Lead optimization and target identification of drugs targeting hypnozoites

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PROJECT SUMMARY/ABSTRACT The goal of this proposal is to optimize a new lead series for treatment of relapsing malaria caused by Plasmodium vivax. When an infectived mosquito bits she inoculates sporozoites that invade hepatocytes. Within the hepatocyte the forms can either develop and reproduce or become dormant. These dormant hypnozoites are the forms that persist for weeks to years and can reactivate to cause disease. There are no good drugs for treating hypnozoites that are safe, especially for glucose-6phosphate dehtdriogenase deficient people. In this project wi wil use a novel liver stage culture system to drive the medicinal chemistry optimization of the new lead series of drugs with anti-hypnozoite activity. Secondly we aim to use the lead and back up series to develop chemical probes to identify the targets for hypnozoite killing. Cyrrently there are no validated targets for drug discovery against hypnozoites. Finally we aim to use a combination of chemical biology, advanced culture techniques, and new metabolic labelling approaches to validate the new leads and gthe liver stage culture model.