MALARIAL PROTEASE INHIBITION VIA COMBINATORIAL CHEMISTRY

Malaria kills 2.1 million people per year and drug resistance to current therapies is becoming a significant problem. Plasmepsin II, an aspartyl protease, is involved in the digestion of hemoglobin which is the major nutrient source for the parasite. Inhibition of hemoglobin degradation has been shown to cause parasite death. At Pharmacopeia, combinatorial libraries of small organic molecules are synthesized on beads and after each synthetic step an encoding molecule or tag is attached to the bead which allows for rapid identification of the structures of compounds having inhibitory activity. By screening two combinatorial libraries targeted for aspartyl proteases (32,000 compounds) for inhibition of plasmepsin II and cathepsin D, we have obtained structure-activity information as well as identified a competitive inhibitor of plasmepsin II with a Ki value of 110 nM that is selective over the structurally related aspartyl protease, cathepsin D. To reduce the peptiditic characteristics of our current inhibitors to further our knowledge of structure-activity relationships and to identify additional selective inhibitors of plasmepsin II, we will synthesize two additional libraries resulting in at least 25,000 compounds. This additional information will help to design libraries to be synthesized in Phase II which will have increased potency, selectivity and efficacy in cell culture which are required prior to further drug development.