选择性FABP4/5双重抑制剂的发现、抗NASH活性评价及作用机制研究

非酒精性脂肪肝炎（NASH）可导致肝硬化和肝衰竭，并可诱发肝细胞癌，严重威胁人类健康。迄今尚未有同时针对NASH病理机制“二次打击”的有效药物被批准用于NASH的治疗。脂肪酸结合蛋白4/5（FABP4/5）与“二次打击”密切相关。但脂肪细胞中单独敲除FABP4可致FABP5的表达代偿性显著上调。据此，我们提出科学假设：FABP4/5双重抑制剂可用于NASH治疗，且比单纯FABP4抑制剂更有效。本项目将对此进行概念证明及机制研究。而FABP4/5双重抑制剂研究的瓶颈问题在于选择性，即如何避免抑制FABP3。本项目将采用分子模拟和结构生物学方法为该问题提供解决方案。前期已获得具有较好FABP4/5抑制活性和选择性的先导化合物，解析了其与FABP4、FABP5的复合物晶体结构。本项目将深入进行结构优化和评价，有望为FABP4/5双重抑制剂用于NASH的治疗提供理论依据及全新结构类型的候选化合物。

Non-alcoholic steatohepatitis (NASH) is threatening human health severely because it can lead to liver cirrhosis, liver failure, and even hepatocellular carcinoma. To date, none effective drug targeting the “two hits” of the NASH pathological mechanism simultaneously has been approved for the treatment of NASH. Fatty acid binding protein 4 and 5 (FABP4/5) are closely related to the "two hits". But the knockout of FABP4 alone in adipocytes led to the significantly compensatory up-regulation of the FABP5 expression. According to these, we proposed our scientific hypothesis that FABP4/5 dual inhibitors can be used for the treatment of NASH and are more effective than FABP4 inhibitors. We will conduct a proof-of-concept and mechanism study in this project. However, the bottleneck of the study of FABP4/5 dual inhibitors lies in selectivity, that is, how to avoid inhibiting FABP3. We will take the methods of molecular simulation and structural biology to provide solution to this problem. The obtained lead compound exhibited potent FABP4/5 inhibitory activity and selectivity. We have also obtained the crystal structures of the lead compound in complex with FABP4 and FABP5, respectively. This project will carry out an in-depth study on structural optimization and biological evaluation, providing the theoretical basis and candidate compounds of novel structural types for the treatment of NASH with FABP4/5 dual inhibitors.