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 problemThe problem What we are doingWhat we are doing What you can doWhat you can do

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

4. Malaria WHO/TDR

5. African Sleeping Sickness (African Trypanosomiasis) Trypanosoma brucei gambiense infection

6. Leishmaniasis Cutaneous Leishmaniasis Visceral Leishmaniasis

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

8. New Drugs Needed Effective vaccines unavailableEffective vaccines unavailable Drugs often toxicDrugs often toxic Resistance mountingResistance mounting

9. U of WA Protozoan Drug Discovery X-Ray CrystallographyX-Ray Crystallography –Wim Hol Group ChemistryChemistry –Mike Gelb Group ParasitologyParasitology –Wes Van Voorhis and Fred Buckner Groups

10. Protein Farnesyltransferase Inhibitors (FTI) Anti-cancer drug developmentAnti-cancer drug development >30 drug companies investigating>30 drug companies investigating FTI toxic to protozoansFTI toxic to protozoans “Piggy-back” approach“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 ED 50 200 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. bruceiPromising results with T. brucei 30 nM inhibitor of Malaria growth30 nM inhibitor of Malaria growth Investigating T. cruzi and LeishmaniaInvestigating T. cruzi and Leishmania

18. Now, the Hard Part PharmacokineticsPharmacokinetics ToxicityToxicity Large animal trialsLarge animal trials Phase I, II, III trialsPhase I, II, III trials

19. New Paradigm for Drug Development Non-profit Drug CompanyNon-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 ParasitesDevelop New Drugs for Parasites –Lab investigation –Field trials –Policy development Get Drugs to Developing CountriesGet Drugs to Developing Countries –Personal involvement –MSF –Policy development

21. Malaria –300-500 million cases/yr 2 million deaths/yr2 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 countriesAt risk: 60 million people, 36 countries –300,000 - 500,000 infected T. bruceiT. brucei –transmitted by tse tse fly Toxic drug therapyToxic drug therapy Resistance to drugs widespreadResistance to drugs widespread Little hope for vaccinesLittle hope for vaccines –antigenic variation

23. Leishmaniasis At risk: 350 million people, 88 countriesAt risk: 350 million people, 88 countries 12 million people infected12 million people infected Annual Incidence: 2 millionAnnual Incidence: 2 million Transmitted by sandfliesTransmitted by sandflies Drugs toxicDrugs toxic Drug resistance mountingDrug resistance mounting Vaccines not availableVaccines not available Sandfly Leishmania in a macrophage

24. Chagas’ Disease American trypanosomiasisAmerican trypanosomiasis Trypanosoma cruziTrypanosoma cruzi Transmitted by reduviid bugsTransmitted by reduviid bugs Drugs toxicDrugs toxic Resistance documentedResistance documented Vaccine not availableVaccine not available