DRUG DISCOVERY FOR TREATMENT OF OBESITY

描述(由申请人提供)：长期目标是发现和开发新的 治疗人类肥胖症的药物。在第一阶段，将通过筛选从化学多样性实验室收集的550,000种公开可获得的化合物中挑选出的库来寻找新的候选药物。筛选候选者将根据ADME标准进行选择，以确定它们对哺乳动物乙酰辅酶A羧基酶2(ACC2)表现出特定抑制活性的可能性。ACC2在线粒体中被发现，在那里它调节脂肪酸氧化。在小鼠中，ACC2的灭活已被证明可以极大地减少体重增加。我们将开发酵母筛选菌株，通过用人ACC2基因取代酵母ACC基因来测试对人ACC2的抑制作用。这些携带小麦叶绿体或弓形虫ACC的替换菌株已经被我们证明对ACC特定的化学抑制剂敏感。携带人类ACC2的测试菌株将受到化合物库的挑战，其中包含大量在结构上与已知的ACC特异性除草剂有关的化合物。通过抑制酵母替代菌株的生长而确定的候选铅，随后将通过生化分析进行评估。 在该项目的第二阶段，将使用更广泛的生物测试和动物试验来从第一阶段候选药物中选择药物开发先导化合物，并进行初步优化研究，从而产生一种或多种候选药物，为扩大动物和临床开发做好准备。

DESCRIPTION (provided by applicant): The long-term objectives are to discover and develop new drugs for the treatment of obesity in humans. In Phase I, new drug lead candidates will be found by screening selected libraries drawn form Chemical Diversity Labs' collection of 550,000 publicly available chemical compounds. Screening candidates will be selected on ADME criteria for the likelihood that they will exhibit specific inhibitory activity against mammalian acetyl CoA carboxylase 2 (ACC2). ACC2 is found in mitochondria, where it regulates fatty acid oxidation. Inactivation of ACC2 in the mouse has been shown to reduce weight gain enormously. We will develop screening strains of yeast to test for inhibition of human ACC2 by replacing the yeast ACC gene by human ACC2 cDNA. Such replacement strains carrying wheat chloroplast or toxoplasma ACC have been shown by us to be sensitive to ACC-specific chemical inhibitors. Test strains carrying the human ACC2 will be challenged with compound libraries containing a large number of compounds related in structure to the known ACC-specific herbicides. Lead candidates, identified by inhibition of growth of yeast replacement strains, will be evaluated subsequently by biochemical assays. In Phase II of the project more extensive bioassays and testing in animals will be used to select drug development lead compounds from among the Phase I lead candidates and perform initial optimization studies, leading to one or more drug candidates ready for extended animal and clinical development.