以FTO为靶标的抗肥胖药物分子设计研究

Obesity is a leading cause of preventable illness and death worldwide. Genome-wide association studies have shown a strong correlation of a single nucleotide polymorphism in the first intron of the FTO gene with increased body mass index and obesity risk. Mouse model studies demonstrated that FTO is functionally involved in energy homeostasis and affects the whole body metabolism, establishing a mechanistic link between FTO and obesity. FTO protein was predicted and biochemically confirmed to belong to the AlkB family of Fe (II)/2-oxoglutarate-dependent oxidative DNA/RNA demethylases.In vitro FTO protein is an AlkB-like DNA/RNA demethylase with a strong preference for 3-methylthymidine (3-meT) in single-stranded DNA or 3-methyluracil (3-meU) in single-stranded RNA. We have determined the crystal structure of human FTO bound by the mono-nucleotide 3-meT. In the present project, we will design and synthesize FTO-specific inhibitors based on the available crystal structure of FTO in complex with a small molecule. FTO inhibitors with more potent activity will be co-crystallized with FTO and the complex structures would be informative to illustrate the structure-activity relationship (SAR) of the FTO inhibitors and further refine their design and synthesis. The efficacies of the FTO inhibitors will be further investigated at cellular and animal levels. Together these studies will help us identify lead compounds for developing anti-obesity (and obesity-related diseases) drugs. The FTO-specific inhibitors will be valuable to probe FTO-mediated signaling pathway that is expected to unravel novel targets for treatment of obesity.

肥胖对人类健康有着重要的影响。2007年，人们利用全基因扫描技术发现FTO基因含有多态性SNP rs9939609纯合子的人群比不含有此等位基因人群的平均体重重3公斤。随后不同国家和民族的调查都确证了此相关性。小鼠体内FTO基因敲除、点突变、过表达等实验也表明FTO基因本身与肥胖直接相关。随着对 FTO基因功能研究的深入，提示FTO的底物可能是甲基化修饰的核苷。我们随后解析了FTO与3-meT复合物的晶体结构。本项目根据FTO复合物的晶体结构来设计和合成相应的抑制性小分子，通过对抑制性小分子与FTO的晶体结构研究来阐明抑制剂的构效关系，通过细胞、模式动物等的研究筛选有效的抑制剂，以期可以达到临床应用的抗肥胖药物。另外，我们也利用抑制剂来阐明FTO致肥胖的作用机制研究。

按期完成了各项研究任务，基于已有活性分子的定量构效关系，利用计算机药物辅助软件等手段，设计并合成三/四元环酰胺、CHTB、根赤壳菌素、萘莫司他、磺酰胺等多个系列的小分子化合物。建立了合适的酶活性评价体系，并对上述各类化合物的酶活性进行筛选和构效关系研究，获得了20个在体外对 FTO酶活性有抑制作用的小分子，并拿到3个相关的复合物晶体结构；在细胞水平上筛到13个有效的小分子，在动物模式中筛选得到2个有效的小分子。其中，化合物A在高脂饮食诱导的肥胖小鼠动物模型中表现出较好的减肥效果。本项目的部分研究成果分别获得国家自然科学二等奖（第二完成人）和河南省科技进步一等奖（第一完成人）各1项；在Journal of Medicinal Chemistry，Biochemistry，Molecular Pharmaceutics等杂志上发表标有本基金资助的SCI论文45篇，获得2项授权发明专利；参加国际会议3次，邀请相关知名专家讲座2次，培养博士研究生5名，硕士研究生20名，博士后2名；与德国科隆大学（清华大学）的柴继杰教授进行了项目合作。