IDENTIFICATION OF NEW ACETYL-COA CARBOXYLASE INHIBITORS

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DESCRIPTION (provided by applicant): Acetyl CoA carboxylase catalyzes the first step in fatty acid biosynthesis and is a key regulator of fat metabolism. Because of ACC's role in regulating fat storage and fat burning, pharmaceutical inhibitors of ACC have promise as treatments for obesity and type 2 diabetes - two urgent US health problems. Because ACC also plays a role in primary metabolism, ACC inhibitors additionally could prove useful as antimicrobial compounds. Currently there are no ACC inhibitors suitable as leads for drug development. The most potent ACC inhibitor known is the structurally complex, natural product soraphen. We propose to identify new small molecule inhibitors of ACC that target the soraphen binding site and that are suitable as leads for drug development. In phase I we will develop the necessary research tools: 1) isolated soraphen binding domains, derived from ACC, to be used as screening agents and in structural studies, 2) a microtiter plate-based assay to screen for new chemical inhibitors that target the soraphen binding site, and 3) structural information on the molecular interactions by which soraphen inhibits ACC. In phase II we will take an integrated approach incorporating the validated assay, in combination with computational chemistry methods based on the acquired structural information, in order to identify novel and synthetically tractable chemical leads that inhibit ACC. The long-term goal is to use these leads to develop and commercialize therapeutics for the treatment of obesity, type 2 diabetes, and microbial infections.