Abstract

The overall goal of this research project is to discover lead compounds that can be developed into therapeutics for treatment of Chagas disease. This life-threatening disease results from infection with the protozoan pathogen Trypanosoma cruzi (T. cruzi). It is endemic in South and Central America, with >16 million people chronically infected and approximately 14,000 deaths per year. More than 100,000 USA citizens are believed to be infected. Current treatment options are inadequate to cure this infection, thus research is needed to discover better chemotherapeutics. The project will focus on making inhibitors to a key enzyme involved in sterol biosynthesis in T. cruzi, sterol 14-demethylase (Tc14DM). This enzyme, the target of azole antifungal drugs, is a well established antimicrobial target. We hypothesize that new compounds can be synthesized with optimal anti-T. cruzi activity and these will be sufficiently active to cure animals (and humans) with chronic T. cruzi infection. We provide preliminary data on two new chemical classes that bind the Tc14DM and that have potent activity against T. cruzi cultures.
The specific aims are: 1) Synthesize analogs of tipifarnib as potential T. cruzi chemotherapeutics. Tipifarnib is an imidazole- containing compound under development for cancer therapy and has excellent pharmacokinetic properties. 2) Synthesize a series of disubstituted imidazoles as potential T. cruzi chemotherapeutics. Preliminary data shows that this series has potent anti-T. cruzi activity when given orally to infected mice. 3) Perform molecular modeling and structure determination of Tc14DM. A molecular model based on a prokaryotic CYP51 structure will initially be utilized to guide structure-based drug design. Concomitantly, a crystal structure of the enzyme with bound inhibitors will be pursued to help guide drug design. 4) Develop a competition binding assay for Tc14DM. The proposed fluorescence polarization assay will assist moderate- to high-throughput screening of compounds. 5) Test compounds for efficacy, pharmacokinetics, and toxicity. A series of in vitro screens will be employed followed by testing selected compounds in mouse models.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI070218-04
Application #
7644017
Study Section
Special Emphasis Panel (ZRG1-DDR-N (01))
Program Officer
Rogers, Martin J
Project Start
2006-07-01
Project End
2011-02-28
Budget Start
2009-07-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2009
Total Cost
$589,661
Indirect Cost

  Institution

Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Buchynskyy, Andriy; Gillespie, J Robert; Hulverson, Matthew A et al. (2017) Discovery of N-(2-aminoethyl)-N-benzyloxyphenyl benzamides: New potent Trypanosoma brucei inhibitors. Bioorg Med Chem 25:1571-1584
Nagle, Advait S; Khare, Shilpi; Kumar, Arun Babu et al. (2014) Recent developments in drug discovery for leishmaniasis and human African trypanosomiasis. Chem Rev 114:11305-47
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
Planer, Joseph D; Hulverson, Matthew A; Arif, Jennifer A et al. (2014) Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. PLoS Negl Trop Dis 8:e2977
Suryadevara, Praveen Kumar; Racherla, Kishore Kumar; Olepu, Srinivas et al. (2013) Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14?-demethylase as anti-Chagas disease agents. Bioorg Med Chem Lett 23:6492-9
Buckner, Frederick S; Urbina, Julio A (2012) Recent Developments in Sterol 14-demethylase Inhibitors for Chagas Disease. Int J Parasitol Drugs Drug Resist 2:236-242
Pérez-Moreno, Guiomar; Sealey-Cardona, Marco; Rodrigues-Poveda, Carlos et al. (2012) Endogenous sterol biosynthesis is important for mitochondrial function and cell morphology in procyclic forms of Trypanosoma brucei. Int J Parasitol 42:975-89
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
Buckner, Frederick S (2011) Experimental chemotherapy and approaches to drug discovery for Trypanosoma cruzi infection. Adv Parasitol 75:89-119
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

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