靶向AAK1的抗冠状病毒候选药物研究：设计合成、构效关系研究，及作用机制探索

包括COVID-19和SARS-CoV在内的冠状病毒对全球人类健康构成严重威胁，造成的经济损失不可估量。迄今，治疗药物有限，特别是尚未有针对COVID-19的特效药物，其主要原因是采用小分子干预冠状病毒入侵和抗病毒的机制尚不清楚。最近国际研究发现，衔接子蛋白相关激酶1型（AAK1）在病毒侵入宿主细胞过程中扮演重要角色，靶向AAK1具有抗登革热和埃博拉病毒的活性。本项目拟在前期发现的吡咯并嘧啶类先导化合物HZNU-1068的基础上，设计6类全新结构的AAK1抑制剂。经循环结构优化，遴选出5-8个强效抑制剂，探索其调控AAK1活性、AP-2磷酸化、干预CME的过程，以及阻止冠状病毒入侵的抗病毒机制。项目的总体目标是：合成120个全新化合物、完成抗病毒活性筛选及机制研究、PK评价和体内抗病毒药效研究，从中发现2-3个强效化合物，并验证AAK1作为抗冠状病毒生物靶点的可行性和广谱性。

Coronaviruses including COVID-19 and SARS-CoV pose a serious threat to global human health and cause inestimable economic losses. Up to date, no specific drug has been developed against these viruses, especially COVID-19. The major reason for this is that the mechanism of using small molecules to intervene coronaviruses infection remains elusive. Recent advances suggest that AP-2 associated protein kinase 1 (i.e. AAK1) plays a pivotal role in viral entry, hence compounds targeting AAK1 showed the antiviral activity against the Dengue virus and Ebola. Based on HZNU-1068, a lead compound of pyrrolopyrimidine class AAK1 inhibitor discovered previously in our laboratory, this project sets up to design six new classes of novel AAK1 inhibitors. After repeated lead optimization, 5-8 potent AAK1 inhibitors will be identified and used in probing anti-coronaviruses mechanism from the following aspects: modulating AAK1 enzymatic activity, AP-2 phosphorylation, clathrin-mediated endocytosis (CME), and prevention of viral invasion. The overall goal of the project is to synthesize 120 new compounds, screening them in the antiviral assay, followed by antiviral mechanism elucidation, PK assessment, and finally the in vivo antiviral efficacy studies. We plan to identify 2-3 preclinical candidates with potent anti-coronavirus activity and verify the feasibility of AAK1 kinase as a broad-spectrum anti-coronavirus biological target.