The goal of the proposed work is the development of novel quinoline-based anti-malarial compounds. The work will be accomplished by the cooperation of of two academic labs, Kip Guy and Joseph DeRisi, and two industrial partners, GenoSpectra, Inc., and Stanford Research Institute (SRI), Inc. Quinolines have a long and rich history of anti-malarial use, yet the diversity of tested compounds to date has been limited by a narrow range of synthetic techniques. Little is known about the effects these drugs have on parasites at the molecular level. Additional information at the whole genome level could thus greatly accelerate both the understanding of these compounds and the optimization of their structure for the purpose of subverting the parasite. The Guy Lab will implement a combinatorial synthesis program aimed at generating a library encoding approximately 80% novel quinolines and test them for activity against Plasmodium falciparum in a high throughput in vitro assay system. In parallel, the Guy Lab will produce and make publicly available a structure activity database for known and tested quinoline structures. The DeRisi lab will commence expression profiling of all the known and available anti-malarial therapeutics using a near-whole genome array and a novel bioreactor growth system. Expression data for known anti-malarial drugs will be used in combination with expression data gathered for top candidate compounds emerging from the Guy Lab synthesis effort to create a structure-activity expression relationship. Top candidates will also be transferred to SRI, Inc., for rigorous toxicology testing. RNA material from cultured hepatocytes treated with candidate compounds will be used to gather expression responses using whole human genome chips developed by GenoSpectra, Inc. The compiled relationships from known anti-malarials, novel quinolines, and toxicology will then be used to guide and optimize additional synthesis efforts toward the ultimate goal of producing effective therapeutics.
