Novel Alkynylamide-Based Nonpeptidic Allosteric Inhibitors for SARS-CoV-2 3-Chymotrypsin-like Protease
Jian Xue, Hongtao Li, Ruyu Wang, Meiting Wang, Xixiang Chen, Yaqi Deng, Jiani Lu, Y.N. Li, Yuheng Song, Jianrong Xu, Tong Zhu, Lili Chen, Shunying Liu · ACS Pharmacology & Translational Science · 2024
Although the coronavirus disease 2019 (COVID-19) crisis has passed, there remains a necessity for continuous efforts toward developing more targeted drugs and preparing for potential future virus attacks. Currently, most of the drugs received authorization for the treatment of COVID-19 have exhibited several limitations, such as poor metabolic stability, formidable preparation, and uncertain effectiveness. It is still significant to develop novel, structurally diverse small-molecule antiviral drugs targeting SARS-CoV-2 3-chymotrypsin-like protease (3CL pro ). Herein, we report a class of alkynylamide-based nonpeptidic 3CL pro inhibitors that can be prepared conveniently by our previously developed one-pot synthetic method. The structure–activity relationships of alkynylamides as SARS-CoV-2 3CL pro inhibitors have been carefully investigated and discussed in this study. The two stereoisomers of the resulting molecules exhibit stereoselective interaction with 3CL pro, and the optimized compound ( S, R )- 4y inhibits 3CL pro with high potency (IC 50 = 0.43 μM), low cytotoxicity, and acceptable cell permeability. Compound ( S, R )- 4y presents as a noncovalent inhibitor of 3CL pro against SARS-CoV-2 by the time-dependent inhibition assay (TDI) and mass spectrometry analysis. The Lineweaver–Burk plots, binding energy, surface plasmon resonance, and molecular docking studies suggest that ( S, R )- 4y specifically binds to an allosteric pocket of the SARS-CoV-2 3CL pro . These findings provide a novel class of nonpeptidic alkynylamide-based allosteric inhibitors with high selectivity against SARS-CoV-2 3CL pro featured by a simplified one-pot synthesis at room temperature in air.