Discovery of Small Molecule hACC2 Inhibitors for Treatment of Obesity

描述(申请人提供)：乙酰-辅酶A羧基酶(ACC)是脂肪酸代谢的关键酶，需要将二氧化碳加到乙酰-辅酶A中生成丙二酰辅酶A。在哺乳动物中，丙二酰辅酶A是合成脂肪酸的前体，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，主要不同的是ACC2上有一个200个残基的N末端延伸，将这种形式的酶定向到线粒体。在那里，ACC2催化合成丙二酰辅酶A导致抑制脂肪酸运输和随后的氧化。合成的丙二酰辅酶A用于合成脂肪酸。我们建议筛选一个小分子文库，以寻找新的ACC2抑制剂作为开发治疗肥胖症的新药物疗法的先导化合物。我们已经构建了依赖于任何一种人ACC生长的酵母基因替换菌株。我们的研究已经表明，这种ACC基因替换菌株的生长可以被针对外源ACCs的化合物抑制。我们已经开发并测试了一种高通量协议，这是筛选大型化学库所必需的。我们还建议进行后续实验，以确定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的酵母基因替换菌株，并使用酶分析确定ACC为其靶标。肥胖是一种常见和普遍的营养障碍，与糖尿病和冠心病等其他严重疾病造成的严重发病率和过早死亡有关。乙酰辅酶A羧基酶是一种关键的脂质代谢酶，正在被研究为治疗这种疾病的新药物疗法的潜在靶点。基于这种酶的小分子抑制剂的新药可以通过氧化增加脂肪酸降解或减少脂肪酸合成来作用，可能成为抗击这种疾病的新的迫切需要的工具。

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.