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New Drugs for Protozoan Parasites Wesley C. Van Voorhis, MD PhD Professor of Medicine University of Washington New Drugs for Protozoan Parasites • The problem • What we are doing • What you can do New Drugs for Protozoan Parasites • Malaria • Leishmaniasis • African Sleeping Sickness • Chagas’ Disease Malaria WHO/TDR African Sleeping Sickness (African Trypanosomiasis) Trypanosoma brucei gambiense infection Leishmaniasis Cutaneous Leishmaniasis Visceral Leishmaniasis Chagas’ Disease Acute infection: Romaña’s sign Chagasic Megacardia Trypanosoma cruzi Chagasic Megacolon (Barium enema) New Drugs Needed • Effective vaccines unavailable • Drugs often toxic • Resistance mounting U of WA Protozoan Drug Discovery • X-Ray Crystallography – Wim Hol Group • Chemistry – Mike Gelb Group • Parasitology – Wes Van Voorhis and Fred Buckner Groups Protein Farnesyltransferase Inhibitors (FTI) • • • • Anti-cancer drug development >30 drug companies investigating FTI toxic to protozoans “Piggy-back” approach Protein Farnesylation SH Protein Farnesyltransferase FPP Pep-CAAX PFT X= Ser, Met, Gln, Cys, Ala AAX S Pep-CAAX Protease T. brucei PFT PFT Residues & Substrates T. brucei + FTI Farnesyl-O-NH-PA ester BMS-214662 FTI CN O N N NH N S O N T. brucei ED50 200 nM BMS FTI vs. T.brucei rhod. in mice Parasitemia Trypos x 10E5/ml 10000 Vehicle (n=5) BMS-FTI (n=5) 7500 5000 2500 0 -2500 0 4 8 12 16 Days post-infection Mice infected on day 0, dosed at 600 mg/kg/day by oral gavage days 0-7 FTI • Promising results with T. brucei • 30 nM inhibitor of Malaria growth • Investigating T. cruzi and Leishmania Now, the Hard Part • Pharmacokinetics • Toxicity • Large animal trials • Phase I, II, III trials New Paradigm for Drug Development • Non-profit Drug Company – Private/Govt. Funded – 100s of Scientists – Chemistry – Pharmacokinetics – Toxicology – Phase I, II, III What Can You Do? • Develop New Drugs for Parasites – Lab investigation – Field trials – Policy development • Get Drugs to Developing Countries – Personal involvement – MSF – Policy development Malaria –300-500 million cases/yr • 2 million deaths/yr – mostly < 5 y.o. children –Transmitted by Anopheles mosquitoes –Drug resistance widespread –Vaccines problematic African Trypanosomiasis • At risk: 60 million people, 36 countries – 300,000 - 500,000 infected • T. brucei – transmitted by tse tse fly • Toxic drug therapy • Resistance to drugs widespread • Little hope for vaccines – antigenic variation Leishmaniasis • At risk: 350 million people, 88 countries • 12 million people infected • Annual Incidence: 2 million • Transmitted by sandflies • Drugs toxic • Drug resistance mounting • Vaccines not available Leishmania in a macrophage Sandfly Chagas’ Disease • • • • • • American trypanosomiasis Trypanosoma cruzi Transmitted by reduviid bugs Drugs toxic Resistance documented Vaccine not available
