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
Suryadevara, Praveen Kumar; Racherla, Kishore Kumar; Olepu, Srinivas et al. (2013) Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14α-demethylase as anti-Chagas disease agents. Bioorg Med Chem Lett 23:6492-9
Spacil, Zdenek; Tatipaka, Haribabu; Barcenas, Mariana et al. (2013) High-throughput assay of 9 lysosomal enzymes for newborn screening. Clin Chem 59:502-11
Buckner, Frederick S; Bahia, Maria Terezinha; Suryadevara, Praveen Kumar et al. (2012) Pharmacological characterization, structural studies, and in vivo activities of anti-Chagas disease lead compounds derived from tipifarnib. Antimicrob Agents Chemother 56:4914-21
Mouchlis, Varnavas D; Magrioti, Victoria; Barbayianni, Efrosini et al. (2011) Inhibition of secreted phospholipases A₂ by 2-oxoamides based on α-amino acids: Synthesis, in vitro evaluation and molecular docking calculations. Bioorg Med Chem 19:735-43
Kraus, James M; Tatipaka, Hari Babu; McGuffin, Sarah A et al. (2010) Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery. J Med Chem 53:3887-98
Hast, Michael A; Fletcher, Steven; Cummings, Christopher G et al. (2009) Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase. Chem Biol 16:181-92
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
Fletcher, Steven; Cummings, Christopher G; Rivas, Kasey et al. (2008) Potent, Plasmodium-selective farnesyltransferase inhibitors that arrest the growth of malaria parasites: structure-activity relationships of ethylenediamine-analogue scaffolds and homology model validation. J Med Chem 51:5176-97
Yokoyama, Kohei; Gillespie, John R; Van Voorhis, Wesley C et al. (2008) Protein geranylgeranyltransferase-I of Trypanosoma cruzi. Mol Biochem Parasitol 157:32-43

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