, M.A. Campbell, M.J. Meyers, D.W. Griggs, and C.D. Huston. 2018. Clinical and microbiologic efficacy of the piperazine-based drug lead MMV665917 in the dairy calf cryptosporidiosis model. PLOS Neglected Trop. Dis. In press.

Drug-development patent applications:

  • 2013 Griggs DW, and Ruminski, P.G., Beta amino acid derivatives as integrin antagonists. Granted US patent 9085606.
  • 2013 Griggs DW, and Ruminski, P. G., 3,5 phenyl-substituted beta amino acid derivatives as integrin antagonists. Granted US Patent 8716226.
  • 2016 Griggs DW, and Ruminski, P.G., Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists. WO 2017117538. Pending.
  • 2017 Griggs DW, and Ruminski, P.G., αVβ1 integrin antagonists. Provisional US patent 62/471,882. Pending.
Marvin Meyers

Chemistry
Pharmacology and Physiology & Chemistry
marvin.meyers@health.slu.edu

The research in Meyer's lab is focused the application of medicinal chemistry towards the discovery of potential drug candidates to treat people with rare and neglected diseases. They collaborate with experts in infectious disease biology, including malaria, tuberculosis, infectious diarrhea (cryptosporidiosis), cryptococcal meningitis, hepatitis B virus, and herpes simplex virus. They also have ongoing collaborations with experts in oncology, FSHD muscular dystrophy, and infant short-gut syndrome.

They use synthetic organic chemistry techniques to prepare new compounds, which are analyzed by their collaborators to assess their biological properties. Using medicinal chemistry and structure-based drug design principles, they optimize the potency, pharmacokinetics, and safety profiles of compounds with the goals of identification of tool compounds and, ultimately, candidate drug molecules for clinical trials.

Drug-development publications:

  • Nasamu, A.S.; Glushakova, S.; Russo, I.; Vaupel, B.; Oksman, A.; Kim, A.S.; Fremont, D.H.; Tolia, N.; Beck, J.R.; Meyers, M.J.; Niles, J.C.; Zimmerberg, J.; Goldberg, D.E. Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion. Science, 2017, 358, 518-522.
  • Montoya, M.C.; DiDone, L.; Heier, R.F.; Meyers, M.J.; Krysan, D.J. Antifungal Phenothiazines: Optimization, Characterization of Mechanism, and Modulation of Neuroreceptor Activity. ACS Infect Dis. 2017, DOI: 10.1021/acsinfecdis.7b00157 Article ASAP. Publication Date (Web): October 23, 2017.
  • Lee S, Harwood M, Girouard D, Meyers MJ, Campbell MA, Beamer G, Tzipori S. (2017) The therapeutic efficacy of azithromycin and nitazoxanide in the acute pig model of Cryptosporidium hominis. PLOS ONE 12(10): e0185906. https://doi.org/10.1371/journal.pone.0185906
  • Welch RD, Guo C, Sengupta M, Carpenter KJ, Stephens NA, Arnett SA, Meyers MJ, Sparks LM, Smith SR, Zhang J, Burris TP, Flaveny CA. Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome. Molecular Metabolism. 2017; 6(7):703-714.
  • Donlin MJ, Zunica A, Lipnicky A, Garimallaprabhakaran AK, Berkowitz AJ, Grigoryan A, Meyers MJ, Tavis JE, Murelli RP. Troponoids Can Inhibit Growth of the Human Fungal Pathogen Cryptococcus neoformans. Antimicrobial Agents and Chemotherapy. 2017; 61(4).
  • Faidallah HM, Panda SS, Serrano JC, Girgis AS, Khan KA, Alamry KA, Therathanakorn T, Meyers MJ, Sverdrup FM, Eickhoff CS, Getchell SG, Katritzky AR. Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates. Bioorganic & Medicinal Chemistry. 2016; 24(16):3527-39.
  • Lu G, Villa JA, Donlin MJ, Edwards TC, Cheng X, Heier RF, Meyers MJ, Tavis JE. Hepatitis B virus genetic diversity has minimal impact on sensitivity of the viral ribonuclease H to inhibitors. Antiviral Research. 2016; 135:24-30.
  • Masaoka T, Zhao H, Hirsch DR, D'Erasmo MP, Meck C, Varnado B, Gupta A, Meyers MJ, Baines J, Beutler JA, et al. Characterization of the C-Terminal Nuclease Domain of Herpes Simplex Virus pUL15 as a Target of Nucleotidyltransferase Inhibitors. Biochemistry 2016, 55, 809-819.
  • Griggs, D.W.; Prinsen, M.J.; Oliva, J.; Campbell, M.A.; Arnett, S.D.; Tajfirouz, D.; Ruminski, P.G.; Yu, Y.; Bond, B.; Ji, Y.; Neckermann, G.; Choy, R.K.M.; de Hostos, E.; Meyers, M.J. Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea. J. Pharm. Exp. Ther. 2016, 357, 423-431.
  • Meyers, M. J.; Anderson, E. J.; McNitt, S. A.; Krenning, T. M.; Singh, M.; Xu, J.; Zeng, W.; Qin, L.; Xu, W.; Zhao, S.; Qin, L.; Eickhoff, C. S.; Oliva, J.; Campbell, M. A.; Arnett, S. D.; Prinsen, M. J.; Griggs, D. W.; Ruminski, P. G.; Goldberg, D. E.; Ding, K.; Liu, X.; Tu, Z.; Tortorella, M. D.; Sverdrup, F. M.; and Chen, X.; Evaluation of Spiropiperidine Hydantoins as a Novel Class of Antimalarial Agents. Bioorg. Med. Chemistry 2015, 23(16):5144-50.
  • Lu, G.; Lomonosova, E.; Cheng, X.; Moran, E.A.; Meyers, M.J.; Le Grice, S.F.J.; Thomas, C.J.; Jiang, J.-K.; Meck, C.; Hirsch, D.R.; D’Erasmo, M.P.; Suyabatmaz, D.M.; Murelli, R.P.; Tavis, J.E. Hydroxylated tropolones inhibit hepatitis B virus replication by blocking viral ribonuclease H activity. Antimicrob Agents Chemother 2015, 59, 1070–1079.
  • Cai, C.W.; Lomonosova, E.; Moran, E.A.; Cheng, X.; Patel, K.B.; Bailly, F.; Cotelle, P.; Meyers, M.J.; and Tavis, J.E. Hepatitis B Virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity. Antiviral Research 2014, 108, 48-55.
  • Meyers, M. J.;* Tortorella, M. D.; Xu, J.; Qin, L.; He, Z.; Lang, X.; Zeng, W.; Xu, W.; Qin, L.; Prinsen, M. J.; Sverdrup, F. M.; Eickhoff, C. S.; Griggs, D. W.; Oliva, J.; Ruminski, P. G.; Jacobsen, E. J.; Campbell, M. A.; Wood, D. C.; Goldberg, D. E.; Liu, X.; Lu, Y.; Lu, X.; Tu, Z.; Lu, X.; Ding, K.; Chen, X.* Evaluation of Aminohydantoins as a Novel Class of Antimalarial Agents. ACS Medicinal Chemistry Letters 2014, 5, 89-93.
  • Panda, S. S., Ibrahim, M. A., Kuecuekbay, H., Meyers, M. J., Sverdrup, F. M., El-Feky, S. A., Katritzky, A. R.* Synthesis and Antimalarial Bioassay of Quinine - Peptide Conjugates. Chemical Biology & Drug Design. 2013, 82, 361-366.
  • Tavis, J.E., Cheng, X., Hu, Y., Totten, M., Cao, F., Michailidis, E., Aurora, R., Meyers M.J., Jacobsen, J., Parniak, M.A., and Sarafianos, S.G. The hepatitis B virus ribonuclease H is sensitive to inhibitors of the human immunodeficiency virus ribonuclease H and integrase enzymes. PLoS Path. 2013, 9(1): e1003125. doi:10.1371/journal.ppat.1003125.
  • Panda, S. S., Bajaj, K., Meyers, M. J., Sverdrup, F. M., and Katritzky, A. R.* Quinine bis-conjugates with quinolone antibiotics and peptides: synthesis and antimalarial bioassay. Org. Biomol. Chem. 2012, 10, 8985-8993.
  • Meyers, M.J. and Goldberg, D.E. Recent Advances in Plasmepsin Medicinal Chemistry and Implications for Future Antimalarial Drug Discovery Efforts. Curr. Top. Med. Chem. 2012, 12, 445-455.
  • Meyers, M.J. Editorial: The Medicinal Chemistry of Novel Approaches for the Treatment of Malaria. Curr. Top. Med. Chem. 2012, 12, 371-372.

Drug-development patent applications:

  • Cao, F., Tavis, J.E., Donlin, M.J., Meyers, M.J., Murelli, R.P., and Orth, C. Provisional US patent 62/507,551. Inhibitors of nucleotidyl transferase superfamily enzymes as antibiotics. 2017
    Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists in combination with an agent which interacts with a chemokine receptor. PCT patent application filed November 2, 2017. PCT/US2017/059777.
  • Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists. Provisional patent application filed September 13, 2017. Attorney docket USTL.P0094US.P1 Provisional Serial No. 62/558,045.
  • Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists. Provisional patent application filed September 6, 2017. Attorney docket USTL.P0093US.P1
  • Meyers, MJ; Wood, DC; Arnett, SA; Yates, MP; Ruminski, PG. Fatty acid modified epidermal growth factor. Provisional patent application filed July 27, 2017. Attorney docket USTL.P0092US.P1. Provisional Serial No. 62/537,808.
  • Meyers, MJ; Singh, M; Stallings, CL; Weiss, LA; Wildman, S; Arnett, SD. Thieno[2,3-d]pyrimidines and benzofuro[3,2-d]pyrimidines as antimicrobial agents. Provisional patent application filed July 17, 2017. Attorney docket USTL.P0084US.P1. Provisional Serial No. 62/533,403.
  • Dowd, D; Wang, X; Brothers, RC; John, ARO; Edwards, R; Meyers, M; Arnett, S; Couch, R. Methods and compounds for treating malaria. Provisional patent application filed June 27, 2017. Attorney docket 130761.00865. Provisional Serial No. 62/525,616.
  • Donlin, M.J., Tavis, J.E., Murelli, R., and Meyers, M. US patent 62/324,675. Anti-fungal compounds.
  • 2016 Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists in combination with an agent which interacts with a chemokine. Provisional patent application filed November 2, 2016. Attorney docket USTL.P0083US.P1.
  • Ruminski, PG; Meyers, MJ; Heier, RF; Rettig, MP; Dipersio, J. Integrin antagonists. Provisional patent application filed November 2, 2016. Attorney docket USTL.P0080US.P1. Provisional Serial No. 62/416,530.
  • Tavis, J.E.; Morrison, L.A.; Meyers, M.J. Inhibitors of nucleotidyl transferases and use in herpes and hepatitis viral infections. WO2016/201306, published December 15, 2016.
  • Tavis, J.E.; Morrison, L.A.; Meyers, M.J. Inhibitors of HSV nucleotidyl transferases and uses. WO2015/077774, published May 28, 2015.
  • Blinn, J.R.; Flick, A.C.; Wennerstaal, G.M.; Jones, P.; Kaila, N.; Kiefer, Jr., J.R.; Kurumbail, R.G.; Mente, S.R.; Meyers, M.J.; Schnute, M.E.; Thorarensen, A.; Xing, L.; Zamaratski, E.; Zapf, C.W. Preparation of N-heteroaryl amides as RORC2 inhibitors. WO2015/015378, published Feb 5, 2015.
  • Chen, X.; Ding, K.; Meyers, M.J.; Tortorella, M.D.; Xu, J. Compositions and methods for the treatment of malaria. WO2014/160775, published Oct 2, 2014. Granted as US 9,353,089. May 31, 2016.
Fran Sverdrup
Biochemistry & Molecular Biology

fran.sverdrup@health.slu.edu

Fran Sverdrup's lab is focused on drug discovery in human genetic diseases as well as infectious diseases. They perform target identification and validation, drug screening and preclinical evaluation of drug candidates. Their major current project targets facioscapulohumeral muscular dystrophy (FSHD), one of the most common forms of muscular dystrophy for which there is no treatment. Their goals are to identify druggable pathways that modulate expression of the toxic DUX4 gene that is responsible for FSHD and translate those finding into potential therapies. Their approach is to perform high throughput screening of chemical libraries to identify compounds intended to epigenetically suppress the DUX4 gene. They are currently advancing three exciting classes of drugs that turn off DUX4 expression including a robust lead optimization program that involves close collaboration with their medicinal chemistry colleagues. They evaluate new compounds by using biochemical and cell based assays. They are now moving these compounds into animal model testing and have established a key collaboration with a pharmaceutical partner to eventually advance one of these into human clinical trials. A second interest is in anti-infectives research with recent programs targeting malaria, lymphatic filariasis and African sleeping sickness. To accomplish these activities, they maintain a network of collaborations with disease experts, medicinal chemists, pharmaceutical/biotech companies and foundations.

Drug-development publications:

  • Campbell AE, Oliva J, Yates MP, Zhong JW, Shadle SC, Snider L, Singh N, Tai S, Hiramuki Y, Tawil R, van der Maarel SM, Tapscott SJ, Sverdrup FM. 2017. BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells. Skelet Muscle. 7(1):16.
  • Faidallah HM, Panda SS, Serrano JC, Girgis AS, Khan KA, Alamry KA, Therathanakorn T, Meyers MJ, Sverdrup FM, Eickhoff CS, Getchell SG, Katritzky AR. 2016. Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates. Bioorganic & Medicinal Chemistry. 24(16):3527-39.
  • Meyers MJ, Anderson EJ, McNitt SA, Krenning TM, Singh M, Xu J, Zeng W, Qin L, Xu W, Zhao S, Qin L, Eickhoff CS, Oliva J, Campbell MA, Arnett SD, Prinsen MJ, Griggs DW, Ruminski PG, Goldberg DE, Ding K, Liu X, Tu Z, Tortorella MD, Sverdrup FM, Chen X. 2015. Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents. Bioorganic & Medicinal Chemistry. 23(16):5144-50.
  • Gillan V, O'Neill K, Maitland K, Sverdrup FM, Devaney E. 2015. A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes. PLoS Neglected Tropical Diseases. 8(2):e2699.
  • Meyers MJ, Tortorella MD, Xu J, Qin L, He Z, Lang X, Zeng W, Xu W, Qin L, Prinsen MJ, Sverdrup FM, Eickhoff CS, Griggs DW, Oliva J, Ruminski PG, Jacobsen EJ, Campbell MA, Wood DC, Goldberg DE, Liu X, Lu Y, Lu X, Tu Z, Lu X, Ding K, Chen X. 2014. Evaluation of aminohydantoins as a novel class of antimalarial agents. ACS Medicinal Chemistry Letters. 5(1):89-93.
  • Panda SS, Ibrahim MA, Küçükbay H, Meyers MJ, Sverdrup FM, El-Feky SA, Katritzky AR. 2013. Synthesis and antimalarial bioassay of quinine - peptide conjugates. Chemical Biology & Drug Design. 82(4):361-6.
  • Panda SS, Bajaj K, Meyers MJ, Sverdrup FM, Katritzky AR. 2012. Quinine bis-conjugates with quinolone antibiotics and peptides: synthesis and antimalarial bioassay. Organic & Biomolecular Chemistry. 10(45):8985-93.
  • Madsen SH, Andreassen KV, Christensen ST, Karsdal MA, Sverdrup FM, Bay-Jensen AC, Henriksen K. 2011. Glucocorticoids exert context-dependent effects on cells of the joint in vitro. Steroids. 76(13):1474 82.
  • Sverdrup FM, Yates MP, Vickery LE, Klover JA, Song LR, Anglin CP, Misko TP. 2010. Protein geranylgeranylation controls collagenase expression in osteoarthritic cartilage. Osteoarthritis and Cartilage. 18(7):948-55.
  • Yates MP, Settle SL, Yocum SA, Aggarwal P, Vickery LE, Aguiar DJ, Skepner AP, Kellner D, Weinrich SL, Sverdrup FM. 2010. IGFBP-5 Metabolism Is Disrupted in the Rat Medial Meniscal Tear Model of Osteoarthritis. Cartilage. 1(1):43-54.
  • Busby WH Jr, Yocum SA, Rowland M, Kellner D, Lazerwith S, Sverdrup F, Yates M, Radabaugh M, Clemmons DR. 2009. Complement 1s is the serine protease that cleaves IGFBP-5 in human osteoarthritic joint fluid. Osteoarthritis and Cartilage. 17(4):547-55.

Drug-development patent applications:

  • 2002 Schmidt, B.F., Allen, M.L., Sverdrup, F., and Carmichael, D.F. US Patent 09/292,036. Connective tissue growth factor (CTGF) and methods of use.
  • 2005 Fisher, C., Bashkin, J.K., Crowley, K., Sverdrup, F.M., Garner-Hamrick, P.A., and Phillion, D.P. WO2005033282. Polyamide compositions and therapeutic methods for treatment of human papilloma virus.
  • 2017 Sverdrup, F.M. and Tapscott, S.J. US Patent 14/491,599. Inhibition of DUX4 expression using bromodomain and extra-terminal domain protein inhibitors (BETi).
  • 2017 Sverdrup, F.M., Tapscott, S.J., Oliva, J., Campbell, A.E. and Meyers, M.J. Provisional US patent 62/589,225. Compositions for modulating DUX4 expression in FSHD. Pending.
John Walker

Pharmacology and Physiology
john.walker@health.slu.edu

Research in the Walker lab focuses mainly on synthetic and medicinal chemistry to develop tool compounds or novel therapeutic agents against a variety of biological targets and therapeutic indications. Their lab is actively involved in multiple research collaborations partnering with investigators both at SLU and other Universities. They use modern synthesis techniques and also a number of in silico approaches to design and synthesize new target molecules.

A major area of research focus and collaboration for their group is developing strategies and molecules to target antibacterial resistance as part of their long-standing collaboration with the Zgurskaya and Rybenkov labs at the University of Oklahoma. They are working to develop molecules that can penetrate the outer membrane of Gram-negative pathogens and inhibit efflux pumps, which contribute both to the intrinsic and acquired resistance of many pathogens to antibiotics. They recently demonstrated that novel ligands they prepared can potentiate the activity of the antibiotics novobiocin and erythromycin in E. coli.

Clinical Studies

Getahun Abate
Infectious Diseases

getahun.abate@health.slu.edu

Development of new drugs against mycobacterial diseases is one of Abate’s key research interests. His lab works closely with the Hoft lab, and has the following capacities: screening new drugs against bacillus Calmitte Guerin (the attenuated TB vaccine) using a rapid growth inhibition assay, testing drugs on reference strains of Mycobacterium tuberculosis and M. avium, studying anti-mycobacterial activities against intracellular mycobacteria using human macrophages from healthy donors, testing interactions of new drugs with first-line anti-TB drugs against extracellular and intracellular mycobacteria, studying the effects of new drugs on mycobacterium-specific immunity and testing the cytotoxicity of new drugs on THP-1 (human) and J774.A1 (murine) macrophage cell lines. His lab also has a protocol to test the anti-TB activities of new drugs in murine TB model.

Drug-development publications:

  • Abate G, Hoffner SE. Synergistic antimycobacterial activity between ethambutol and the beta-lactam drug cefepime. Diagn Microbiol Infect Dis. 1997; 28:119-22.
  • Abate G, Miörner H. Susceptibility of multidrug-resistant strains of Mycobacterium tuberculosis to amoxycillin in combination with clavulanic acid and ethambutol. J Antimicrob Chemother. 1998; 42:735-40.
  • Abate G, Koivula T, Hoffner SE. In vitro activity of thiacetazone on mycobacterial species belonging to the Mycobacterium tuberculosis complex. Int J Tuberc Lung Dis. 2002; 6:933-5.
  • Abate G, Ruminiski PG, Kumar M, Singh K, Hamzabegovic F, Hoft DF, Eickhoff CS, Selimovic A, Campbell M, Chibale K. New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells. Antimicrob Agents Chemother. 2015; 60:1216-25.
  • Kumar M, Singh K, Naran K, Hamzabegovic F, Hoft DF, Warner DF, Ruminski P, Abate G, Chibale K. Design, Synthesis, and Evaluation of Novel Hybrid Efflux Pump Inhibitors for Use against Mycobacterium tuberculosis. ACS Infect Dis. 2016; 2: 714-725.
  • Reversed Isoniazids: Design, synthesis and evaluation against Mycobacterium tuberculosis Kumar M, Singh K, Ngwane AH, Hamzabegovicc F, Abate G, Baker B, Wiid I, Hoft DF, Ruminski PG, Chibale K. Submitted (BMC).
Robin Chamberland
Director of Clinical Microbiology
Medical Director of Molecular Microbiology
SLU Hospital
robin.chamberland@health.slu.edu

Chamberland directs the clinical microbiology labs at the SSM-SLU hospital. She assists SLU-DDG investigators who may need access to clinical samples and provides clinical perspective to SLU-DDG investigators.
Soumya Chatterjee
Infectious Diseases

soumya.chatterjee@health.slu.edu

The Chatterjee lab is focused on vaccine development and “host directed” therapeutics against tuberculosis (TB). There has been considerable interest in enhancing immune responses to TB as a therapeutic strategy. Current anti-mycobacterial therapy with antibiotics is too long and too complex. This leads to emergence of multi-drug resistant and extremely drug resistant organisms. As the bacteria have evolved over millennia, it inevitably develops mechanisms of resistance to every new class of antibiotic developed. Augmenting host immune strategies by targeting specific cellular receptors and pathways bypasses the issue of resistance and can shorten treatment duration. They are collaborating with the nanomedicine division at Houston Methodist to use nanoparticles conjugated with thioaptamers against specific cellular receptors. Thioaptamers have increased binding stability compared to antibodies. Not only do these particles elicit unique immune responses. The lab has the capacity to test these particles in vitro as well as indifferent mouse models in vivo. They are also proficient in cellular immunology, cytokine assays, assays of phagocytic function and flow cytometry.

Sharon Frey

SLU Infectious Diseases Division
sharon.frey@health.slu.edu

Sharon Frey is a practicing infectious diseases physician. Her research expertise is in testing of vaccine candidates in Phase I – III clinical trials. She provides guidance to SLU-DDG members regarding in the medical needs and issues associated with microbial infections of human patients, and also helps guide design of clinical trials of novel drug candidates.

Sarah George

St. Louis Veteran's Administration Hospital & SLU Infectious Diseases Division
sarah.george@health.slu.edu

Sarah George is a clinician-scientist who both cares for patients and conducts biomedical research. Her laboratory effort focuses on innate and adaptive immune responses to flavivirus infections. Her lab is currently focused on identifying human adaptive immune responses which control dengue replication in target cells. George has been the Principal Investigator on seven vaccine trials, including six funded by the NIH, and has extensive expertise in developing clinical trials protocols and monitoring human subject safety in clinical trials. Her laboratory can measure ex vivo efficacy of agents designed to boost human memory immune responses which control dengue replication. George’s lab also has extensive experience with HIV and human pegivirus (HPgV), and can test compounds which may inhibit HIV replication or enhance HPgV’s inhibitory effect on HIV replication.

Daniel Hoft
Infectious Diseases

daniel.hoft@health.slu.edu

Hoft is the Chief of the SLU Division of Infectious Diseases, Allergy and Immunology. He has three drug-development projects in his lab.

  1. Tuberculosis: Hoft's group has been supporting the study of new drugs for TB. Abate is the leader of these efforts in the Infectious Diseases division. They have the capacity to study the effects of new drugs against extracellular Mycobacterium tuberculosis (Mtb), intracellular Mtb in human primary monocytes and cell lines, in vivo studies in murine models and human trials. This recent work has already resulted in 2 published papers. In addition, they recently received a VTEU award (~$6 million in total funding) to conduct a multi-drug resistant (MDR)-TB treatment trial in South Africa and Uganda with the goal of comparing the current standard of care treatment (involving 1-2 years of total treatment including an injectable agent daily for at least the first 6 months) with a new all oral drug regimen (replacing the injectable with delamanid, a newly approved oral TB drug).
  2. Chagas disease: Hoft has studied infections with Trypanosoma cruzi in mice for 30 years. Most of his work has focused on basic immunology and vaccine development. However, the Hoft lab has developed high throughput assays for screening new compounds for inhibitory effects against extracellular life stages of the parasite, low-moderate throughput assays for screening for intracellular effects of drugs on parasites infecting human primary monocytes and/or cell lines, and has in vivo murine models for testing protective effects of new drugs.
  3. Influenza: Hoft's lab has been developing a T cell targeting universal vaccine for influenza A, and has been engaged in multiple clinical trials of currently licensed and experimental influenza vaccines. This work has led to in vitro assays capable of measure immune and/or drug effects against intracellular development of viral progeny in primary human monocytes. In addition, Hoft is developing a human influenza challenge unit for testing the efficacy of new drugs and/or vaccines.
William Wold
Molecular Microbiology and Immunology

bill.wold@health.slu.edu

The Wold lab's main expertise lies with the design, execution, and analysis of animal experiments. Most of their experience is with adenoviruses and noroviruses, but the techniques they use can be extended to other pathogens as well. They have worked with various infection models using mice, Syrian hamsters, cotton rats, and Guinea pigs. They can investigate the natural history of an infection in a given model (pathogenesis, replication of the pathogen in target organs), they can test the efficacy (effect on pathogenesis and pathogen burden) of an anti-infective, they can perform the in-life portion of toxicology and pharmacokinetics experiments and collect samples for analysis. They have collaborated with numerous pharmaceutical companies, and executed large scale, in-the-spirit-of GLP studies that formed the basis of a successful IND submission.

Besides animal experiments, they have extensive experience with in vitro experiments with adenoviruses, and to a lesser extent, noroviruses. They have the capacity to produce large scale purified stocks of these viruses, quantify them using both physical and biological assays, and perform molecular biology-type studies.

They have a Beckman Coulter BioMek 2000 robot (base unit plus side extensions) with various tools. This robot can be used to automate basic liquid handling procedures in the 96-well format.

Supporting Technologies

Yie-Hwa Chang
Biochemistry and Molecular Biology

yiehwa.chang@health.slu.edu

Yie-Hwa Chang has been interested in developing anti-cancer drugs and antibiotics for the past 15 years. His lab has discovered and characterized two types of methionine aminopeptidases (MetAPs). The type-2 MetAP plays a key role in angiogenesis, and has been identified as a potential target for developing anti-cancer and anti-obesity drugs. Their discovery was licensed to 11 major pharmaceutical companies for their drug discovery projects. His lab has worked with David Griggs and Eric Jacobsen. Together, they have identified promising leading compounds as potential anti-TB drugs via inhibition of the MetAPs. In addition, he has been collaborating with Tomasz Heyduk, and have developed a series of novel homogeneous assays that have been used by many pharmaceutical companies for high-throughput drug screening projects. For example, his lab developed the first homogeneous assay for cAMP, S-adenosylmethionine (SAMe) and L-tryptophan. The cAMP assay has been used for developing drugs targeting GPCRs. The SAMe assay has been used for developing drugs for targeting methyltransferases. Finally, the L-tryptophan assay has been used for developing drugs targeting Indoleamine 2,3-dioxygenase (IDO1/IDO2). IDO1 is an important immunotherapy target for cancer treatment.

Drug Discovery Publications:

  • Zuo SL, Guo Q, Chang YH. A protease assay via pre-column derivatization and high pressure liquid chromatography. Analytical Biochemistry 1994, 222:514-516.
  • Li X, Chang YH. Amino-terminal protein processing in Saccharomyces cerevisiae is an essential function that requires two distinct methionine aminopeptidases. Proc. Natl. Sci. Acad. USA 1995, 92:12357-12361.
  • Griffith EC, Su Z, Turk B, Chen S, Chang YH, Wu Z, Biemann K, Liu JO. Methionine aminopeptidase (Type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin. Chemistry and Biology, 1997, 4:461-471.
  • Griffith EC, Su, Z, Niwayama S, Ramsay CA, Chang YH. Molecular recognition of angiogenesis inhibitors fumagillin and ovalicin by methionine aminopeptidase 2. Proc. Natl. Acad. Sci. USA 1998, 95:15183-15188.
  • Turk BE, Griffith EC, Wolf S, Bieman K, Chang YH, Liu JO. Selective inhibition of N-terminal processing by TNP-470 and Ovalicin in endothelial cells. Chemistry and Biology 1999, 6:823-833.
  • Udagawa T, Yuan J, Panigrahy D, Chang YH, Shah J, D'Amato RJ. Cytochalasin E, an epoxide containing Aspergillus-derived fungal metabolite, inhibits angiogenesis and tumor growth. J. Pharmacol. Exp. Ther. 2000, 294:421-427.
  • Kwon JY, Jeong HW, Kim HK, Kang KH, Chang YH, Bae KS, Choi JD, Lee UC, Son KH, Kwon BM cis-Fumagillin, a new methionine aminopeptidase (type 2) inhibitor produced by Penicillium sp. F2757. J. Antibiotics. 2000, 53:799-80.
  • Asami, Y.; Kakeya, H.; Onose, R.; Chang, Y.-H.; Toi, M.; Osada, H. RK-805, an endothelial-cell-growth inhibitor produced by Neosartorya sp., and a docking model with methionine aminopepidase-2. Tetrahedron, 2004, 60:7085-7091.
  • Heyduk E, Dummitt B, Chang YH, Heyduk T. Molecular pincers: antibody- based homogeneous protein sensors. Anal Chem. 2008, 80:5152-5159.
  • Tian L, Wang RE, Fei Y, Chang YH. A homogeneous fluorescent assay for cAMP-phosphodiesterase enzyme activity. J Biomol Screen. 2011, 17:409-414.
  • Chang YH. Common therapeutic target for both cancer and obesity. World journal of biological chemistry. 2017, 8:102-107.

Drug-development patent applications:

  • Chang YH. Patent No. 5,888,796. (1999) Clone of a Nucleotide Sequence Encoding a Protein Having Two Functions.
  • Chang YH. Patent No. 6,593,454. (2001) Methods for Identifying Inhibitors of Methionine Aminopeptidases.
  • Ray R, Ray R, Basu A and Chang YH. Patent No. 7232893. (2007) Method of manufacturing a stellate cell death factor.
  • Heyduk T, Tian L, Wang RE and Chang YH. Patent No. 8,956,857, (2015) Three-component biosensors for detecting macromolecules and other analytes.
  • Heyduk T, Tian L, Wang RE and Chang YH. Patent No. 9,618,505, (2017) Biosensors for detecting macromolecules and other analytes.
  • Chang YH, Tian L, Heyduk T. Patent No. 9,797,892 (2017) Molecular biosensors capable of signal amplification.
Ian Mitchelle de Vera

Pharmacology and Physiology
ian.devera@health.slu.edu

The de Vera lab focuses on drug discovery efforts targeting orphan nuclear receptors (NRs). They have developed and utilized an array of biophysical methods for high-throughput screening of compounds binding the Germ Cell Nuclear Factor (GCNF), which holds great promise to the future of stem cell therapy and the development of anti-sterility drugs for men. Their goal is to identify the endogenous metabolite of orphan nuclear receptors using in-silico molecular docking of compound libraries to orphan NR targets, in tandem with a liquid chromatography-mass spectrometry (LC-MS) metabolomics platform. The deorphanization of NRs could provide crucial clues to the structure of synthetic compounds that would fit the binding pocket. They will use X-ray crystallography to structurally confirm specific binding of drugs and endogenous metabolites to NRs, and NMR spectroscopy techniques to characterize the interaction dynamics. The invaluable structural and dynamics information will aid structure optimization of synthetic compounds for better drug potency and efficacy. They will be working closely with other members of the SLU-DDG, including John Tavis, Marvin Meyers, Feng Cao, Maureen Donlin, Lynda Morrison, and Getahun Abate on drug discovery efforts.

Drug-development publications:

  • de Vera, I. M. S., Zheng, J., Novick, S., Shang, J., Hughes, T. S., Brust, R., Munoz-Tello, P., Gardner, Jr. W. J., Marciano, D. P., Kong, X., Griffin, P. R. and Kojetin, D. J., “Synergistic regulation of coregulator/nuclear receptor interaction by ligand and DNA.” Structure, 25, 10, 1506-1518.e4, 2017. 

  • Weikum, E., de Vera, I. M. S., Nwachukwu, J.C., Hudson, W. H., Nettles, K. W., Kojetin, D. J., and Ortlund, E. “Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes.” Nucleic Acids Research, 45, 14, 8596-8608, 2017. 

  • de Vera, I. M. S., Giri, P., Munoz-Tello, P., Brust, R., Fuhrmann, J., Matta- Camacho, E., Shang, J., Campbell, S., Wilson, H. D., Granados, J., Gardner, W. J., Creamer, T. P., Solt, L. A. and Kojetin, D. J., “Identification of a binding site for unsaturated fatty acids in the orphan nuclear receptor Nurr1.” ACS Chem Biol, 11, 7, 1795-1799, 2016. 

  • Thenin-Houssier, S., de Vera, I. M. S., Pedro-Rosa, L., Brady, A., Richard, A., Konnick, B., Opp, S., Buffone, C., Fuhrmann, J., Kota, S., Billack, B., Pietka-Ottlik, M., Tellinghuisen, T., Choe, H., Spicer, T., Scampavia, L., Diaz-Griffero, F., Kojetin, D. J. and Valente, S. T., “Ebselen, a small molecule capsid-inhibitor of HIV replication.” Antimicrob Agents Chemother, 60, 4, 2195-2208, 2016. 

  • Hughes, T. S., Shang, J., Brust, R., de Vera, I. M. S., Fuhrmann, J., Ruiz, C., Cameron, M. D., Kamenecka, T. M. and Kojetin, D. J., “Probing the complex binding modes of the PPARg partial agonist 2-Chloro-N-(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4 (trifluoromethyl)benzene sulfonamide (T2384) to orthosteric and allosteric sites with NMR spectroscopy, J Med Chem, 59, 22, 10335-10341, 2016.
  • Hudson, W. H., Kossmann*, B. R., de Vera, I. M. S.*, Chuo, S., Weikum, E. R., Eick, G. N., Thornton, J. W., Ivanov, I. N., Kojetin, D. J. and Ortlund, E. A., “Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformation space.” Proc Natl Acad Sci, USA, 113, 2, 326-331, 2016. *contributed equally
  • Liu, Z., Casey, T. M., Blackburn, M. E., Huang, X., Pham, L., de Vera, I. M. S., Carter, J. D., Kear-Scott, J. L., Veloro, A. M., Galiano, L. and Fanucci, G. E., “Pulsed EPR characterization of HIV-1 protease conformational sampling and inhibitor-induced population shifts.” Phys Chem Chem Phys, 18, 8, 5819-5831, 2015.
  • Hughes, T. S., Giri, P. K., de Vera, I. M. S., Marciano, D. P., Kuruvilla, D. S., Shin, Y.,
  • Blayo, A. L., Kamenecka, T. M., Burris, T. P., Griffin, P. R., and Kojetin, D. J. “An alternate binding site for PPARγ ligands.” Nature Communications, 5, 3571, 2014.
  • Hudson, W. H., Pickard, M., de Vera, I. M. S. , Kuiper, E., Mourtada-Maarabouni, M., Conn, G., Kojetin, D., Williams, G. and Ortlund, E., “Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate.” Nature Communications, 5, 5395, 2014.
  • Carter, J. D., Gonzales, E. G. Huang, X., Smith, A. N., de Vera, I. M. S., D’Amore, P. D. Rocca, J. R. Goodenow, M., Dunn, B. M. and Fanucci, G. E. “Effects of PRE and POST therapy drug-pressure selected mutations on HIV-1 protease conformational sampling.” FEBS Lett., 588, 17, 3123-3128, 2014.
  • de Vera, I. M. S., Smith, A. N., Dancel, M. C., Huang, X., Dunn, B. M. and Fanucci, G. E. “Elucidating a relationship between conformational sampling and drug resistance in HIV-1 protease.” Biochemistry, 52, 3278–3288, 2013. 

  • de Vera, I. M. S., Blackburn, M.E. and Fanucci, G.E. “Correlating conformational shift induction with altered inhibitor potency in a multidrug resistant HIV-1 protease variant.” Biochemistry, 51, 7813-7815, 2012. 

  • Huang, X., de Vera, I. M. S., Veloro, A., Blackburn, M. E., Kear, J. L., Carter, J., Rocca, J.R., Simmerling, C., Dunn, B.M. and Fanucci, G.E. “Inhibitor-induced conformational shifts and ligand exchange dynamics for HIV-1 protease by pulsed EPR and NMR spectroscopy.” J. Phy. Chem. B, 116, 14235–14244, 2012.
Duane Grandgenett

Institute for Molecular Virology
duane.grandgenett@health.slu.edu

Duane Grandgenett's laboratory has been studying retroviruses since 1970 and discovered the viral integrase (IN) in 1978 in avian retroviruses. IN is responsible for integration of the viral DNA into the host chromosomes. Since the early 1990’s, they have focused on HIV-1 IN and helped Merck & Co develop the first major lead inhibitors directed against IN. The first FDA-approved inhibitor, Raltegravir, was in 2007. Two other companies are marketing similar active site inhibitors, one of which (Dolutegravir, GSK) is far superior at the clinical level. Their current efforts are directed towards understanding the mechanisms associated with the assembly of HIV-1 and Rouse Sarcoma Virus (RSV) IN-DNA complexes and their analyses at atomic resolution level. There are no HIV-1 IN-DNA complexes where detailed active site inhibitors can be thoroughly evaluated, except though a very distantly related surrogate prototype foamy virus IN-DNA model. They are now investigating whether the RSV IN-DNA complex can be utilized to study HIV-1 inhibitors at the atomic level. Their recent publications strongly suggest that RSV IN will serve as an excellent surrogate model for HIV-1 IN inhibitors. RSV and HIV-1 IN are similar genetically and structurally and, are equally inhibited in vivo and in vitro by the HIV-1 clinical inhibitors.

Drug-development publications:

  • Pandey,K.K., Bera, S., Korolev, S.,Campbell, M., Yin, Z., Aihara, H. and Grandgenett, D. (2014) Rous sarcoma virus synaptic complex capable of concerted integration is kinetically trapped by human immunodeficiency virus integrase strand transfer inhibitors. J. Biol. Chem. 289:19648-19658.
  • Yin, Z., Shi., K., Banerjee, S., Pandey K.K., Bera, S. Grandgenett, D.P., and Aihara, H. (2016) Crystal structure of the Rous sarcoma virus intasome. Nature 530:362-366.
  • Pandey, K.K., Bera, Sibes, Shi, K., Aihara, H. and Grandgenett, D. P. (2017) Assembly of Rous sarcoma virus intasome containing integrase octamers is facilitated by the C-terminal “tail” region. J. Biol. Chem. 292: doi:10.1074
David Griggs

Molecular Microbiology and Immunology
david.griggs@health.slu.edu

David Griggs' laboratory specializes in drug discovery and the translation of basic discoveries to therapeutic application. They perform assay development and optimization for high-throughput screening of compounds, assessment of target potency and selectivity for lead characterization, and in vitro and in vivo assessment of compound pharmacokinetics and metabolism (ADME). A major interest of his for many years, both at SLU and in prior research performed while working at global pharmaceutical companies (Searle/Pharmacia/Pfizer), has been the roles of integrins in physiology and disease. Griggs' lab has recently discovered and characterized new small molecule compounds which are making exciting progress toward development of an effective treatment to reduce or reverse the destructive organ fibrosis that occurs in many disease conditions. They are also currently applying their molecular, cellular, and pharmacology expertise in sponsored research programs to develop new medicines for treatment of tuberculosis, cryptosporidiosis, and bone disorders. His lab maintains diverse and productive collaborations with companies, foundations, and researchers at SLU and around the world, all of which aim to advance new and better treatments for patients.

Drug-development publications:

Henderson, N.C., T.D. Arnold, Y. Katamura, M.M. Giacomini, J.D. Rodriquez, J.H. McCarty, A. Pellicoro, A.C. Mackinnon, P.G. Ruminski, D.W. Griggs, M.J. Prinsen, J.J. Maher, J.P. Iredale, A. Lacy-hulbert, R.H. Adams, and D. Sheppard. 2013. Targeting av integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nature Medicine. 19:1617-1624
Meyers, M.J., M.D. Tortorella, J. Xu, L. Qin, Z. He, X. Lang, W. Zeng, W. Xu, L. Qin, M.J. Prinsen, F.M. Sverdrup, C.S. Eickhoff, D.W. Griggs, J. Oliva, P.G. Ruminski, E.J. Jacobsen, M.A. Campbell, D.C. Wood, D.E. Goldberg, X. Liu, Y. Chen, Z. Tu, X. Lu, K. Ding, and X. Chen. 2013. Evaluation of aminohydantoins as a novel class of antimalarial agents. 2014. ACS Med. Chem. Lett. 5:89-93.
Meyers, M.J., E.J. Anderson, S.A. McNitt, T.M. Krenning, M. Singh, J. Xu, W. Zeng, L. Qin, C.S.. Eickhoff, J. Oliva, M.A. Campbell, S.D. Arnett, M.J. Prinsen, D.W. Griggs, P.G. Ruminski, D.E. Goldberg, K. Ding, X. Liu, Z. Tu, M.D. Tortorella, F. M, Sverdrup, and X. Chen. Evaluation of spiropiperadine hydantoins as a novel class of antimalarial agents. 2015. Bioorg Med Chem 23:5144-5150.
Ulmasov, B., B.A. Neuschwander-Tetri, J. Lai, V. Monastyrskiy, T. Bhat, M. Yates, J. Oliva, M.J. Prinsen, P. Ruminski, D.W. Griggs. Targeted pharmacologic inhibition of RGD-binding integrins suppresses pancreatic fibrosis in mice. 2016. Cell Mol Gastroenterol Hepatol 2:499-518.
Griggs, D.W. M.J. Prinsen, J. Oliva, M.A. Campbell, S.D. Arnett, D. Tajfirouz, P.G. Ruminski, Y. Yu, B.R. Bond, Y. Ji, G. Neckermann, R.K.M Choy, E. de Hostos, M.J. Meyers. 2016. Pharmacologic comparison of clinical neutral endopeptidase inhibitors in a rat model of acute secretory diarrhea. J Pharmacol Exp Ther 367:423-431.
Murray, I.R., Z.N. Gonzalez, J. Baily, R. Dobie, R.J. Wallace, A.C. Mackinnon, J.R. Smith, S.N. Greenhaigh, A.I. Thompson, K.P. Conroy, D.W. Griggs, P.G. Ruminski, G.A. Gray, M. Singh, M.A. Campbell, T.J. Kendall, J. Dai, Y. Li, J.P Iredale, H. Simpson, J. Huard, B. Peault, N.C. Henderson. 2017. Alpha v integrins on mesenchymal cells critically regulate skeletal and cardiac muscle fibrosis. Nature Communications 8(1):1118.
Stebbins, E., R.S. Jumani, C. Klopfer, J. Barlow, P. Miller, M.A. Campbell, M.J. Meyers, D.W. Griggs, and C.D. Huston. 2018. Clinical and microbiologic efficacy of the piperazine-based drug lead MMV665917 in the dairy calf cryptosporidiosis model. PLOS Neglected Trop. Dis. In press.
Drug-development patent applications:

2013 Griggs DW, and Ruminski, P.G., Beta amino acid derivatives as integrin antagonists. Granted US patent 9085606.
2013 Griggs DW, and Ruminski, P. G., 3,5 phenyl-substituted beta amino acid derivatives as integrin antagonists. Granted US Patent 8716226.
2016 Griggs DW, and Ruminski, P.G., Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists. WO 2017117538. Pending.
2017 Griggs DW, and Ruminski, P.G., αVβ1 integrin antagonists. Provisional US patent 62/471,882. Pending.

Sergey Korolev
E.A. Doisy Department of Biochemistry and Molecular Biology

sergey.korolev@health.slu.edu

The Korolev lab studies mechanism of protein function using X-ray crystallography combined with biophysical and biochemical methods. They are deciphering an atomic resolution structures to understand mechanism of protein function under normal conditions, the effect of disease-related mutations and the mechanism of protein interactions with ligands, cofactors and inhibitors. They are developing high throughput inhibitor screening assays for DNA binding and peptide interacting proteins. Systems of interest include 1) recombination mediator proteins (RMPs) important for genome maintenance, DNA repair and implicated in cancer and other diseases; 2) DNA helicases involved in DNA replication and repair; 3) calcium-independent phospholipase critical for inflammation, calcium homeostasis and implicated in a wide spectrum of diseases from ischemia to neurodegeneration. They work closely with other members of the SLU-DDG, including John Tavis, Duane Grandgenett, and David Griggs.

Drug Development and Protein Ligand Interaction Publications:

  • Li, Y., Korolev, S. and Waksman, G., Crystal structure of open and closed forms of binary and ternary complexes of the large fragment of Thermus aquaticus DNA polymerase I: structural basis for nucleotide incorporation. EMBO J. 1998, 17:7514-7525. PMCID: PMC1171095
  • Li, Y., Kong. M., Korolev, S. and Waksman, G. Crystal structures of the Klenow Fragment of Thermus aquaticus DNA Polymerase I Complexed with Deoxyribonucleoside Triphosphates. Protein Science 1998, 7:1116-1123. PMCID: PMC2144016
  • Bhantgar, R.S., Futterer, K., Farazi, T.A., Korolev, S., Murray, C.L., Jackson-Machelski, E., Gokel, G.W., Gordon, J.I. and Waksman, G., Structure of N-myristoyltransferase with bound myristoylCoA and peptide substrate analogs. Nature Str. Biol. 1998, 5:1091-1097.
  • Lu, D., Futterer, K., Korolev, S., Zheng, X., Tan, K., Waksman, G., Sadler, J.E. Crystal structure of enteropeptidase light chain complexed with an analog of the trypsinogen activation peptide. J. Mol. Biol.1999, 292:361-73.
  • Korolev S, Ikeguchi Y, Skarina T, Beasley S, Arrowsmith C, Edwards A, Joachimiak A, Pegg AE, Li, Y., Savchenko A. The crystal structure of spermidine synthase with a multisubstrate adduct inhibitor. Nat. Struct. Biol. 2002, 9(1):27-31.
  • Pandey KK, Bera S, Korolev S, Campbell M, Yin Z, Aihara H, Grandgenett DP. (2014) Rous sarcoma virus synaptic complex capable of concerted integration is kinetically trapped by human immunodeficiency virus integrase strand transfer inhibitors. J. Biol. Chem. 2014; 289(28):19648-58.
  • Lu X, Malley KR, Brenner CC, Koroleva O, Korolev S*, Downes BP. A MUB E2 structure reveals E1 selectivity between cognate ubiquitin E2s in eukaryotes. Nat. Commun. 2016, 7:12580
    Malley K.R., Olga Koroleva O., Miller I., Sanishvili R., Jenkins C.M., Gross R.M. Korolev S. A novel dimeric active site and regulation mechanism revealed by the crystal structure of iPLA2β. BIORXIV/2017/196097

Drug-development patent applications:

  • Brian Downs, Sergey Korolev, Xiaolong Lu. “MUB Motif is an inhibitor of e2-ubiquitin thioester formation”. PATENT USTL.P0061US.P1
Nicola Pozzi
Biochemistry and Molecular Biology

nicola.pozzi@health.slu.edu

Pathological activation of the complement and clotting cascades leads to thrombosis and chronic inflammation, and is linked to the onset and progression of autoimmune disorders. In Nicola Pozzi's laboratory, they study the unknown biology of complement and clotting factors, investigate their structure-function relationships, identify new ligands and define their mechanisms of recognition. Finally, they engineer novel constructs with the desired functional properties to correct the disease state. To achieve their goals, they routinely express recombinant proteins from bacteria and mammalian cells for biophysical (single molecule fluorescence, DLS, analytical centrifugation, calorimetry) and structural analysis (X-ray crystallography and SAXS). They develop and perform kinetic and binding assays based on absorbance, fluorescence and luminescence spectroscopy, and surface plasmon resonance. The recent development of a novel family of anticoagulant fusion proteins to ameliorate the outcome of patients suffering from thrombosis in acute clinical settings such as sepsis and stroke is a representative example of their work.

Drug-development publications:

  • Barranco-Medina S, Murphy M, Pelc L, Chen Z, Di Cera E, Pozzi N. Rational Design of Protein C Activators. Sci Rep. 2017 Mar 15;7:44596.
  • Acquasaliente L, Peterle D, Tescari S, Pozzi N, Pengo V, De Filippis V. Molecular mapping of α-thrombin (αT)/β2-glycoprotein I (β2GpI) interaction reveals how β2GpI affects αT functions. Biochem J. 2016 Dec 15;473(24):4629-4650.
  • Pozzi N, Bystranowska D, Zuo X, Di Cera E. Structural Architecture of Prothrombin in Solution Revealed by Single Molecule Spectroscopy. J Biol Chem. 2016 Aug 26;291(35):18107-16.
  • Pozzi N, Zerbetto M, Acquasaliente L, Tescari S, Frezzato D, Polimeno A, Gohara DW, Di Cera E, De Filippis V. Loop Electrostatics Asymmetry Modulates the Preexisting Conformational Equilibrium in Thrombin. Biochemistry. 2016 Jul 19;55(28):3984-94.
  • Wood DC, Pelc LA, Pozzi N, Wallisch M, Verbout NG, Tucker EI, Gruber A, Di Cera E. WEDGE: an anticoagulant thrombin mutant produced by autoactivation. J Thromb Haemost. 2015 Jan;13(1):111-4.
  • Pozzi N, Chen Z, Zapata F, Niu W, Barranco-Medina S, Pelc LA, Di Cera E. Autoactivation of thrombin precursors. J Biol Chem. 2013 Apr 19;288(16):11601-10.
  • Banzato A, Pozzi N, Frasson R, De Filippis V, Ruffatti A, Bison E, Padayattil SJ, Denas G, Pengo V. Antibodies to Domain I of β(2)Glycoprotein I are in close relation to patients risk categories in Antiphospholipid Syndrome (APS). Thromb Res. 2011 Dec;128(6):583-6.
  • Pozzi N, Banzato A, Bettin S, Bison E, Pengo V, De Filippis V. Chemical synthesis and characterization of wild-type and biotinylated N-terminal domain 1-64 of beta2-glycoprotein I. Protein Sci. 2010 May;19(5):1065-78.

Drug-development patent applications:

  • 2011 Di Cera E., Gruber A., Gandhi P., Pelc L., Pozzi N., Wood D.C. Expression of thrombin variants. US8940297B2. Granted
  • 2012 Pozzi N., Di Cera E., Barranco-Medina S. Recombinant auto-activating protease precursors. US15004280. Pending.
  • 2017 Barranco-Medina S., Di Cera E., Pozzi N. WO2017189943A1. Thrombin-thrombomodulin fusion proteins as a powerful anticoagulant. Application
  • 2017 Barranco-Medina S., Di Cera E., Pozzi N. WO2016176440A9. Thrombin-thrombomodulin fusion
David C. Wood
Biochemistry and Molecular Biology
Director, SLU Protein Core Facility
david.wood@health.slu.edu
 
The Protein Core Facility provides protein production and analytical services to the University and regional research community. The laboratory carries out recombinant protein production, purification, and analysis to produce high quality reagents for inhibitor screening and structural biology. They also carry out purification process development for protein and peptide biotherapeutic candidates. For proteomics analyses, they employ one and two-dimensional electrophoresis and MALDI-QIT-TOF mass spectrometry for protein identification and characterization.
 

Drug-development publications:

  • Wood DC, Pelc LA, Pozzi N, Wallisch M, Verbout NG, Tucker EI, Gruber A, Di Cera E (2015) WEDGE: An anticoagulant thrombin mutant produced by autoactivation, Journal of Thrombosis and Haemostasis 13, 111-114.
  • Marvin J. Meyers, * Micky D. Tortorella, Jing Xu, Limei Qin, Zhengxiang He, Xingfen Lang, Wentian Zeng,Wanwan Xu, Li Qin, Michael J. Prinsen, Francis M. Sverdrup, Christopher S. Eickhoff, David W. Griggs, Jonathan Oliva, Peter G. Ruminski, E. Jon Jacobsen, Mary A. Campbell, David C. Wood, Daniel E.Goldberg, Xiaorong Liu, Yongzhi Lu, Xin Lu, Zhengchao Tu, Xiaoyun Lu, Ke Ding, and Xiaoping Chen (2013) Evaluation of aminohydantoins as a novel class of antimalarial agents, ACS Med Chem Lett. Dec 6;5(1):89-93. doi: 10.1021/ml400412x.
  • Mileni M, Kamtekar S, Wood DC, Benson, TE, Cravatt BF, and Stevens RC, (2010) Crystal structure of fatty acid amide hydrolase bound to the carbamate inhibitor URB597: discovery of a deacylating water molecule and insight into enyzyme inactivation, Journal of Molecular Biology 400, 743-54.
  • Wood, David C.; Mathis, Karl J.; Joy, William D.; Minnerly, John C.; Pegg, Lyle E.; Welply, Joseph K. (2003), Mammalian Cell Production and Purification of Progenipoietin, a Dual-agonist Chimaeric Haematopoietic Growth Factor, Biotechnology and Applied Biochemistry 37, 31-38.
Brent M. Znosko
Chemistry
brent.znosko@slu.edu
 

Research in the Znosko laboratory focuses on the thermodynamics and structural features of RNA motifs. While sequences of many important RNAs have been determined, little is known about structure-function relationships of RNA. One reason for this lack of information is that there is little definitive secondary and tertiary structural information about RNA. X-ray crystallography and NMR methods are providing an increasing number of RNA structures, but it is unlikely that these methods will keep pace with the rate at which interesting sequences are being discovered. Thus, there is a need for reliable, rapid methods to predict secondary and tertiary structures of RNA. Being able to predict secondary and tertiary structures of RNA provides a foundation for determining structure-function relationships for RNA and for targeting RNA with therapeutics. thereforee, one broad, long-term objective of the laboratory is to improve RNA secondary and tertiary structure prediction from sequence.

Nucleic acids are attractive target molecules for therapeutics as they direct replication, transcription, and translation. The ability to rationally design drugs that target nucleic acids, thereforee, is important in developing pharmaceuticals to combat cancer, tumor growth, etc. Naphthalimides are DNA intercalating agents that are useful as therapeutic agents due to their conjugated pi system and ability for moiety attachment. Due to the success of the originally studied 1,8-naphthalimides, different analogues continue to be investigated for therapeutic activity. With the ongoing study of naphthalimide intercalators and their derivatives, there is still a need to understand these molecules and their ability to interact with DNA. While most studies focus on developing new intercalating compounds, few studies focus on the effects of small changes to a core intercalator structure. Also, most studies of naphthalimide derivatives use either calf thymus or salmon testes DNA as the target nucleic acid. By using such large DNA, it is difficult to understand DNA-intercalator interactions that are a result of the specific DNA sequence. Our team has recognized the need to understand intercalator interactions with short oligonucleotides. To evaluate the interactions important in DNA-intercalator complexes, they are performing systematic studies with mono- and di-substituted naphthalimides. The results of this work will provide a framework for more detailed studies of other known intercalators, as well as aid in the rational design of novel intercalators that may serve as therapeutic agents.

Structural biology and drug-development publications:

  • Jolley, E. A. and Znosko, B. M. (2017) “The loss of a hydrogen bond: Thermodynamic contributions of a non-standard nucleotide,” Nucleic Acids Res. 45, 1479-1487.
  • Richardson, K. E. and Znosko, B. M. (2016) “Nearest-neighbor parameters for 7-deaza-adenosine·uridine base pairs in RNA duplexes,” RNA 22, 934-942.
  • Liu, B., Childs-Disney, J. L., Znosko, B. M., Wang, D., Fallahi, M., Gallo, S. M., and Disney, M. D. (2016) “Analysis of secondary structural elements in human microRNA hairpin precursors,” BMC Bioinformatics 17, 112.
  • Jolley, E. A., Lewis, M., and Znosko, B. M. (2015) “A computational model for predicting experimental RNA nearest-neighbor free energy rankings: Inosine-uridine pairs,” Chem. Phys. Lett. 639, 157-160.
  • Tomcho, J. C., Tillman, M. R., and Znosko, B. M. (2015) “Improved model for predicting the free energy contribution of dinucleotide bulges to RNA duplex stability,” Biochemistry 54, 5290-5296.
  • Johnson, C. A., Hudson, G. A., Hardebeck, L. K. E., Jolley, E. A., Ren, Y., Lewis, M., and Znosko, B. M. (2015) “Effect of intercalator substituent and nucleotide sequence on the stability of DNA- and RNA-naphthalimide complexes,” Bioorg. Med. Chem. 23, 3586-3591.
  • Murray, M. H., Hard, J. A., and Znosko, B. M. (2014) "Improved model to predict the free energy contribution of trinucleotide bulges to RNA duplex stability," Biochemistry 53, 3502-3508.
  • Hardebeck, L. K. E., Johnson, C. A., Hudson, G. A., Ren, Y., Watt, M., Kirkpatrick, C. C., Znosko, B. M., and Lewis M. (2013) Predicting DNA-intercalator binding: The development of an arene-arene stacking parameter from SAPT analysis of benzene-substituted benzene complexes, J. Phys. Org. Chem. 26, 879-884.
  • Hudson, G. A., Bloomingdale, R. J., and Znosko, B. M. (2013) Thermodynamic contribution and nearest neighbor parameters of pseudouridine-adenosine base pairs in oligoribonucleotides, RNA 19, 1474-1482.
  • Chen, Z. and Znosko, B. M. (2013) Effect of sodium ions on RNA duplex stability, Biochemistry 52, 7477-7485.
  • Grohman, J. K., Gorelick, R. J., Lickwar, C. R., Lieb, J. D., Bower, B. D., Znosko, B. M., and Weeks, K. M. (2013) A guanosine-centric mechanism for RNA chaperone function, Science 340, 190-195.
  • Johnson, C. A., Bloomingdale, R. J., Ponnusamy, V. E., Tillinghast, C. A., Znosko, B. M., and Lewis, M. (2012) Reply to “Comment on “Computational model for predicting experimental RNA and DNA nearest-neighbor free energy rankings,’” J. Phys. Chem. B 116, 8333-8334.
    Hausmann, N. Z. and Znosko, B. M. (2012) Thermodynamic characterization of RNA 2x3 nucleotide internal loops, Biochemistry 51, 5359-5368.
  • Vanegas, P. L., Horwitz, T. S., and Znosko, B. M. (2012) Effects of non-nearest neighbors on the thermodynamic stability of RNA GNRA hairpin tetraloops, Biochemistry 51, 2192-2198.
  • Levengood, J. D., Rollins, C., Mishler, C. H., Johnson, C. A., Miner, G., Rajan, P., Znosko, B. M., and Tolbert, B. S. (2012) Solution structure of the HIV-1 exon splicing silencer 3, J. Mol. Biol. 415, 680-698.
  • Vanegas, P. L., Hudson, G. A., Davis, A. R., Kelly, S. C., Kirkpatrick, C. C., and Znosko, B. M. (2012) RNA CoSSMos: Characterization of secondary structure motifs - A searchable database of secondary structure motifs in RNA three-dimensional structures, Nucleic Acids Res. 40, D439-D444.
  • Johnson, C. A., Bloomingdale, R. J., Ponnusamy, V. E., Tillinghast, C. A., Znosko, B. M., and Lewis, M. (2011) Computational model for predicting experimental RNA and DNA nearest-neighbor free energy rankings, J. Phys. Chem. B 115, 9244-9251.
  • Davis, A. R., Kirkpatrick, C. C., and Znosko, B. M. (2011) Structural characterization of naturally occurring RNA single mismatches, Nucleic Acids Res. 39, 1081-1094.
  • Thulasi, P., Pandya, L. K., and Znosko, B. M. (2010) Thermodynamic characterization of RNA triloops, Biochemistry 49, 9058-9062.
  • Davis, A. R. and Znosko, B. M. (2010) Positional and neighboring base pair effects on the thermodynamic stability of RNA single mismatches, Biochemistry 49, 8669-8679.
  • Sheehy, J. P., Davis, A. R., and Znosko, B. M. (2010) Thermodynamic characterization of naturally occurring RNA tetraloops, RNA 16, 417-429.
  • Christiansen, M. E. and Znosko, B. M. (2009) Thermodynamic characterization of tandem mismatches in naturally occurring RNA, Nucleic Acids Res. 37, 4696-4706.
  • Davis, A. R. and Znosko, B. M. (2008) Thermodynamic characterization of naturally occurring RNA single mismatches with G-U nearest neighbors, Biochemistry 47, 10178-10187.
  • Christiansen, M. E. and Znosko, B. M. (2008) Thermodynamic characterization of the complete set of sequence symmetric tandem mismatches in RNA and an improved model for predicting the free energy contribution of sequence asymmetric tandem mismatches, Biochemistry 47, 4329-4336.
  • Badhwar, J., Karri, S., Cass, C. K., Wunderlich, E. L., and Znosko, B. M. (2007) Thermodynamic characterization of RNA duplexes containing naturally occurring 1x2 nucleotide internal loops, Biochemistry 46, 14715-14724.
  • Davis, A. R. and Znosko, B. M. (2007) Thermodynamic characterization of single mismatches found in naturally occurring RNA, Biochemistry 46, 13425-13436.
  • Wright, D. J., Rice, J. L., Yanker, D. M., and Znosko, B. M. (2007) Nearest neighbor parameters for inosine-uridine pairs in RNA duplexes, Biochemistry 46, 4625-4634.
  • Chen, G., Znosko, B. M., Kennedy, S. D., Krugh, T. R., and Turner, D. H. (2005) Solution structure of an RNA internal loop with three consecutive sheared GA pairs, Biochemistry 44, 2845-2856.
  • Znosko, B. M., Kennedy, S. D., Wille, P. C., Krugh, T. R., and Turner, D. H. (2004) Structural features and thermodynamics of the J4/5 loop from the Candida albicans and Candida dubliniensis group I introns, Biochemistry 43, 15822-15837.
  • Chen, G., Znosko, B. M., Jiao, X., and Turner, D. H. (2004) Factors affecting thermodynamic stabilities of RNA 3x3 internal loops, Biochemistry 43, 12865-12876.
  • Znosko, B. M., Barnes T. W., Krugh T. R., and Turner, D. H. NMR studies of DNA single strands and DNA:RNA hybrids with and without 1-propynylation at C5 of oligopyrimidines. (2003) J. Am. Chem. Soc. 125, 6090-6097.
  • Znosko, B. M., Burkard, M. E., Krugh, T. R., and Turner, D. H. (2002) Molecular recognition in purine-rich internal loops: Thermodynamic, structural, and dynamic consequences of purine for adenine substitutions in 5’(rGGCAAGCCU)2, Biochemistry 41, 14978-14987.
  • Znosko, B. M., Burkard, M. E., Schroeder, S. J., Krugh, T. R., and Turner, D. H. (2002) Sheared Aanti×Aanti base pairs in a destabilizing 2x2 internal loop: The NMR structure of 5’(rGGCAAGCCU)2, Biochemistry 41, 14969-14977.
  • Znosko, B. M., Silvestri, S. B., Volkman, H., Boswell, B., and Serra, M. J. (2002) Thermodynamic parameters for an expanded nearest-neighbor model for the formation of RNA duplexes with single nucleotide bulges, Biochemistry 41, 10406-10417
Silviya Petrova Zustiak

Biomedical Engineering
silviya.zustiak@slu.edu

Zustiak’s laboratory focuses on hydrogel biomaterials and soft tissue engineering, with emphasis on developing novel biomaterials as cell scaffolds, drug screening platforms and protein delivery devices.

A major challenge of tissue engineering is to build three-dimensional (3D) in vitro models for studying tissue physiology and pathology. 3D in vitro models are the bridge between conventional two-dimensional (2D) tissue culture, which does not capture the complexity of human tissue, and animal models, which are costly, time-consuming and raise ethical concerns. One area in which 3D models are underrepresented but where they can have an immediate impact is the development of platforms for toxicology screening. Such in vitro models have the potential to address the growing concerns of drug failures in clinical trials due to lack of efficacy or unexpected side effects. Further, they can play a role in preventive medicine by answering the urgent need for efficient platforms enabling the screening of the plethora of environmental hazards linked to incidences of diseases such as cancer. Zustiak applies her expertise in the design and characterization of synthetic biomaterials, to provide a complete toolbox for building 3D in vitro models as platforms for toxicology screening and for the study of disease progression. Her current focus is on solid tumors in soft tissues.

Zustiak’s laboratory also develops injectable and biodegradable hydrogel formulations for sustained localized protein release. These technologies enable novel and effective protein-based therapeutic strategies by: i) providing sustained protein release and hence increased protein residence time in vivo, ii) preserving the proteins’ bioactivity prior to release, iii) decreasing protein immunogenicity, and iv) localizing protein release to reduce protein dosage needed for a therapeutic effect and reduce systemic side effects.

Drug-development publications:

  • E. Jain, S. Sheth, A. Dunn, *S. P. Zustiak, *S. Sell, “Sustained release of multicomponent platelet-rich plasma proteins from hydrolytically degradable PEG hydrogels”, Journal of Biomedical Materials Research: Part A, In Press; (IF: 3.076)
  • S. Sheth, E. Jain, K. Polito, *S. Sell, *S. P. Zustiak, “Storage stability of biodegradable polyethylene glycol microspheres”, Materials Research Express, In Press; (IF: 1.068)
  • A. S. Qayyum, E. Jain, G. Kolar, Y. Kim, S. Sell, *S. P. Zustiak, “Design of electrohydrodynamic sprayed polyethylene glycol hydrogel miscrospheres for cell encapsulation”, Biofabrication, 2017, 9(2), 025019; (IF: 5.240)
  • E. Jain, L. Hill, E. Canning, *S. Sell, *S. P. Zustiak, “Control of gelation, degradation and physical properties of polyethylene glycol hydrogels through the chemical and physical identity of the crosslinker”, Journal of Materials Chemistry B, 2017, 5, 2679-2691; (IF: 4.543)
  • F. Ordikhani, S. Sheth, *S. P. Zustiak, “Polymeric particle-mediated therapies to treat spinal cord injury”, International Journal of Pharmaceutics, 2017, 516(1-2), 71-81; (IF: 3.649)
  • F. Ordikhani, *S. P. Zustiak, *A. Simchi, “Surface modifications of titanium implants by multilayer bioactive coatings with drug delivery potential: antimicrobial, biological, and drug release studies”, Journal of the Minerals, Metals, and Materials Society (JOMJ), 2016, 68(4), 1100-1108; (IF: 1.860)
  • S. P. Zustiak, C. Medina, S. Dadhwal, S. Steczina, Y. Chehreghanianzabi, A. Ashraf, P. Asuri, “Three-dimensional matrix stiffness and adhesive ligands affect cancer cell response to toxins”, Biotechnology & Bioengineering, 2016, 113(2), 443-452; (IF: 4.481)
  • E. Jain, K. Scott, *S. P. Zustiak, *S. Sell, “Fabrication of polyethylene glycol-based hydrogel microspheres through electrospraying”, Macromolecular Materials and Engineering, 2015, 300(8), 823-835; (IF: 2.834)
  • *S. P. Zustiak, “The role of matrix compliance on cell responses to drugs and toxins: towards predictive drug screening platforms”, Macromolecular Bioscience, 2015, 15(5), 589-599; (IF: 3.850)
  • *S. P. Zustiak, R. Nossal, D. Sackett, “Multiwell stiffness assay for the study of cell responsiveness to cytotoxic drugs”, Biotechnology & Bioengineering, 2014, 111(2), 396-403; (IF:4.481)
  • S. P. Zustiak, *J. B. Leach, “Characterization of Protein Release from Hydrolytically Degradable Poly(ethylene glycol) Hydrogels”, Biotechnology & Bioengineering, 2011, 108, 197-206; (IF: 4.481)
  • S. P. Zustiak, *J. B. Leach, “Hydrolytically Degradable Poly(ethylene glycol) Hydrogel Scaffolds with Tunable Degradation and Mechanical Properties”, Biomacromolecules, 2010, 11, 1348-1357; (IF: 5.246)

Drug-development patent applications:

  • Provisional patent: A. Montano, E. Jain, S. P. Zustiak, “Delivering enzyme using an injectable hydrogel depot”, U.S. Patent Application Serial No. 62/580,699; SLU Ref No: 17-008, November 2017
  • Provisional patent: E. Jain, *S. P. Zustiak, *S. A. Sell, “Fabrication of hydrogel microsphere delivery vehicles through electrospraying and timed gelation”, U.S. Patent Application Serial No. 62/136,089; SLU Ref No: 14-013, March 2015