New Drugs for Protozoan New Drugs for Protozoan ParasitesParasites

Wesley C. Van Voorhis, MD PhDWesley C. Van Voorhis, MD PhD

Professor of MedicineProfessor of Medicine

University of WashingtonUniversity of Washington

New Drugs for Protozoan New Drugs for Protozoan ParasitesParasites

• The problemThe problem

• What we are doingWhat we are doing

• What you can doWhat you can do

New Drugs for Protozoan New Drugs for Protozoan ParasitesParasites

• MalariaMalaria

• African African Sleeping Sleeping SicknessSickness

• LeishmaniasisLeishmaniasis

• Chagas’ Chagas’ DiseaseDisease

MalariaMalaria

WHO/TDR

African Sleeping African Sleeping SicknessSickness

(African (African Trypanosomiasis)Trypanosomiasis)

Trypanosoma bruceiTrypanosoma bruceigambiense gambiense infectioninfection

LeishmaniasisLeishmaniasis

Cutaneous Leishmaniasis

Visceral Leishmaniasis

Chagasic Chagasic MegacardiaMegacardia

Acute infection:Acute infection:Romaña’s signRomaña’s sign

Chagasic Chagasic MegacolonMegacolon

(Barium enema)(Barium enema)

Chagas’ Chagas’ DiseaseDisease

Trypanosoma cruziTrypanosoma cruzi

New Drugs NeededNew Drugs Needed• Effective vaccines unavailableEffective vaccines unavailable

• Drugs often toxicDrugs often toxic

• Resistance mountingResistance mounting

U of WA Protozoan Drug DiscoveryU of WA Protozoan Drug Discovery• X-Ray CrystallographyX-Ray Crystallography

– Wim Hol GroupWim Hol Group

• ChemistryChemistry– Mike Gelb GroupMike Gelb Group

• ParasitologyParasitology– Wes Van Voorhis and Fred Buckner GroupsWes Van Voorhis and Fred Buckner Groups

Protein Farnesyltransferase Protein Farnesyltransferase Inhibitors (FTI)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” approachPiggy-back” approach

Protein FarnesylationProtein Farnesylation

ProteinFarnesyl-

transferase

T. brucei T. brucei PFTPFT

PFT Residues & SubstratesPFT Residues & Substrates

T. bruceiT. brucei + FTI + FTI

Farnesyl-O-NH-PA ester

BMS-214662 FTIBMS-214662 FTI

T. bruceiT. brucei ED ED5050 200 nM 200 nM

NN

N NH

SO

O

N

CN

BMS FTI vs. BMS FTI vs. T.brucei rhod. T.brucei rhod. in micein mice

Mice infected on day 0, dosed at 600 mg/kg/day by oral gavage days 0-7

Parasitemia

0 4 8 12 16-2500

0

2500

5000

7500

10000Vehicle (n=5)BMS-FTI (n=5)

Days post-infection

Try

po

s x

10E

5/m

l

FTIFTI• Promising results with Promising results with T. bruceiT. brucei

• 30 nM inhibitor of Malaria growth30 nM inhibitor of Malaria growth

• Investigating Investigating T. cruzi T. cruzi and and LeishmaniaLeishmania

Now, the Hard PartNow, the Hard Part

• PharmacokineticsPharmacokinetics

• ToxicityToxicity

• Large animal trialsLarge animal trials

• Phase I, II, III trialsPhase I, II, III trials

New Paradigm for Drug DevelopmentNew Paradigm for Drug Development

• Non-profit Drug CompanyNon-profit Drug Company– Private/Govt. FundedPrivate/Govt. Funded

– 100s of Scientists100s of Scientists

– ChemistryChemistry

– PharmacokineticsPharmacokinetics

– ToxicologyToxicology

– Phase I, II, IIIPhase I, II, III

What Can You Do?What Can You Do?

• Develop New Drugs for ParasitesDevelop New Drugs for Parasites– Lab investigationLab investigation– Field trialsField trials– Policy developmentPolicy development

• Get Drugs to Developing CountriesGet Drugs to Developing Countries– Personal involvementPersonal involvement– MSFMSF– Policy developmentPolicy development

MalariaMalaria–300-500 million cases/yr300-500 million cases/yr

• 2 million deaths/yr2 million deaths/yr– mostly < 5 y.o. childrenmostly < 5 y.o. children

–Transmitted by Transmitted by AnophelesAnopheles mosquitoes mosquitoes–Drug resistance widespreadDrug resistance widespread–Vaccines problematicVaccines problematic

African Trypanosomiasis African Trypanosomiasis • At risk: 60 million people, 36 countriesAt risk: 60 million people, 36 countries

– 300,000 - 500,000 infected300,000 - 500,000 infected

• T. bruceiT. brucei – transmitted bytransmitted by

tse tse flytse tse fly

• Toxic drug therapyToxic drug therapy• Resistance to drugs widespreadResistance to drugs widespread• Little hope for vaccinesLittle hope for vaccines

– antigenic variationantigenic variation

LeishmaniasisLeishmaniasis• At risk: 350 million people, 88 At risk: 350 million people, 88

countriescountries• 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’ DiseaseChagas’ 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