Protein farnesylation is the attachment of the 15-carbon farnesyl group to the C-termini of proteins in eukaryotic cells. We have shown that this post-translational modification occurs in trypanosomatids and malaria, parasites that cause devastating tropical diseases. We have also shown that the enzyme that attaches farnesyl groups to parasite proteins, protein farnesyltransferase (PFT), is a good target for the development of novel drugs that irreversibly inhibit the growth of the parasite that causes African sleeping sickness (Trypanosoma brucei) and malaria (Plasmodium falciparum). We have made considerable progress in the design and discovery of potent inhibitors of parasite PFTs that block the growth of parasites in culture and also cure experimental rodents infected with parasites. However, our best compounds are not good enough to advance into clinical trials because they are metabolized too quickly to allow for once or twice daily dosing over a 3-day period, a dose schedule that is optimal for treatment of tropical diseases. We want to continue to apply the principles of structure-guided medicinal chemistry to improve the drug-like properties of our PFT inhibitors. In vitro assessment of drug metabolism and intestinal absorption will be used to screen potent PFT inhibitors. Our best compounds will be further explored for efficacy in parasite- infected rodents. Our overall goal is to develop new drugs for the treatment of parasitic diseases that cause suffering among millions of people worldwide.

Public Health Relevance

The relevance of our work is to discover new therapeutics for the treatment of the devastating tropical diseases malaria and African sleeping sickness. Malaria and African sleeping sickness kill about 2 million and 200,000 people, respectively, each year. New drugs are needed because existing drugs are either ineffective or resistance has developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054384-22
Application #
8278597
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Rogers, Martin J
Project Start
1991-04-20
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
22
Fiscal Year
2012
Total Cost
$611,813
Indirect Cost
$219,625
Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Tatipaka, Hari Babu; Gillespie, J Robert; Chatterjee, Arnab K et al. (2014) Substituted 2-phenylimidazopyridines: a new class of drug leads for human African trypanosomiasis. J Med Chem 57:828-35
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Olepu, Srinivas; Suryadevara, Praveen Kumar; Rivas, Kasey et al. (2008) 2-Oxo-tetrahydro-1,8-naphthyridines as selective inhibitors of malarial protein farnesyltransferase and as anti-malarials. Bioorg Med Chem Lett 18:494-7
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Yokoyama, Kohei; Gillespie, John R; Van Voorhis, Wesley C et al. (2008) Protein geranylgeranyltransferase-I of Trypanosoma cruzi. Mol Biochem Parasitol 157:32-43
Eastman, Richard T; White, John; Hucke, Oliver et al. (2007) Resistance mutations at the lipid substrate binding site of Plasmodium falciparum protein farnesyltransferase. Mol Biochem Parasitol 152:66-71
Bendale, Pravin; Olepu, Srinivas; Suryadevara, Praveen Kumar et al. (2007) Second generation tetrahydroquinoline-based protein farnesyltransferase inhibitors as antimalarials. J Med Chem 50:4585-605
Gelb, Michael H (2007) Drug discovery for malaria: a very challenging and timely endeavor. Curr Opin Chem Biol 11:440-5

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