Parthenolide reveals an allosteric mode to inhibit the delSGylation activity of SARS-CoV-2 papain-like protease  

作　　者：Zhihui Zou Huizhuang Shan Demeng Sun Li Xia Yulong Shi Jiahui Wan Aiwu Zhou Yunzhao Wu Hanzhang Xu Hu Lei Zhijian Xu Yingli Wu 

机构地区：[1]Hongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Chinese Academy of Medical Sciences Research Unit 2019RU043,Shanghai Jiao Tong University School of Medicine(SJTU-SM),Shanghai 200025,China [2]Laboratory Medicine,Guangdong Provincial People’s Hospital,Guangdong Academy of Medical Sciences,Guangzhou,Guangdong 510000,China [3]Tsinghua-Peking Center for Life Sciences,Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology(Ministry of Education),Beijing Advanced Innovation Center for Structural Biology,Department of Chemistry,Tsinghua University,Beijing 100084,China [4]CAS Key Laboratory of Receptor Research,Drug Discovery and Design Center,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China

出　　处：《Acta Biochimica et Biophysica Sinica》2022年第8期1133-1139,共7页生物化学与生物物理学报（英文版）

基　　金：This work was supported in part by the grants from the National Key Research and Development Program of China(No.2017YFA0505200);Science and Technology Committee of Shanghai(Nos.19ZR1428700,and 20ZR1430600);the National Natural Science Foundation of China(Nos.82170145,81700157,and 81700475);Innovative research team of high-level local universities in Shanghai(No.SHSMU-ZDCX20211802).

摘　　要：The coronavirus papain-like protease(PLpro)of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is responsible for viral polypeptide cleavage and the deISGylation of interferon-stimulated gene 15(ISG15),which enable it to participate in virus replication and host innate immune pathways.Therefore,PLpro is considered an attractive antiviral drug target.Here,we show that parthenolide,a germacrane sesquiterpene lactone,has SARS-CoV-2 PLpro inhibitory activity.Parthenolide covalently binds to Cys-191 or Cys-194 of the PLpro protein,but not the Cys-111 at the PLpro catalytic site.Mutation of Cys-191 or Cys-194 reduces the activity of PLpro.Molecular docking studies show that parthenolide may also form hydrogen bonds with Lys-192,Thr-193,and Gln-231.Furthermore,parthenolide inhibits the deISGylation but not the deubiquitinating activity of PLpro in vitro.These results reveal that parthenolide inhibits PLpro activity by allosteric regulation.

关 键 词：COVID-19 SARS-CoV-2 PLpro PARTHENOLIDE deISGylation 

分 类 号：R563.1[医药卫生—呼吸系统]