Steven E. Patterson, PhD

Expertise

Anti-microbial drugs, cancer therapy, antiviral therapy, cyanide antidotes

Research Summary

Anti-microbial Drugs

Over the years, bacteria, fungi and protozoa have increasingly developed resistance to traditional antibiotics. In particular fungi and protozoa are recognized as emerging problems; in the past 25 years the number of life threatening infections caused by these organisms due to their resistance to traditional drugs has been growing with reports that metronidazole has a 40% failure rate in treatment of giardiasis. Research on new medicines to fight these infections is a focus of our labs. In collaboration with Sid Das we are targeting enzymes in these organisms that synthesize necessary components of their cell walls. The cell wall is an attractive target since it is required by the pathogens for growth, but has no counterpart in humans and other mammals.

Cancer Therapy

The simplest description of cancer is uncontrolled cell growth. In collaboration with Lee Wattenberg, Kris Pankiewicz and Dan Billadeau our lab is interested in stopping growth of tumors by causing tumor cells to differentiate or by interfering with cell signaling pathways involved with cell growth. This based on the concept that cancer cells are normal cells that are trapped in an immature (or less differentiated) state, where they lack the ability to control their own growth. We have designed and synthesized a class of molecules that causes differentiation of many types of cancer cells. This does not destroy the cancer cells, but instead causes them to mature into cells that can regulate their own growth. This approach is less toxic than conventional chemotherapy, which attempts to kill the cells completely.

Antiviral Therapy

In collaboration with Lou Mansky we are investigating the effect of novel combination therapy and its potential for clinical use as treatment for viral infections such as HIV and Hepatitis.

Cyanide Antidotes

Cyanide is a well known toxin with potential as an international threat, a weapon of mass destruction and an accidental hazard through industrial exposure, medical crisis or smoke inhalation. Current treatments for cyanide poisoning are slow acting and can have serious life threatening side effects. In collaboration with Herb Nagasawa and Bob Vince we are developing a series of andidotes that use a ubiquitous enzyme that converts cyanide to a non-toxic substance. We have shown that our antidotes are more effective than the current treatments. In addition, our treatments work prophylactically. Currently we are working to expand our series of antidotes, to improve their efficacy in reversing cyanide toxicity, and to move these potential treatments into clinical trials.

Synthetic Methods

Because many drug design projects involve molecules known as nucleosides, nucleotides, and carbohydrates, our group is interested in finding improved ways to make these molecules.

• Characterization of Permeability, Stability, and Anti-HIV-1 Activity of Decitabine and Gemcitabine Divalerate Prodrugs. Clouser CL, Bonnac L, Mansky LM, and Patterson SE. Antivir Chem Chemother. 2014;23(6):223-30. Abstract
• Discovery of novel ribonucleoside analogues with activity against human immunodeficiency virus type-1. Dapp MJ, Bonnac L, Patterson SE, Mansky LM. J Virol. 2014;88:356-63. Abstract
• Determination of 3-mercaptopyruvate in rabbit plasma by high performance liquid chromatography tandem mass spectrometry Stuttleberg MW, Vinnakota CV, Mitchell BL, Monteil AR, Patterson SE, and Logue BA. J Chromatog B. 2014;949-950:94-8. Abstract
• Novel inhibitors of human immunodeficiency virus type 2 infectivity. Beach LB, Rawson JM, Kim B, Patterson SE, Mansky LM. J Gen Virol. 2014;95(12):2778-83. Abstract
• Noninvasive optical cytochrome c oxidase redox state measurements using diffuse optical spectroscopy Lee J, Kim JG, Mahon SB, Mukai D, Yoon D, Boss GR, Patterson SE, Rockwood G, Isom G, Brenner M. J Biomed Opt. 2014;19(5):055001, doi: 10.1117/1.JBO.19.5.055001. Abstract
• 5,6-Dihydro-5-aza-2'-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors. Rawson JM, Heineman RH, Beach LB, Martin JL, Schnettler EK, Dapp MJ, Patterson SE, and Mansky LM. Bioorg Med Chem. 2013;21:7222-8. Abstract
• Polyoxin and nikkomycin analogs: recent design and synthesis of novel peptidyl nucleosides. Jackson KE, Pogula PK, and Patterson SE. Heterocycl Lett. 2013;19:375-86. Abstract
• Determination of 3-mercaptopyruvate in plasma by high performance liquid chromatography tandem mass spectrometry. Stutelberg MW, Vinnakota, CV Mitchell BL, Monteil AR, Patterson SE, and Logue BA. J. Chromatog. B (in press).
• Characterization of permeability, stability and anti-HIV-1 activity of decitabine and gemcitabine divalerate prodrugs. Clouser CL, Bonnac L, Mansky LM, Patterson SE. Antivir. Chem. Chemother. 2013; doi: 10.3851/IMP2682. [Epub ahead of print] Abstract

• Structure-Activity Relationships and Design of Viral Mutagens and Application to Lethal Mutagenesis. Bonnac LF, Mansky LM, Patterson SE. J. Med. Chem. 2013 Aug 5;Ahead of Print; doi: 10.1021/jm400653j. Abstract
• Cyanide Antidotes for Mass Casualties: Water-Soluble Salts of the Dithiane (Sulfanegen) from 3-Mercaptopyruvate for Intramuscular Administration. Patterson SE, Monteil AR, Cohen JF, Crankshaw DL, Vince R, Nagasawa, HT. J. Med. Chem. 2013;56:1346-49. Abstract
• Seasonal pasture myopathy/atypical myopathy in North America associated with ingestion of hypoglycin A within seeds of the box elder tree. Valberg SJ, Sponseller BT, Hegeman AD, Earing J, Bender JB, Martinson KL, Patterson SE, Sweetman L. Equine Vet. J. 2013;45(4):419-26. Abstract
• Back to the future: revisiting HIV-1 lethal mutagenesis. Dapp MJ, Patterson SE, Mansky LM. Trends Microbiol. 2013;21(2):56-62. Abstract
• IP-FCM measures physiologic protein-protein interactions modulated by signal transduction and small-molecule drug inhibition. Smith SEP, Bida AT, Davis TR, Sicotte H, Patterson, SE, Gil D, Schrum AG. PLoS One. 2012 Sep;7(9):e45722. Abstract
• Anti-HIV-1 activity of resveratrol derivatives and synergistic inhibition of HIV-1 by the combination of resveratrol and decitabine. Clouser CL, Chauhan J, Bess MA, Oploo, JL, Zhou D, Dimick-Gray S, Mansky, LM, Patterson SE. Bioorg. Med. Chem. Lett. 2012 Nov 1;22(21):6642-6646. Abstract
• Cyanide Toxicity in Juvenile Pigs and Its Reversal by a New Prodrug, Sulfanegen Sodium. Belani KG, Singh H, Beebe DS, George P, Patterson SE, Nagasawa HT, Vince R. Anesth Analg. 2012 Mar;114(5): 956-61. Abstract
• Activity of a Novel Combined Antiretroviral Therapy of Gemcitabine and Decitabine in a Mouse Model for HIV-1. Clouser CL, Holtz CM, Mullett M, Crankshaw DL, Briggs JE, O'Sullivan MG, Patterson SE, Mansky LM. Antimicrob. Agents Chemother. 2012 Apr;56(4):1942-8. Abstract
• Discovery of drugs that possess activity against feline leukemia virus. Greggs WM 3rd, Clouser CL, Patterson SE, Mansky LM. J Gen Virol. 2012 Apr;93(Pt 4):900-5.
• The combination of cobinamide and sulfanegen is highly effective in mouse models of cyanide poisoning. Chan A, Crankshaw DL, Monteil A, Patterson SE, Nagasawa HT, Briggs JE, Kozocas JA, Mahon SB, Brenner M, Pilz RB, Bigby TD, Boss GR. Clin Toxicol (Phila). 2011 Jun;49(5):366-73. Abstract
• Broadening the use of antiretroviral therapy: the case for feline leukemia virus. Greggs WM 3rd, Clouser CL, Patterson SE, Mansky LM. Ther Clin Risk Manag. 2011;7:115-22.
• Analysis of the ex vivo and in vivo antiretroviral activity of gemcitabine. Clouser CL, Holtz CM, Mullett M, Crankshaw DL, Briggs JE, Chauhan J, VanHoutan IM, Patterson SE, Mansky LM. PLoS One 2011 Abstract
• Phosphonoxins III: synthesis of ?-aminophosphonate analogs of antifungal polyoxins with anti-Giardia activity. Staake M, Chauhan J, Zhou D, Shanker A, De Chatterjee A, Das S, Patterson SE. Org Lett. 2010 Oct 15;12(20):4596-9. Abstract
• Sulfanegen sodium treatment in a rabbit model of sub-lethal cyanide toxicity. Brenner M, Kim JG, Lee J, Mahon SB, Lemor D, Ahdout R, Boss GR, Blackledge W, Jann L, Nagasawa HT, Patterson SE. Toxicol Appl Pharmacol. 2010 Nov 1;248(3):269-76. Abstract
• Exploiting drug repositioning for discovery of a novel HIV combination therapy. Clouser CL, Patterson SE, Mansky LM. J Virol. 2010 Sep;84(18):9301-9. Abstract
• Phosphonoxins II: diastereoselective synthesis of phosphonic acid analogues of polyoxins. Zhou D, Staake M, Patterson SE. Org Lett. 2008; 10, 2179-82 Abstract
• Efficient synthesis of benzamide riboside, a potential anticancer agent. Bonnac LF, Gao GY, Chen L, Patterson SE, Jayaram HN, Pankiewicz KW. Nucleosides Nucleotides Nucleic Acids 2007; 26(10-12): 1249-53. Abstract
• Novel, orally effective cyanide antidotes. Nagasawa HT, Goon DJ, Crankshaw DL, Vince R, Patterson SE. J Med Chem. 2007;50(26):6462-4. Abstract
• A novel paradigm for assessing efficacies of potential antidotes against neurotoxins in mice. Crankshaw DL, Goon DJ, Briggs JE, DeLong D, Kuskowski M, Patterson SE, Nagasawa HT. Toxicol Lett. 2007;175(1-3):111-7. Abstract
• Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues. Chen L, Gao G, Felczak K, Bonnac L, Patterson SE, Wilson D, Bennett EM, Jayaram HN, Hedstrom L, Pankiewicz KW. J Med Chem. 2007;50(23):5743-51. Abstract
• Phosphonoxins: rational design and discovery of a potent nucleotide anti-Giardia agent. Suk DH, Rejman D, Dykstra CC, Pohl R, Pankiewicz KW, Patterson SE. Bioorg. Med. Chem. Lett. 2007, 17(10): 2811-16. Abstract
• Rational Design and Synthesis of Novel Nucleotide Anti-Giardia agents. Suk DH, Bonnac L., Dykstra CC, Pankiewicz KW, Patterson SE. Bioorg. Med. Chem. Lett. 2007, 17(10): 2811-16. Abstract
• Probing binding requirements of NAD kinase with modified substrate (NAD) analogues. Bonnac L, Chen L, Pathak R, Gao G, Ming Q, Bennett EM, Felczak K, Kullberg M, Patterson SE, Mazzola F, Magnia G, Pankiewicz KW. Bioorg Med Chem Lett 2007 6(15): 1512-15. Abstract
• Fujita-Ban QSAR analysis and CoMFA study of quinoline antagonists of immunostimulatory CpG-oligodeoxynucleotides. Paliakov E, Henary M, Say M, Patterson SE, Parker A, Manzel L, Macfarlane DE, Bojarski AJ, Strekowski L. Bioorg Med Chem Lett 2007, 15: 324-332. Abstract
• Novel Methylenephosphophosphonate Analogues of Mycophenolic Adenine Dinucleotide. Inhibition of Inosine Monophosphate Dehydrogenase. Rejman D, Olesiak M, Chen L, Patterson SE, Wilson D, Jayaram HN, Hedstrom L, Pankiewicz KW. J Med Chem 49, 5018-5022 (2006). Abstract
• Synthesis of N3,5'-cyclo-4-(beta-D-ribofuranosyl)-vic-triazolo[4,5-b]pyridin-5-one and its 3'-deoxysugar analogue as potential anti-hepatitis C virus agents. Wang, P.; Hollecker, L.; Pankiewicz, K. W.; Patterson, S. E.; Whitaker, T.; McBrayer, T. R.; Tharnish, P. M.; Stuyver, L. J.; Schinazi, R. F.; Otto, M. J.; Watanabe, K. A. Nucleosides Nucleotides Nucleic Acids 24, 957-960 (2005). Abstract
• Synthesis and in vitro anti-hcv activity of beta-D- and 1-2'-deoxy-2'-fluororibonucleosides. Shi, J.; Du, J.; Ma, T.; Pankiewicz, K. W.; Patterson, S. E.; Hassan, A. E.; Tharnish, P. M.; McBrayer, T. R.; Lostia, S.; Stuyver, L. J.; Watanabe, K. A.; Chu, C. K.; Schinazi, R. F.; Otto, M. J. Nucleosides Nucleotides Nucleic Acids 24, 875-879 (2005). Abstract
• Synthesis and anti-viral activity of a series of D- and L-2'-deoxy-2'-fluororibonucleosides in the subgenomic HCV replicon system. Shi, J.; Du, J.; Ma, T.; Pankiewicz, K. W.; Patterson, S. E.; Tharnish, P. M.; McBrayer, T. R.; Stuyver, L. J.; Otto, M. J.; Chu, C. K.; Schinazi, R. F.; Watanabe, K. A. Bioorg Med Chem. 13, 1641-1652 (2005). Abstract
• Design, synthesis, and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. Clark, J. L.; Hollecker, L.; Mason, J. C.; Stuyver, L. J.; Tharnish, P. M.; Lostia, S.; McBrayer, T. R.; Schinazi, R. F.; Watanabe, K. A.; Otto, M. J.; Furman, P. A.; Stec, W. J.; Patterson, S. E.; Pankiewicz, K. W. J Med Chem 48, 5504-5508 (2005). Abstract
• Synthesis of N3,5'-cyclo-4-(beta-D-ribofuranosyl)-vic-triazolo[4,5-b]pyridin-5-one, a novel compound with anti-hepatitis C virus activity. Peiyuan Wang, Laurent Hollecker, Krzysztof W. Pankiewicz, Steven E. Patterson, Tony Whitaker, Tamara R. McBrayer, Phillip M. Tharnish, Robert W. Sidwell, Lieven J. Stuyver, Michael J. Otto, Raymond F. Schinazi, and Kyoichi A. Watanabe, J .Med. Chem. 47(24), 6100-3 (2004). Abstract
• Synthesis of 5'-C-methyl-1',3'-dioxolan-4'-yl nucleosides. Jinfa Du, Steven Patterson, Junxing Shi, Byoung-Kwon Chun, Lieven J. Stuyver and Kyoichi A. Watanabe. Bioorg. Med. Chem. Lett. 14(5), 1243-5 (2004). Abstract
• Cofactor mimics as selective inhibitors of NAD-dependent inosine monophosphate dehydrogenase (IMPDH)--the major therapeutic target. Krzysztof W. Pankiewicz, Steven E. Patterson, Paul L. Black, Hiremagalur N. Jarayam, Dipesh Risal, Barry M. Goldstein, Lieven J. Stuyver, and Raymond F. Schinazi. Curr. Med. Chem. 11(7), 887-900 (2004). Abstract
• The mechanism of action and antileukemic activity of bis(phosphonate) analogue of mycophenolic adenine dinucleotide (C2-MAD); An alternative for tiazofurin. Patterson SE, Black PL, Clark JL, Risal D, Goldstein BM, Jayaram HN, Schinazi, RF, Pankiewicz KW. Developments in Nucleic Acids, Schinazi RF, Liotta D. eds. Elsevier (2004).
• The reaction of alcohols and nucleosides with methylenebis(phosphonic acid dichloride): Facile synthesis of methylenebis-(phosphonic acid) monoesters. Patterson SE, Clark JL, Mason JC, Pankiewicz KW. Developments in Nucleic Acids, Schinazi RF, Liotta D. eds. Elsevier (2004).
• Triple-helix DNA selective 2-(2-naphthyl)quinoline intercalators. Strekowski L, Parker AN, Hojjat M, Say M, Zegrocka-Stendel O, Patterson SE, Tanious FA, Wilson WD. Acta Pol Pharm. 61 Suppl: 70-72 (2004). Abstract
• Cofactor analogues as inhibitors of IMP dehydrogenase; design and new synthetic approaches. Inosine Monophosphate Dehydrogenase A Major Therapeutic Target Pankiewicz KW, Patterson SE, Jayaram, HN, Goldstein BM. Pankiewicz KW, Goldstein BM Eds., ACS Symposium Series No. 839, 2003, p.247-282.
• Inhibitors of the IMPDH enzyme as potential anti-bovine viral diarrhea virus agents. Lieven J. Stuyver, Stefania Lostia, Steven E. Patterson, Jeremy L. Clark, Kyoichi A. Watanabe, Michael J. Otto, and Krzysztof W. Pankiewicz. Antivir. Chem. Chemother. 13(6), 345-52 (2002). Abstract
• Cytotoxicity and cellular differentiation activity of methylenebis(phosphonate) analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer cell lines. Joel A. Yalowitz, Krzysztof W. Pankiewicz, Steven E. Patterson, and Hiremagalur N. Jayaram. Cancer Lett. 181(1), 31-8 (2002). Abstract
• Novel Inhibitors of Inosine Monophosphate Dehydrogenase. J.L. Clark, S.E. Patterson, J.C. Mason, M.J. Otto, R.F. Schinazi, K.A. Watanabe, D. Risal, B.M. Goldstein and K. Pankiewicz. Coll.Czech.Chem. Comm.Symp.Ser. 5, 256 (2002).
• Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia. Krzysztof W. Pankiewicz, Krystyna B. Lesiak-Watanabe, Kyoichi A. Watanabe, Steven E. Patterson, Hiremagalur N. Jayaram, Joel A. Yalowitz, Michael D. Miller, Michael Seidman, Alokes Majumdar, Gerd Prehna, and Barry M. Goldstein. J. Med. Chem. 45(3), 703-12 (2002). Abstract
• Further studies on the cyclization of aromatic azomethines ortho-substituted with a trifluoromethyl group: synthesis of 2,4-di- or 2,3,4-trisubstituted quinolines Lucjan Strekowski, Steven E. Patterson, Lubomir Janda, Roman L. Wydra, Donald B. Harden, Malgorzata Lipowska, Marek T. Cegla J. Org. Chem. 57(1), pp 196–201 (1992). Abstract
• Synthesis and quantitative structure-activity relationship analysis of 2-(aryl or heteroaryl)quinolin-4-amines, a new class of anti-HIV-1 agents Lucjan Strekowski, Jerzy L. Mokrosz, Vidya A. Honkan, Agnieszka Czarny, Marek T. Cegla, Roman L. Wydra, Steven E. Patterson, Raymond F. Schinazi J. Med. Chem. 34(5), pp 1739–1746 (1991). Abstract
• An unusual base-mediated cyclization of ketimines derived from 2-(trifluoromethyl)aniline that involves the trifluoromethyl group: an expedient route to 2-arylquinolines Lucjan Strekowski, Roman L. Wydra, Marek T. Cegla, Agnieszka Czarny, Donald B. Harden, Steven E. Patterson, Merle A. Battiste, James M. Coxon J. Org. Chem. 55(16), pp 4777–4779 (1990). Abstract