Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

The main protease (Mpro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent Mpro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent Mpro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent Mpro inhibitors with desirable properties have been developed based on available crystal structures of Mpro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent Mpro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent Mpro inhibitors are also discussed.We gratefully acknowledge financial support from Major Basic Research Project of Shandong Provincial Natural Science Foundation (ZR2021ZD17, China), Science Foundation for Outstanding Young Scholars of Shandong Province (ZR2020JQ31, China), Foreign Cultural and Educational Experts Project (GXL20200015001, China), Guangdong Basic and Applied Basic Research Foundation (2021A1515110740, China), China Postdoctoral Science Foundation (2021M702003). This work was supported in part by the Ministry of Science and Innovation of Spain through grant PID2019-104176RB-I00/AEI/10.13039/501100011033 awarded to Luis Menéndez-Arias; An institutional grant of the Fundación Ramón Areces (Madrid, Spain) to the CBMSO is also acknowledged.Peer reviewe