IDENTIFICATION OF NEW ACETYL-COA CARBOXYLASE INHIBITORS

描述（由申请人提供）：乙酰辅酶A羧化酶催化脂肪酸生物合成的第一步，是脂肪代谢的关键调节剂。由于ACC在调节脂肪储存和脂肪燃烧中的作用，ACC的药物抑制剂有望作为肥胖和2型糖尿病的治疗方法-这是美国两个紧迫的健康问题。由于ACC也在初级代谢中起作用，ACC抑制剂另外可以证明可用作抗微生物化合物。目前还没有适合作为药物开发先导的ACC抑制剂。已知最有效的ACC抑制剂是结构复杂的天然产物soraphen。我们建议确定新的小分子ACC抑制剂的目标soraphen结合位点，并适合作为药物开发的线索。在第一阶段，我们将开发必要的研究工具：1）分离的soraphen结合结构域，衍生自ACC，用作筛选剂和用于结构研究，2）基于微量滴定板的测定以筛选靶向soraphen结合位点的新化学抑制剂，和3）的方法soraphen抑制ACC的分子相互作用的结构信息。在第二阶段，我们将采取综合方法，分析，结合计算化学方法的基础上获得的结构信息，以确定新的和合成易处理的化学线索，抑制ACC的长期目标是使用这些线索开发和商业化的治疗肥胖症，2型糖尿病和微生物感染的治疗。

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.