新型抗糖尿病药物靶标FABP4及其小分子抑制剂药理机制研究

The development of type 2 diabetes is highly associated with abnormal lipids metabolism and non-infectious inflammatory in peripheral tissues. Recently, the adipocyte fatty acid binding protein (FABP4) has been proven to contribute to obesity related type 2 diabetes and plays a key role in lipid metabolism and inflammatory response. Deficiency of FABP4 genes could improve high fatty food-induced diabetes in rodents. Clinical studies also confirmed that there could be reduced risk of diabetes in persons whom have lower serum FABP4 level. Therefore, research on FABP4 inhibitors has become hotspot in development of anti-diabetic drugs. We discovered novel FABP4 inhibitors with proprietary intellectual property rights via in vitro screening. One of the small molecule inhibitor, I-10, could inhibit FABP4 with high efficiency and specificity. It could decrease blood glucose in type 2 diabetic db/db mice, insulin resistance and inflammatory in peripheral tissues. In this study, the pharmacological mechanism of the anti-diabetic effect of I-10 would be further investigated in multiple in vitro and in vivo models, and the druggability of I-10 would be also evaluated. Meanwhile, gene interference and overexpression technology would be used to study the role of FABP4 in the development of type 2 diabetes. This study would provide novel evidences to increase the validity and safety of FABP4 as a drug target in the treatment of diabetes.

2型糖尿病的发生发展与脂质代谢异常及外周组织非感染性炎症反应关系密切。脂肪细胞型脂肪酸结合蛋白（FABP4）近年来被证实与肥胖2型糖尿病密切相关，在脂质代谢及炎症反应中起极其重要作用。FABP4基因缺陷可减轻高脂诱导糖尿病小鼠症状，血清FABP4水平较低的个体患2型糖尿病的机率降低。FABP4抑制剂已成为新型抗糖尿病药物研发热点。我们发现了一类新型具有自主知识产权的FABP4小分子抑制剂，其中化合物I-10与已报道的FABP4抑制剂相较有其独特优势，其对FABP4具有良好的抑制作用及选择性，能有效降低db/db 2型糖尿病小鼠血糖，减轻外周组织胰岛素抵抗及炎症。本项目拟在多种体外细胞模型及糖尿病动物模型中评价化合物I-10降糖药效机制，评估其成药性。同时结合体内外基因干扰及过表达技术，深入研究FABP4在糖尿病发生发展过程中的作用，为FABP4作为抗糖尿病靶标的有效性和安全性提供依据。

2型糖尿病的发生发展与脂质代谢异常及外周组织非感染性炎症反应关系密切。脂肪细胞型脂肪酸结合蛋白（FABP4）近年来被证实与肥胖2 型糖尿病密切相关，在脂质代谢及炎症反应中发挥极其的重要作用。我们对FABP4小分子抑制剂I-10在体内多种模型上进行了药理药效学研究，发现其能在2型糖尿病db/db模型小鼠、高血FABP4模型小鼠上拮抗FABP4的作用，改善了肥胖诱导的高胰岛素血症和外周胰岛素抵抗；我们的机制研究结果证实，外源高水平FABP4可以通过下调Beclin1和Atg7抑制细胞自噬活性，进而干预胰岛β细胞中储备胰岛素的正常降解、促进肝细胞脂质异位聚集，推动高胰岛素血症和外周胰岛素抵抗的发生和发展，另一方面可以通过显著下调PPARγ、C/EBPα的表达抑制了脂肪细胞的脂质聚集和分化；通过促进脂解激活P38 MAPK和NFκB通路，进而促进了脂肪细胞的炎症因子分泌，诱导了脂肪细胞的炎症，并减少Adiponectin的表达，扰乱了脂肪细胞的正常分泌功能。FABP4抑制剂能够改善上述外源FABP4引起的病理改变。对I-10的成药性进行了相关评价，结果发现其成药性质不够理想，我们随后通过结构改造发现了活性更好、选择性更高的新颖FABP4小分子抑制剂；继之，为解决FABP5代偿引起的FABP4抑制剂药效不够理想的弊端，开展了FABP4/5双靶抑制剂的研究，并发现了一类FABP4/5双靶抑制剂，其在细胞水平生物活性优于FABP4单靶抑制剂，为FABP4/ FABP5双重抑制剂作为抗糖尿病药物的研发奠定了基础。综上所述，我们的研究揭示了FABP4促进高胰岛素血症和胰岛素抵抗的机制，为2型糖尿病发病机制研究及糖尿病防治提供了新的思路，同时研究发现了新型FABP4小分子抑制剂和FABP4/5双重抑制剂，项目的研究结果对研究开发基于全新机制的抗糖尿病药物和防治糖尿病具有积极而重大的意义。