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Virologica Sinica 2016年第4期31卷 288-299页

作者： Jian Lei Rolf Hilgenfeld Institute of Biochemistry Center for Structural and Cell Biology in MedicineUniversity of Lübeck German Center for Infection Research (DZIF) University of Lübeck

The papain-like protease(PL^(pro)) of Middle-East respiratory syndrome coronavirus(MERS-CoV) has proteolytic,deubiquitinating,and de ISGylating *** latter two are involved in the suppression of the antiviral innate immune response of the host *** contribute to an understanding of this process,we present here the X-ray crystal structure of a complex between MERS-CoV PL^(pro) and human ubiquitin(Ub) that is devoid of any covalent linkage between the two *** regions of the PL^(pro) bind to two areas of the *** C-terminal five residues of Ub,RLRGG,are similar to the P5–P1 residues of the polyprotein substrates of the PL^(pro) and are responsible for the major part of the interaction between the two *** sitedirected mutagenesis,we demonstrate that conserved Asp165 and non-conserved Asp164 are important for the catalytic activities of MERS-CoV PL^(pro).The enzyme appears not to be optimized for catalytic efficiency; thus,replacement of Phe269 by Tyr leads to increased peptidolytic and deubiquitinating *** binding by MERS-CoV PL^(pro) involves remarkable differences compared to the corresponding complex with SARS-CoV PL^(pro).The structure and the mutational study help understand common and unique features of the deubiquitinating activity of MERS-CoV PL^(pro).

关键词： coronavirus Middle-East respiratory syndrome(MERS) papain-like protease ubiquitin deubiquitinase

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

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Journal of Pharmaceutical Analysis 2020年第6期10卷 546-559页

作者： Mubarak A.Alamri Muhammad Tahir ul Qamar Muhammad Usman Mirza Safar M.Alqahtani Matheus Froeyen Ling-Ling Chen Department of Pharmaceutical Chemistry College of PharmacyPrince Sattam Bin Abdulaziz UniversityAlkarjSaudi Arabia College of Life Science and Technology Guangxi UniversityNanningChina Department of Pharmaceutical and Pharmacological Sciences Rega Institute for Medical ResearchMedicinal ChemistryUniversity of LeuvenB-3000LeuvenBelgium Hubei Key Laboratory of Agricultural Bioinformatics College of InformaticsHuazhong Agricultural UniversityWuhan430070China

The papain-like protease(PLpro)is vital for the replication of coronaviruses(Co Vs),as well as for escaping innate-immune responses of the ***,it has emerged as an attractive antiviral *** this study,computational approaches were employed,mainly the structure-based virtual screening coupled with all-atom molecular dynamics(MD)simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)PLpro,which can be further developed as potential pan-PLprobased broad-spectrum antiviral *** sequence,structure,and functional conserveness of most deadly human Co Vs PLprowere explored,and it was revealed that functionally important catalytic triad residues are well conserved among SARS-Co V,SARS-Co V-2,and middle east respiratory syndrome coronavirus(MERS-Co V).The subsequent screening of a focused protease inhibitors database composed of^7,000 compounds resulted in the identification of three candidate compounds,ADM13083841,LMG15521745,and *** three compounds established conserved interactions which were further explored through MD simulations,free energy calculations,and residual energy contribution estimated by MM-PB(GB)SA *** these compounds showed stable conformation and interacted well with the active residues of SARS-Co V-2 PLpro,and showed consistent interaction profile with SARS-Co V PLproand MERS-Co V PLproas ***,the reported SARS-Co V-2 PLprospecific compounds could serve as seeds for developing potent pan-PLprobased broad-spectrum antiviral drugs against deadly human ***,the presented information related to binding site residual energy contribution could lead to further optimization of these compounds.

关键词： COVID-19 MERS-CoV Molecular dynamic simulation Pan-inhibitors papain-like protease SARS-CoV SARS-CoV-2 Virtual screening

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

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4189-4192页

作者： Mianling Yang Meehyein Kim Peng Zhan Department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesShandong UniversityJi’nan 250012China Infectious Diseases Therapeutic Research Center Korea Research Institute of Chemical Technology(KRICT)Daejeon 34114Republic of Korea

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(PL^(pro)).The study demonstrated nanomolar PL^(pro) inhibitory potency with K_(i) 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(Val70^(Ub))-binding site and the known blocking loop(BL2)groove near the S4 subsite of PL^(pro).Furthermore,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-pronged”binding 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(EC_(50):0.44-2.02 μmol/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。

关键词： SARS-CoV-2 papain-like protease Broad-spectrum Anti-drug resistance Drug candidate

Schaftoside inhibits 3CL^(pro)and PL^(pro)of SARS-CoV-2 virus and regulates immune response and inflammation of host cells for the treatment of COVID-19

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Acta Pharmaceutica Sinica B 2022年第11期12卷 4154-4164页

作者： Yang Yi Meng Zhang Heng Xue Rong Yu Yang-Oujie Bao Yi Kuang Yue Chai Wen Ma Jing Wang Xiaomeng Shi Wenzhe Li Wei Hong Junhua Li Elishiba Muturi Hongping Wei Joachim Wlodarz Szczepan Roszak Xue Qiao Hang Yang Min Ye State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China CAS Key Laboratory of Special Pathogens and Biosafety Center for Biosafety Mega-ScienceWuhan Institute of VirologyChinese Academy of SciencesWuhan 430071China University of Chinese Academy of Sciences Bejing 100049China Faculty of Science and Technology University of SilesiaKatowice 40-007Poland Department of Phrysical and Quantum Chenmistry Faculty of ChemistryWroclaw University of Science and Technology Wroclaw 50-370Poland

It is an urgent demand worldwide to control the coronavirus disease 2019(COVID-19)pandemic caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)*** 3-chymotrypsin-like protease(3CL^(pro))and papain-like protease(PL^(pro))are key targets to discover SARS-CoV-2 *** screening 12 Chinese herbal medicines and 125 compounds from licorice,we found that a popular natural product schaftoside inhibited 3CL^(pro)and PL^(pro)with IC_(50)values of 1.73±0.22 and 3.91±0.19μmol/L,respectively,and inhibited SARS CoV-2 virus in Vero E6 cells with EC_(50)of 11.83±3. 23μmol/L. Hydrogen-deuterium exchange mass spectrometry analysis, quantum mechanics/molecular mechanics calculations, together with site-directed mutagenesis indicated the antiviral activities of schaftoside were related with non-covalent interactions with H41, G143 and R188 of3CLpro, and K157, E167 and A246 of PLpro. Moreover, proteomics analysis and cytokine assay revealed that schaftoside also regulated immune response and inflammation of the host cells. The antiinflammatory activities of schaftoside were confirmed on lipopolysaccharide-induced acute lung injury mice. Schaftoside showed good safety and pharmacokinetic property, and could be a promising drug candidate for the prevention and treatment of COVID-19.

关键词： COVID-19 SARS-CoV-2 3-Chymotrypsin-like protease papain-like protease Licorice Schaftoside Immune response Infammation

Coronavirus papain-like proteases induce incomplete autophagy through interacting with Beclin 1 to negatively regulate antiviral innate immunity

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Coronavirus papain-like proteases induce incomplete autophag...

Coronavirus papain-like proteases induce autophagy but block autophagosome fusion with lysosomes through interacting with Beclinl

第九届全国免疫学学术大会

作者： Zhongbin Chen Xiaojuan Chen Kai Wang Yaling Xing Xingxing Yang Qian Zhao Beijing Institute of Radiation Medicine

Autophagy plays important roles in modulating viral replication and antiviral immune *** infection is associated with the autophagic process,however,little is known about the mechanisms of autophagy induction and its contribution to coronavirus regulation of host innate ***,we show that the membrane-associated papain-like protease PLP2(PLP2-TM)of coronaviruses acts as a novel autophagy-inducing ***,PLP2-TM induces incomplete autophagy process by increasing the accumulation of autophagosomes but blocking the fusion of autophagosomes with ***,PLP2-TM interacts with the key autophagy regulators,LC3 and Beclinl,and promotes Beclinl interaction with STING,the key regulator for antiviral IFN ***,Knockdown of Beclin 1partially reverses PLP2-TM’s inhibitory effect on innate immunity which resulting in decreased coronavirus *** results suggested that coronavirus papain-like protease induces incomplete autophagy by interacting with Beclin 1,which in turn modulates coronavirus replication and antiviral innate immunity.

关键词： Coronavirus papain-like protease Autophagy Antiviral immunity Beclinl STING

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Coronavirus papain-like proteases induce autophagy but block...

High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors

细胞—生命的基础——中国细胞生物学学会2013年全国学术大会·武汉

作者： Zhongbin Chen Kai Wang Xiaojuan Chen Yaling Xing Xingxing Yang Beijing Institute of Radiation Medicine

关键词： Coronavirus NL63 papain-like protease Autophagy Beclinl STING

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Protein & Cell 2021年第11期12卷 877-888页

作者： Yao Zhao Xiaoyu Du Yinkai Duan Xiaoyan Pan Yifang Sun Tian You Lin Han Zhenming Jin Weijuan Shang Jing Yu Hangtian Guo Qianying Liu Yan Wu Chao Peng Jun Wang Chenghao Zhu Xiuna Yang Kailin Yang Ying Lei Luke W.Guddat Wenqing Xu Gengfu Xiao Lei Sun Leike Zhang Zihe Rao Haitao Yang Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China Laboratory of Structural Biology School of Life Sciences and School of MedicineTsinghua UniversityBeijing 100091China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China The Fifth People's Hospital of Shanghai Fudan University and Shanghai Key Laboratory of Medical EpigeneticsInstitutes of Biomedical SciencesFudan UniversityShanghai 200032China Zhangjiang Lab National Facility for Protein Science in ShanghaiShanghai Advanced Research InstituteChinese Academy of ScienceShanghai 201210China Taussig Cancer Center Cleveland ClinicClevelandOH 44195USA School of Chemistry and Molecular Biosciences The University of QueenslandBrisbaneQueensland 4072Australia

A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 ***,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identify new anti-COVID-19 *** this study,we screened over 6,000 compounds that included approved drugs,drug candidates in clinical trials,and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease(PLpro).Together with main protease(Mpro),PLpro is responsible for processing the viral replicase polyprotein into functional ***-fore,it is an attractive target for antiviral drug *** we discovered four compounds,YM155,cryptotanshinone,tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 pmol/*** compounds also exhibit strong antiviral activities in cell-based ***155,an anti-cancer drug candidate in clinical trials,has the most potent antiviral activity with an EC50 value of 170 nmol/*** addition,we have determined the crystal structures of this enzyme and its complex with YM155,revealing a unique binding ***155 simultaneously targets three"hot"spots on PLpro,including the substrate-binding pocket,the interferon stimulating gene product 15(ISG15)binding site and zinc finger *** results demonstrate the efficacy of this screening and repur-posing strategy,which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.

关键词： SARS-CoV-2 papain-like protease YM155 interferon stimulating gene product 15 drug repurposing

Coronavirus papain-like proteases induce autophagy but block autophagosome fusion with lysosomes through interacting with Beclin 1

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Coronavirus papain-like proteases induce autophagy but block...