IDENTIFICATION OF NEW ACETYL-COA CARBOXYLASE INHIBITORS

描述(申请人提供)：乙酰辅酶A羧基酶催化脂肪酸生物合成的第一步，是脂肪代谢的关键调节器。由于ACC在调节脂肪储存和脂肪燃烧方面的作用，ACC的药物抑制剂有望成为肥胖和2型糖尿病的治疗药物，这两个问题是美国迫切需要解决的健康问题。由于ACC也在初级新陈代谢中发挥作用，ACC抑制剂还可以被证明是有用的抗菌化合物。目前还没有适合作为药物开发先导的ACC抑制剂。已知的最有效的ACC抑制剂是结构复杂的天然产物索拉芬。我们建议寻找新的针对山梨醇结合部位的ACC小分子抑制剂，它们适合作为药物开发的先导。在第一阶段，我们将开发必要的研究工具：1)从ACC中分离出的索拉芬结合域，用作筛选剂和结构研究；2)以微量平板为基础的分析方法，以筛选针对索拉芬结合位点的新的化学抑制剂；以及3)关于索拉芬抑制ACC的分子相互作用的结构信息。在第二阶段，我们将采取一种综合的方法，结合验证的分析方法，结合基于所获得的结构信息的计算化学方法，以识别抑制ACC的新的和可合成的易处理的化学先导。长期目标是利用这些线索开发治疗肥胖症、2型糖尿病和微生物感染的疗法并将其商业化。

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.