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

作　　者：Letian Song Shenghua Gao Bing Ye Mianling Yang Yusen Cheng Dongwei Kang Fan Yi Jin-Peng Sun Luis Menéndez-Arias Johan Neyts Xinyong Liu Peng Zhan 

机构地区：[1]Department of Medicinal Chemistry,Key Laboratory of Chemical Biology(Ministry of Education),School of Pharmaceutical Sciences,Cheeloo College of Medicine,Shandong University,Jinan 250012,China [2]Shenzhen Research Institute of Shandong University,Shenzhen 518057,China [3]The Key Laboratory of Infection and Immunity of Shandong Province,Department of Pharmacology,School of Basic Medical Sciences,Shandong University,Jinan 250012,China [4]Key Laboratory Experimental Teratology of the Ministry of Education,Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Cheeloo College of Medicine,Shandong University,Jinan 250012,China [5]Centro de Biologı´a Molecular“Severo Ochoa”(Consejo Superior de Investigaciones Cientı´ficas&Autonomous University of Madrid),Madrid 28049,Spain [6]KU Leuven,Department of Microbiology and Immunology,Rega Institute for Medical Research,Laboratory of Virology and Chemotherapy,Leuven 3000,Belgium

出　　处：《Acta Pharmaceutica Sinica B》2024年第1期87-109,共23页药学学报（英文版）

基　　金：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 PID2019-104176RBI00/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.Luis Menéndez-Arias is member of the Global Virus Network.

摘　　要：The main protease(M^(pro))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 M^(pro)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 M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable druggability.Numerous non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)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 M^(pro)inhibitors are also discussed.

关 键 词：COVID-19 SARS-CoV-2 Main protease Non-covalent inhibitors Medicinal chemistry strategies 

分 类 号：R914[医药卫生—药物化学]