Targeting papain-like protease for broad-spectrum coronavirus inhibition
作者机构：State Key Laboratory of Emerging Infectious DiseasesLi Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina Department of MicrobiologyLi Ka ShingFaculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina NHC Key Laboratory of Systems Biology of PathogensInstitute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China School of Biomedical SciencesLi Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina Department of Molecular and Medical PharmacologyDavid Geffen School of MedicineUniversity of California Los AngelesLos AngelesCAUSA Key Laboratory of Tropical Translational Medicine of Ministry of EducationHainan Medical UniversityHaikou 571199China Academician Workstation of Hainan ProvinceHainan Medical UniversityHaikou 571199China Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious DiseasesThe University of Hong KongPokfulamHong Kong Special Administrative RegionChina Guangzhou LaboratoryGuangzhou 510320China Department of Clinical Microbiology and Infection ControlThe University of Hong Kong-Shenzhen HospitalShenzhen 518053China
出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)
年 卷 期：2022年第13卷第12期
页 面：940-953页
核心收录：
学科分类：0710[理学-生物学] 0831[工学-生物医学工程（可授工学、理学、医学学位）] 1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 0703[理学-化学] 0836[工学-生物工程] 10[医学]
基 金：partly supported by funding from Health@InnoHK,Innovation and Technology Commission,the Government of the Hong Kong Special Administrative Region Theme-Based Research Scheme of the Research Grants Council(T11-709/21-N) the National Program on Key Research Project of China(2020YFA0707500 and 2020YFA0707504) Guangdong Natural Science Foundation(2022A1515010099) the University of Hong Kong Outstanding Young Researcher Award the University of Hong Kong Li Ka Shing Faculty of Medicine Research Output Prize the High Level-Hospital Program,Health Commission of Guangdong Province,China the research project of Hainan Academician Innovation Platform(YSPTZX202004) Emergency Key Program of Guangzhou Laboratory(EKPG22-01) the Swiss National Science Foundation,the National Research Programme Covid-19(No.4078P0_198290/1)
主 题：protease inhibitor coronavirus Nsp3 antiviral
摘 要：The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral *** the multi-functional papain-like protease(PLpro)domain of the viral nsp3 holds ***,none of the known coronavirus PLpro inhibitors has been shown to be in vivo ***,we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity,including against the Sarbecoviruses(SARSCoV-1 and SARS-CoV-2),Merbecovirus(MERS-CoV),as well as the Alphacoronavirus(hCoV-229E and hCoVOC43).Importantly,F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice.F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage,as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase *** the significant difference of substrate recognition,mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue,whereas an allosteric inhibitor of MERSPLpro interacting with its 271E *** proof-ofconcept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anticoronavirus *** orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
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