New drugs for malaria are greatly needed. This program is directed toward the development of new boron-containing small molecules as antimalarial drugs. Our preliminary results suggest that novel boron-containing small molecules (oxaboroles) have potent antimalarial activity and, importantly, are likely to meet standard pharmacokinetic and safety criteria for new drugs and also the unique requirements for antimalarials. We hypothesize that a systematic drug discovery program will identify optimized oxaboroles that are relatively simple to produce and meet established criteria for new antimalarial agents. Further, we will use a systematic approach to identify a specific antimalarial mechanism of action for oxaboroles. Appreciation of the mechanism of action will aid in drug optimization and in the understanding of drug resistance. Specifically, we will test the hypothesis that antimalarial oxaboroles inhibit a plasmodial leucyl tRNA synthetase (LeuRS). This hypothesis is based on specific activity of other oxaboroles against fungal or bacterial LeuRS. In addition, we will assess mechanisms of resistance. Our program will entail continued collaboration between Anacor, the world leader in boron chemistry and a malaria research group at the University of California, San Francisco with nearly two decades experience in antimalarial drug discovery.
Specific aims of our program will be 1) hit-to-lead discovery of oxaborole antimalarials, 2) lead optimization of oxaborole antimalarials, and 3) characterization of the mechanisms of action and resistance for lead oxaboroles. We anticipate that, within the time-frame of this project, we will identify a candidate oxaborole antimalarial for development and that we will gain important insights into the antimalarial mechanisms of action of these compounds.

Public Health Relevance

New drugs to treat malaria are greatly needed. This project is directed toward the development of new boron-containing antimalarial drugs and entails collaboration between Anacor, a company with extensive experience with boron-containing drugs, and an experienced malaria research group at the University of California, San Francisco. Key aims of the project will be to identify and optimize active antimalarial compounds and to characterize the mechanisms by which these compounds inhibit malaria parasites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI095324-02S1
Application #
8724100
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Rogers, Martin J
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2013-08-19
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$44,713
Indirect Cost
$13,870
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143