The project is designed to generate a robust pipeline of anti-trypanosomatid drugs with product profiles suitable for clinical trials and deployment. It will be conducted by a highly organized Trypanosomatid Drug Development Consortium (TDDC) with extensive and diverse expertise, technical capabilities, facilities, and ongoing studies with these pathogens. The TDDC consortium includes SBRI/University of Washington, UCSF, University of North Carolina at Chapel Hill, and the Eskitis Institute of Griffiths University, each of which has collaborative or consulting ties with various other public and private institutions. The consortium has the essential technologies and equipment, compound and natural product libraries, in vitro and in vivo models, expertise, and project management skills to conduct the project. It will use a milestone based, decision matrix supported, product development approach to: 1) Identify trypanosomatid candidate drug targets by comprehensive literature and informatic analyses and prioritize them for experimental validation and initial assay development. 2) Develop high throughput screens (HTSs) for prioritized targets. The HTSs will use sensitive and specific reporter systems, typically with recombinant proteins, and will be robust, reproducible, and sensitive. 3) Screen selected libraries of synthetic and natural product compounds with these HTSs as well as trypanosomatid cell viability assays. Active compounds in natural product hits will be isolated and their structures determined, and IC50s will be determined for all promising hits. 4) Perform hit-to lead chemistry to provide high-quality lead candidates and iterative lead optimization and SAR analysis using compound analogs. 5) Lead-like compounds will be tested for efficacy and toxicology, ADME, and PK to generate a select set of compounds for clinical analyses. 6) Generate a centralized project and information management system that will be instituted as an information-based interface among the sites and as a community resource. It will facilitate workflow and aid coordination and decision making. The outcome will be a set of targets and chemical entities distributed along the pipeline from target discovery to preclinical validation thus providing a rich ongoing resource of drug candidates for clinical studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI075641-05
Application #
8131789
Study Section
Special Emphasis Panel (ZAI1-TP-M (M1))
Program Officer
Rogers, Martin J
Project Start
2007-09-01
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$428,657
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Holla, Harish; Labaied, Mehdi; Pham, Ngoc et al. (2011) Synthesis of antitrypanosomal 1,2-dioxane derivatives based on a natural product scaffold. Bioorg Med Chem Lett 21:4793-7
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