Discovery of inhibitors against cryptosporidial fatty acyl-CoA synthetase
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PROJECT SUMMARYCryptosporidium (or Crypto for short) can cause life threatening opportunistic infection (OI) in AIDS patients.It is also a category B agent in the biodefense program. Currently, no drug is FDA-approved to treatcryptosporidiosis in AIDS patients, although a single drug nitazoxanide has been approved for use inimmune-healthy patients.Our preliminary data have shown that triacsin C, an inhibitor against fatty acyl-CoA synthetase (ACS), couldeffectively inhibit C. parvum infections in vitro (e.g., IC50 = 136 nM). Most importantly, triacsin C (8-15mg/kg/d) reduced the production of C. parvum oocysts in an acute infection mouse model by 56% - 88%with no observable toxicity to animals. These observations indicate that essential lipid metabolic enzymescould serve as novel drug targets in the parasite.The long-term goal of this translational research is to explore fatty acid metabolic enzymes as therapeutictargets against cryptosporidiosis. Because fatty acids are essential to all organisms, we hypothesize thatACS and ACC could serve as rational drug targets in Cryptosporidium. To test this hypothesis, we plan toperform experiments to achieve the following two specific aims.In aim 1, we will determine the efficacy of the ACS inhibitor triacsin C (TrC) in a chronic mouse modelrepresenting Crypto AIDS-OI. This aim is to extend the study from acute infection model to an AIDS-OIrelevant chronic model. The pharmacokinetic (PK) properties of TrC in mice will also be determined forestablishing the relationship between the anti-Crypto efficacy and the kinetics of TrC in mouse plasma andin the lumen of the intestine. In aim 2, we will discover new chemotypes with highly improved medicinalchemistry properties by modifying triacsin C (TrC) and by high-throughput screening (HTS) of compoundlibraries. Using two approaches here, we will increase the chance to obtain a more tractable lead compound,generate alternative leads, and diversify the lead structures.Upon completion of the proposed experiments, we expect to have generated key data, i.e., identified newlead structures with desired efficacy and medicinal chemical properties, for the next phase of ACS inhibitordevelopment for the treatment of Crypto in AIDS patients.
