Discovery and optimization of AAK1 inhibitors based on 1H-indazole scaffold for the potential treatment of SARS-CoV-2 infection.

The process of various virus entry into host cells, including SARS-CoV-2, is mediated by clathrin-mediated endocytosis (CME). AP-2 plays a crucial role in this process by recognizing membrane receptors and binding with clathrin, facilitating the formation of clathrin-coated vesicles and promoting CME. AAK1 catalyzes the phosphorylation of AP2M1 subunit at Thr156. Therefore, suppressing AAK1 activity can hinder virus invasion by blocking CME. indicating that AAK1 could be a potential target for developing novel antiviral drugs against SARS-CoV-2. In this study, we present a series of novel AAK1 inhibitors based on previously reported AAK1 inhibitors. Drug design was carried out by fusing the 1H-indazole scaffold of SGC-AAK1-1 with pharmacophore groups of compound 6, and further optimized with the assistance of molecular docking. Among the 42 compounds novelly synthesized, compounds 9i, 9s, 11f and 11l exhibited comparable antiviral activity against SARS-CoV-2 infection compared to reference compound 6 at the concentration of 3 μM. Particularly, 11f showed almost no cytotoxicity at all tested concentrations. Additionally, 11f exhibited favorable predictive pharmacokinetic properties. These findings support the potential of 11f as a lead compound for developing antiviral drugs targeting SARS-CoV-2 infection, as well as potentially other viruses which are dependent on the CME process to enter host cells. In summary, we have expanded the structural types of AAK1 inhibitors and successfully obtained effective AAK1 inhibitors with antiviral capabilities.