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New Drugs for Protozoan Parasites

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. Malaria African Sleeping Sickness. Leishmaniasis Chagas’ Disease.

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New Drugs for Protozoan Parasites

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  1. New Drugs for Protozoan Parasites Wesley C. Van Voorhis, MD PhD Professor of Medicine University of Washington

  2. New Drugs for Protozoan Parasites • The problem • What we are doing • What you can do

  3. Malaria African Sleeping Sickness Leishmaniasis Chagas’ Disease New Drugs for Protozoan Parasites

  4. Malaria WHO/TDR

  5. African Sleeping Sickness(African Trypanosomiasis)Trypanosoma bruceigambiense infection

  6. Leishmaniasis Cutaneous Leishmaniasis Visceral Leishmaniasis

  7. Chagas’ Disease Acute infection: Romaña’s sign Chagasic Megacolon (Barium enema) Chagasic Megacardia Trypanosoma cruzi

  8. New Drugs Needed • Effective vaccines unavailable • Drugs often toxic • Resistance mounting

  9. U of WA Protozoan Drug Discovery • X-Ray Crystallography • Wim Hol Group • Chemistry • Mike Gelb Group • Parasitology • Wes Van Voorhis and Fred Buckner Groups

  10. Protein Farnesyltransferase Inhibitors (FTI) • Anti-cancer drug development • >30 drug companies investigating • FTI toxic to protozoans • “Piggy-back” approach

  11. Protein Farnesylation Protein Farnesyl- transferase

  12. T. brucei PFT

  13. PFT Residues & Substrates

  14. T. brucei + FTI Farnesyl-O-NH-PA ester

  15. BMS-214662 FTI T. brucei ED50 200 nM

  16. BMS FTI vs. T.brucei rhod. in mice Mice infected on day 0, dosed at 600 mg/kg/day by oral gavage days 0-7

  17. FTI • Promising results with T. brucei • 30 nM inhibitor of Malaria growth • Investigating T. cruzi and Leishmania

  18. Now, the Hard Part • Pharmacokinetics • Toxicity • Large animal trials • Phase I, II, III trials

  19. New Paradigm for Drug Development • Non-profit Drug Company • Private/Govt. Funded • 100s of Scientists • Chemistry • Pharmacokinetics • Toxicology • Phase I, II, III

  20. 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

  21. Malaria • 300-500 million cases/yr • 2 million deaths/yr • mostly < 5 y.o. children • Transmitted by Anopheles mosquitoes • Drug resistance widespread • Vaccines problematic

  22. 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

  23. 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

  24. Chagas’ Disease • American trypanosomiasis • Trypanosoma cruzi • Transmitted by reduviid bugs • Drugs toxic • Resistance documented • Vaccine not available

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