Transcript 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
New Drugs for Protozoan
Parasites
• Malaria
• Leishmaniasis
• African
Sleeping
Sickness
• Chagas’
Disease
Malaria
WHO/TDR
African Sleeping
Sickness
(African
Trypanosomiasis)
Trypanosoma brucei
gambiense infection
Leishmaniasis
Cutaneous
Leishmaniasis
Visceral Leishmaniasis
Chagas’
Disease
Acute infection:
Romaña’s sign
Chagasic
Megacardia
Trypanosoma cruzi
Chagasic
Megacolon
(Barium enema)
New Drugs Needed
• Effective vaccines unavailable
• Drugs often toxic
• Resistance mounting
U of WA Protozoan Drug Discovery
• X-Ray Crystallography
– Wim Hol Group
• Chemistry
– Mike Gelb Group
• Parasitology
– Wes Van Voorhis and Fred Buckner Groups
Protein Farnesyltransferase
Inhibitors (FTI)
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Anti-cancer drug development
>30 drug companies investigating
FTI toxic to protozoans
“Piggy-back” approach
Protein Farnesylation
SH
Protein
Farnesyltransferase
FPP
Pep-CAAX
PFT
X= Ser, Met,
Gln, Cys, Ala
AAX
S
Pep-CAAX
Protease
T. brucei PFT
PFT Residues & Substrates
T. brucei + FTI
Farnesyl-O-NH-PA ester
BMS-214662 FTI
CN
O
N
N
NH
N
S
O
N
T. brucei ED50 200 nM
BMS FTI vs. T.brucei rhod. in mice
Parasitemia
Trypos x 10E5/ml
10000
Vehicle (n=5)
BMS-FTI (n=5)
7500
5000
2500
0
-2500
0
4
8
12
16
Days post-infection
Mice infected on day 0, dosed at 600
mg/kg/day by oral gavage days 0-7
FTI
• Promising results with T. brucei
• 30 nM inhibitor of Malaria growth
• Investigating T. cruzi and
Leishmania
Now, the Hard Part
• Pharmacokinetics
• Toxicity
• Large animal trials
• Phase I, II, III trials
New Paradigm for Drug Development
• Non-profit Drug Company
– Private/Govt. Funded
– 100s of Scientists
– Chemistry
– Pharmacokinetics
– Toxicology
– Phase I, II, III
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
Malaria
–300-500 million cases/yr
• 2 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 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
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
Chagas’ Disease
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American trypanosomiasis
Trypanosoma cruzi
Transmitted by reduviid bugs
Drugs toxic
Resistance documented
Vaccine not available