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Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

Signal Transduction and Targeted Therapy 2024年第4期9卷 1651-1664页

作者： Xiong Xie Qiaoshuai Lan Jinyi Zhao Sulin Zhang Lu Liu Yumin Zhang Wei Xu Maolin Shao Jingjing Peng Shuai Xia Yan Zhu Keke Zhang Xianglei Zhang Ruxue Zhang jian Li Wenhao Dai Zhen Ge Shulei Hu Changyue Yu Jiang Wang Dakota Ma Mingyue Zheng Haitao Yang Gengfu Xiao zihe rao Lu Lu Leike Zhang Fang Bai Yao Zhao Shibo Jiang Hong Liu Drug Discovery and Design Center State Key Laboratory of Drug ResearchCAS Key Laboratory of Receptor ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS) School of Basic Medical SciencesShanghai Institute of Infectious Disease and BiosecurityFudan UniversityShanghai 200032China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China School of Chinese Materia Medica Nanjing University of Chinese Medicine138 Xian Lin RoadJiangsu 210023 NanjingChina School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China National Clinical Research Center for Infectious Disease Shenzhen Third People's HospitalShenzhen 518112China

Respiratory disease caused by coronavirus infection remains a global health *** several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their effcacy on emerging coronaviruses in the future,including SARS-CoV-2 variants,might be ***-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging *** L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune ***,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and *** X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of a-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of *** showed potent and broad-spectrum anticoronaviral activities in vitro,and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern(VOCs)with ECso values ranging from 0.80 to 161.7 nM in various *** mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral ***,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in *** addition,both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse *** 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%.Further evaluation showed that 14a and 14b exhibited excellent antiinflammatory effects in Raw 264.7 mouse macrophages and in mice with acute *** together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with anti

关键词： calpain overcome entrance

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MCP-1-induced protein-1,an immune regulator

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Protein & Cell 2012年第12期3卷 903-910页

作者： Jiwei Xu Sheng Fu Wei Peng zihe rao National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China

MCP-1-induced protein-1(MCPIP1)is a newly identified protein that is crucial to immune *** lack-ing MCPIP1 gene suffer from severe immune disorders,and most of them cannot survive longer than 12 *** progress has been made in revealing the mechanism underlying the immune regulatory function of ***1 can act as an RNase to promote the mRNA degradation of some inflammatory cytokines,such as IL-6 and ***-microRNAs are also confirmed to be the substrate of MCPIP1 *** structure of MCPIP1 N-terminal conserved domain shows a PilT N-terminus-like RNase structure,further supporting the notion that MCPIP1 has RNase ***1 can also deubiquitinate TNF receptor-associated factor family proteins,which are known to mediate immune and inflammatory *** this review,we summarize recent progress on the immune regulatory role of MCPIP1 and discuss the mechanisms underlying its function.

关键词： MCPIP1 immune regulation RNase deubiquitinating enzyme crystal structure

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High-level expression and secondary structure analysis of the bovine mature prion protein

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Chinese Science Bulletin 2000年第14期45卷 1312-1315页

作者： WANG Dawei YANG Huaiyi rao zihe TIAN Bo Institute of Microbiology Chinese Academy of SciencesBeijing 100080China Laboratory of Structure Biology Tsinghua UniversityBeijing 100084China

By using the recombinant DNA technology, the gene of the bovine mature prion protein bPrPcL) has been cloned into pET30a and the resulting plasmid has been expressed in *** BL21(DE3). After solubilizing in 8 mol/L urea, the expression product was purified by cation ion exchange chromatography. The purified product was refolded by dilution and the recovery was about 15%. Analysis of mass spectrum, circular dichroism (CD) spectrum and Fourier transform infrared (FTIR) spectrum demonstrate that the molecular weight of the bPrPcL is 23 630 u, the bPrPcL has a high α-helix content (36.1%) and low (3-sheet content (11.9%).

关键词： bPrPCL expression CD FTIR secondary structure.

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Crystallization and preliminary X-ray crystallographic analysis of yeast prion protein Ure2p with shortened N-terminal

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Chinese Science Bulletin 2001年第12期46卷 1012-1014页

作者： WANG Liwei ZHU Li ZHOU Junmei rao zihe Laboratory of Structural Biology Department of Biological Sciences and Biotechnology&Protein Sciences Laboratory of MOETsinghua UniversityBeijing 100084China National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China

An orthorhombic crystal form of a recombi-nant yeast prion protein with shortened N-terminal, 90Ure2p, has been obtained. Crystals were grown by the vapordiffu-sion technique against a mother liquor containing imidazole. Crystals belong to the primitive orthorhombic lattice with the cell parameters a = 54.5 A, b = 74.7 A, c = 131.0 A. The crystals diffract to beyond 3.0 A resolution at a synchrotron beamline.

关键词： yeast prion Ure2p crystallization.

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Structures of the N- and C-terminal domains of MHV-A59 nucleocapsid protein corroborate a conserved RNA-protein binding mechanism in coronavirus

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Protein & Cell 2010年第7期1卷 688-697页

作者： Yanlin Ma Xiaohang Tong Xiaoling Xu Xuemei Li Zhiyong Lou zihe rao Life National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Graduate University of the Chinese Academy of Sciences Beijing 100049China Laboratory of Structural Biology Tsinghua UniversityBeijing 100084China

Coronaviruses are the causative agent of respiratory and enteric diseases in animals and *** example is SARS,which caused a worldwide health threat in *** coronaviruses,the structural protein N(nucleocapsid protein)associates with the viral RNA to form the filamentous nucleocapsid and plays a crucial role in genome replication and *** structure of Nterminal domain of MHV N protein also implicated its specific affinity with transcriptional regulatory sequence(TRS)*** we report the crystal structures of the two proteolytically resistant N-(NTD)and C-terminal(CTD)domains of the N protein from murine hepatitis virus(MHV).The structure of NTD in two different crystal forms was solved to 1.5Å.The higher resolution provides more detailed structural information than previous reports,showing that the NTD structure from MHV shares a similar overall and topology structure with that of SARS-CoV and IBV,but varies in its potential surface,which indicates a possible difference in RNA-binding *** structure of CTD was solved to 2.0-Åresolution and revealed a tightly intertwined *** is consistent with analytical ultracentrifugation experiments,suggesting a dimeric assembly of the N *** similarity between the structures of these two domains from SARS-CoV,IBV and MHV corroborates a conserved mechanism of nucleocapsid formation for coronaviruses.

关键词： crystal structure nucleocapsid protein murine hepatitis virus

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Crystal structures of NAC domains of human nascent polypeptide-associated complex (NAC) and its αNAC subunit

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Protein & Cell 2010年第4期1卷 406-416页

作者： Lanfeng Wang Wenchi Zhang Lu Wang Xuejun C.Zhang Xuemei Li zihe rao National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of Sciences15 Datun RoadBeijing 100101China Structure Biology Laboratory Tsinghua UniversityBeijing 100084China Tianjin Key Laboratory of Protein Science College of Life SciencesNankai UniversityTianjin 300071China

Nascent polypeptide associated complex(NAC)and its two isolated subunits,αNAC and βNAC,play important roles in nascent peptide *** determined a 1.9Åresolution crystal structure of the interaction core of NAC heterodimer and a 2.4Åresolution crystal structure ofαNAC NAC domain *** structures provide detailed information of NAC heterodimerization and αNAC *** found that the NAC domains of αNAC and βNAC share very similar folding despite of their relative low identity of amino acid ***,different electric charge distributions of the two subunits at the NAC interface provide an explanation to the observation that the heterodimer of NAC complex is more stable than the single subunit *** addition,we successfully built a βNAC NAC domain homodimer model based on homologous modeling,suggesting that NAC domain dimerization is a general property of the NAC *** 3D structures allow further studies on structurefunction relationship of NAC.

关键词： nascent polypeptide-associated complex αNAC homodimer βNAC crystal structure

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New nsp8 isoform suggests mechanism for tuning viral RNA synthesis

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Protein & Cell 2010年第2期1卷 198-204页

作者： Shuang Li Qi Zhao Yinjie Zhang Yang Zhang Mark Bartlam Xuemei Li zihe rao National Laboratory of Macromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Structural Biology Laboratory Tsinghua UniversityBeijing 100084China Tianjin Key Laboratory of Protein Science College of Life SciencesNankai UniversityTianjin 300071China

During severe acute respiratory syndrome coronavirus(SARS-CoV)infection,the activity of the replication/transcription complexes(RTC)quickly peaks at 6 hours post infection(h.p.i)and then diminishes significantly in the late post-infection ***“down-up-down”regulation of RNA synthesis distinguishes different viral stages:primary translation,genome replication,and finally viron *** the nsp8 as the primase in RNA synthesis,we confirmed that the proteolysis product of the primase(nsp8)contains the globular domain(nsp8C),and indentified the resectioning site that is notably conserved in all the three groups of *** subsequently crystallized the complex of SARS-CoV nsp8C and nsp7,and the 3-D structure of this domain revealed its capability to interfuse into the hexadecamer *** specific proteolysis may indicate one possible mechanism by which coronaviruses to switch from viral infection to genome replication and viral assembly stages.

关键词： nsp8 SARS-CoV RNA primase viral life cycle

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Crystal structure of a secreted lipase from Gibberella zeae reveals a novel “double-lock” mechanism

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Protein & Cell 2010年第8期1卷 760-770页

作者： Zhiyong Lou Ming Li Yuna Sun Ye Liu Zheng Liu Wenping Wu zihe rao Laboratory of Structural Biology Tsinghua UniversityBeijing 100084China Novozymes China 14 Xinxi LuShangdi ZoneHaidian DistrictBeijing 100085China National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China

Fusarium graminearum(sexual stage:Gibberella zeae)is the causative agent of Fusarium Head Blight(FHB),which is one of the most destructive plant disease of cereals,accounting for high grain yield losses,especially for wheat and *** other fungal pathogens,several extracellular enzymes secreted by *** are known to be involved in host *** these secreted lipases,*** lipase(GZEL),which is encoded by the FGL1 gene,was demonstrated to be crucial to *** ***,the precise mechanism of GZEL remains unclear due to a lack of detailed structural *** this study,we report the crystal structure of GZEL at the atomic *** structure of GZEL displays distinct structural differences compared to reported homologues and indicates a unique“double lock”enzymatic *** gain insight into substrate/inhibitor recognition,we proposed a model of GZEL in complex with substrate and the lipase inhibitor ebelactone B(based on the reported structures of GZEL homologues),which defines possible substrate binding sites within the catalytic cleft and suggests an“anti sn-l”binding *** results pave the way to elucidating the mechanism of GZEL and thus provide clues for the design of anti-FHB inhibitors.

关键词： lipase Gibberella zeae crystal structure mechanism inhibitor

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An open conformation determined by a structural switch for 2A protease from coxsackievirus A16

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Protein & Cell 2013年第10期4卷 782-792页

作者： Yao Sun Xiangxi Wang Shuai Yuan Minghao Dang Xuemei Li Xuejun CZhang zihe rao National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China

Coxsackievirus A16 belongs to the family Picornaviridae,and is a major agent of hand-foot-and-mouth disease that infects mostly children,and to date no vaccines or antivi-ral therapies are available.2A protease of enterovirus is a nonstructural protein and possesses both self-cleavage activity and the ability to cleave the eukaryotic translation initiation factor *** we present the crystal structure of coxsackievirus A162A protease,which interestingly forms hexamers in crystal as well as in *** structure shows an open conformation,with its active site accessible,ready for substrate binding and cleav-age *** conjunction with a previously reported“closed”state structure of human rhinovirus 2,we were able to develop a detailed hypothesis for the conforma-tional conversion triggered by two“switcher”residues Glu88 and Tyr89 located within the bll2-cII *** recognition assays revealed that amino acid residues P1′,P2 and P4 are essential for substrate specificity,which was verifi ed by our substrate binding *** addition,we compared the in vitro cleavage effi ciency of 2A pro-teases from coxsackievirus A16 and enterovirus 71 upon the same substrates by fl uorescence resonance energy transfer(FRET),and observed higher protease activity of enterovirus 71 compared to that of coxsackievirus *** conclusion,our study shows an open conformation of coxsackievirus A162A protease and the underlying mechanisms for conformational conversion and substrate specifi *** new insights should facilitate the future rational design of effi cient 2A protease inhibitors.

关键词： coxsackievirus A16 2A protease crystal structure switcher

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Crystal structure of cytotoxin protein suilysin from Streptococcus suis

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Protein & Cell 2010年第1期1卷 96-105页

作者： Lingfeng Xu Bo Huang Huamao Du Xuejun CZhang Jianguo Xu Xuemei Li zihe rao National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of Sciences15 Datun RoadBeijing 100101China College of Biotechnology Southwest UniversityChongqing 400715China State Key Laboratory for Infectious Disease Prevention and Control National Institute for Communicable Disease Control and PreventionBeijing 102200China Protein Studies Program Oklahoma Medical Research Foundation825 N.E.13th streetOklahoma CityOK 73104USA

Cholesterol-dependent cytolysins(CDC)are pore forming toxins.A prototype of the CDC family members is perfringolysin O(PFO),which directly binds to the cell membrane enriched in cholesterol,causing cell ***,an exception of this general observation is intermedilysin(ILY)of Streptococcus intermedius,which requires human CD59 as a receptor in addition to cholesterol for its hemolytic activity.A possible explanation of this functional difference is the conformational variation between the C-terminal domains of the two toxins,particularly in the highly conserved undecapeptide termed tryptophan rich ***,we present the crystal structure of suilysin,a CDC toxin from the infectious swine pathogen Streptococcus *** PFO,suilysin does not require a host receptor for hemolytic activity;yet the crystal structure of suilysin exhibits a similar conformation in the tryptophan rich motif to *** observation suggests that the current view of the structure-function relationship between CDC proteins and membrane association is far from complete.

关键词： suilysin cholesterol-dependent cytolysin crystal structure

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