Jun12682, a potent SARS-CoV-2 papain-like protease inhibitor with exceptional antiviral efficacy in mice

作     者：Yang, Mianling Kim, Meehyein Zhan, Peng 

作者机构：Shandong Univ Sch Pharmaceut Sci Dept Med Chem Key Lab Chem BiolMinist Educ Jinan 250012 Peoples R China Korea Res Inst Chem Technol KRICT Infect Dis Therapeut Res Ctr Daejeon 34114 South Korea 

出 版 物：《ACTA PHARMACEUTICA SINICA B》 (药学学报（英文版）)

年 卷 期：2024年第14卷第9期

页      面：4189-4192页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：Key Research and Development Program Ministry of Science and Technology of the People's Republic of China [2023YFC2606500] Shandong Laboratory Program [SYS202205] Korea Health Industry Development Institute (KHIDI) - Ministry of Health Welfare Republic of Korea [HI22C2067] 

主　　题：SARS-CoV-2 Papain-like protease Broad-spectrum Anti-drug resistance Drug candidate 

摘      要：Recently,a collaborative research study published in Science,led by Jun Wang,Xufang Deng,Eddy Arnold,and Francesc Xavier Ruiz1,identified a series of potent small molecule inhibitors that specifically target SARS-CoV-2 papain-like protease(PLpro).The study demonstrated nanomolar PLpro inhibitory potency with Ki values ranging from 13.2 to 88.2 nmol/*** employing a structure-based drug design strategy,the researchers discovered an exceptionally promising compound,named Jun12682,that effectively targets both the newly discovered ubiquitin Val70(Val70Ub)-binding site and the known blocking loop(BL2)groove near the S4 subsite of ***,studies on the mechanism of action revealed that Jun12682 inhibits the deubiquitinating and deISGylating activities of PLpro,which are crucial for antagonizing the host’s innate immune response upon viral *** biology studies confirmed the“two-prongedbinding mode of Jun12682,aligning perfectly with their drug design ***,Jun12682 exhibited potent antiviral activity against SARS-CoV-2 and its variants,including nirmatrelvir-resistant mutants,in Caco-2 cells(EC50:0.44e2.02 mmol/L).It is noteworthy that its oral administration significantly improved survival rates and alleviated both lung virus loads and histopathological lesions in a lethal SARS-CoV-2 mouse *** conclusion。