Discovery of Small Molecule hACC2 Inhibitors for Treatment of Obesity

说明（申请人提供）：乙酰辅酶a羧化酶（Acetyl-CoA carboxylase， ACC）是将CO2加入到乙酰辅酶a中生成丙二酰辅酶a所需的脂肪酸代谢关键酶。在哺乳动物中，丙二酰辅酶a作为脂肪酸合成的前体，但它也调节线粒体中的脂肪酸氧化。人类有两种ACC同工酶，氨基酸序列非常相似，主要区别在于ACC2上的200个残基n端延伸，该延伸将这种形式的酶引导到线粒体。在那里，acc2催化丙二酰辅酶a的合成导致脂肪酸运输和随后的氧化受到抑制。ACC1合成丙二酰辅酶a用于脂肪酸合成。我们建议筛选一个小分子文库来寻找新的ACC2抑制剂，作为开发新的药物治疗肥胖的先导化合物。我们已经构建了酵母基因替代菌株，依赖于人类ACC的生长。我们的研究已经表明，这种ACC基因替代菌株的生长被靶向外源ACC的化合物所抑制。我们已经开发并测试了筛选大型化学文库所需的高通量协议。我们还建议进行后续实验，以确定在筛选中发现的任何新抑制剂的特异性，使用我们收集的携带不同ACC的酵母基因替代菌株，并使用酶分析确认ACC是它们的靶标。肥胖是一种常见和普遍的营养失调，与糖尿病和冠心病等其他严重疾病引起的严重发病率和过早死亡有关。乙酰辅酶a羧化酶是一种关键的脂质代谢酶，正在被研究作为治疗这种疾病的新药物治疗的潜在靶点。基于这种酶的小分子抑制剂的新药物，通过增加脂肪酸氧化降解或减少脂肪酸合成来起作用，可能成为对抗这种疾病迫切需要的新工具。

DESCRIPTION (provided by applicant): Acetyl-CoA carboxylase (ACC) is a key enzyme of fatty acid metabolism required for the addition of CO2 to acetyl-CoA to make malonyl-CoA. In mammals, malonyl-CoA serves as a precursor for the synthesis of fatty acids but it also regulates fatty acid oxidation in mitochondria. There are two ACC isozymes in humans, with very similar amino acid sequences, differing mainly by a 200-residue N-terminal extension on ACC2 that directs this form of the enzyme to mitochondria. There, ACC2-catalyzed synthesis of malonyl- CoA leads to suppression of fatty acid transport and subsequent oxidation. ACC1- synthesized malonyl-CoA is used for fatty acid synthesis. We propose to screen a small- molecule library to find novel inhibitors of ACC2 as lead compounds for the development of new pharmacotherapies to treat obesity. We have constructed yeast gene- replacement strains depending for growth on either human ACC. Our research has already shown that growth of such ACC gene-replacement strains is inhibited by compounds targeting foreign ACCs. We have developed and tested a high throughput protocol necessary to screen large chemical libraries. We also propose to conduct follow-up experiments to determine the specificity of any new inhibitor identified in the screen, using our collection of yeast gene-replacement strains carrying different ACCs, and to confirm ACC as their target, using enzymatic assays. Obesity is a common and prevalent nutritional disorder linked to significant morbidity and premature mortality caused by other serious medical conditions such as diabetes and coronary disease. Acetyl-CoA carboxylase, a key lipid metabolic enzyme, is being investigated as a potential target for new pharmacotherapies to treat the disorder. New medications based on small-molecule inhibitors of the enzyme acting by increasing fatty acid degradation by oxidation or decreasing fatty acid synthesis could become new urgently needed tools to combat the disease.