靶向MyD88的PROTACs的发现及其在急性肺损伤中的作用研究

新冠肺炎病毒、肺炎链球菌等引起的急性肺损伤一直危害着人类的健康，且目前临床上尚无有效的靶向药物。髓样分化因子88（MyD88）是炎症信号传导的关键衔接蛋白，近几年被认为是研发治疗急性肺损伤药物的重要靶标，但现有的MyD88拟肽类抑制剂普遍存在结构不稳定、抗炎效果弱等缺陷。前期申请人发现了新型噻唑酰胺类化合物LM9，它能够特异性地结合于 MyD88的TIR结构域，从而抑制MyD88寡聚化和炎症信号传导。在本项目中，我们拟基于LM9，针对MyD88蛋白表面平滑而“难靶”的特点，设计合成一类针对MyD88的蛋白降解靶向嵌合体（PROTAC）分子。随后测试化合物对MyD88蛋白的亲和力、降解效率，考察体内外抗炎活性，进而评价该类PROTAC分子在急性肺损伤中的作用。本项目将为MyD88抑制剂及感染性急性肺损伤的治疗提供新的研究思路。

Acute lung injury caused by infectious pathogens has always been a threat of human health and there is no effective targeting drug in clinical practice. Myeloid differentiation factor 88 (MyD88) is a key adaptor protein in inflammatory signaling pathways. Recently, MyD88 has been considered as an important target for the treatment of acute inflammatory diseases. Currently reported MyD88 inhibitors, generally have defects such as unstable structure and weak anti-inflammatory effect. The new thiazolamide compound LM9 discovered by the applicant can specifically bind to the TIR domain of MyD88, thereby inhibiting the MyD88 oligomerization. Based on the smooth surface of MyD88 protein, in this project, we plan to design and synthesize a class of PROTAC molecules that can act as degraders. The binding affinities and degradation efficiency of the inhibitor against MyD88 protein and the anti-inflammatory activity in vitro and in vivo are tested to evaluate the pharmacological effects of the compound in acute lung injury. This project will provide novel potent MyD88 inhibitors for the treatment of pathogens caused acute lung injury.