基于激酶Mnk1/2选择性抑制的海洋天然产物结构改造及其在代谢性疾病中应用

过度饮食和其他不良生活方式导致肥胖和相关疾病，造成严重且迅速增加的代谢性疾病及相关并发症，这增加了卫生保健负担，也是导致这次新冠肺炎病死率提高的主因之一。蛋白激酶Mnks存在于肝脏、骨骼肌、心脏和脂肪组织中，参与脂肪细胞分化及胰岛素调节的新陈代谢，是代谢性疾病药物研发的新靶点。本课题在前期研究基础上，1）利用Mnk1的晶体结构，通过计算机辅助分析，在海洋天然产物3D结构数据库中获得海洋苗头化合物；2）通过分析Mnk1/2的蛋白基因特点，基于Mnk1结构特征对海洋来源的苗头化合物进行结构优化、分子设计、合成和生物活性测试，获得特异性MnK1/2的抑制剂，而不影响其他激酶活性；3）通过肥胖、糖尿病小鼠的降脂、降糖等作用机制进行成药性研究。本课题首次以Mnks为靶点研发代谢性疾病药物，通过控制脂质的堆积和代谢，从而控制体重的增加，预防肥胖引发的二型糖尿病。本课题具有海洋药物研究与开发的特色。

Overeating and other unhealthy living habits led to obesity and related diseases, resulting in severe and rapidly increasing metabolic diseases and related complications in the world, which aroused a huge and rapidly increasing burden on health care, and are also one of the main causes of the increase in case fatality rate of COVID 19. Mnks (Mitogen-activated Protein Kinase (MAPK) Interacting Kinases) is the only enzyme that phosphorylates eIF4E and it is found in the liver, skeletal muscle, heart and adipose tissues. Moreover, Mnks are involved in the differentiation of precursor cells into adipocytes and insulin - regulated metabolism. So it is a new target for drug development in metabolic diseases. Based on our preliminary study, the task of this project include: 1) obtain the marine hit compounds from the 3D structure database of marine natural products (MarinChem3D，http://mc3d.qnlm.ac/) by analyzing the protein characteristics of Mnk1/2 and using computer-assisted analysis; 2) obtain specific Mnk1/2 inhibitors which don’t affect other kinase activities by structure optimization of marine hit compound, molecular design, chemical synthesis and biological activity screening on the study of Mnk1 structure characteristics, 3) obtain the lead compound of MNK inhibitors by study the drug-ability through the research of reducing fat and glucose in obese and diabetic mice in vivo. This is the first time that Mnks has been targeted to develop a drug for metabolic diseases. The aim of this project is to obtain drugs for weight control and type II diabetes prevention by controlling lipid accumulation and metabolism. This subject has the characteristics of research and development of marine drugs.