Malaria is a serious threat to human health in many regions of the world, with an estimated 500 million cases occurring annually. Increased global drug resistance by malaria parasites has rendered traditional therapies ineffective. Continued efforts to develop a protective vaccine are not expected to bear fruit in near future. New pharmaceutical agents with novel mechanisms of action are urgently needed to control the spread of this disease. This proposal intends to address this need by identifying small molecule inhibitors targeted to malarial kinesin motor proteins for future development into novel antiparasitic pharmaceutical candidates. Cytokinetics is uniquely suited for this task, being the leading drug discovery company with extensive experience in cytoskeletal targets. The proposed project will focus on two Plasmodium falciparum kinesin motor proteins with sequence homology to essential mitotic kinesins from several other species. These targets have proven to be attractive in other therapeutic areas. Cytokinetics has developed high throughput screens that allow rapid and systematic identification of potent inhibitors of kinesin motor activity. The goal for Phase I of this proposal is to determine the feasibility of uncovering small molecule agents with inhibitory activity against recombinant malarial kinesins in our high throughput screens. The objectives of the proposed work under Phase II are 1) to evaluate active compounds from the primary biochemical screens for antiproliferative activity against cultured P. falciparum and lack of toxicity towards mammalian cells, and 2) to characterize new malarial kinesin genes to maintain a pipeline of candidate targets.
