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
