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

New Drugs for Protozoan Parasites The problemThe problem What we are doingWhat we are doing What you can doWhat you can do

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

Malaria WHO/TDR

African Sleeping Sickness (African Trypanosomiasis) Trypanosoma brucei gambiense infection

Leishmaniasis Cutaneous Leishmaniasis Visceral Leishmaniasis

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

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

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

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

Protein Farnesylation Protein Farnesyl- transferase

T. brucei PFT

PFT Residues & Substrates

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

BMS FTI T. brucei ED nM

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

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

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

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

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

Malaria – million cases/yr 2 million deaths/yr2 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 countriesAt risk: 60 million people, 36 countries –300, ,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

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

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