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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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Structure basis for allosteric regulation of lymphocytic choriomeningitis virus polymerase function by Z matrix protein

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Protein & Cell 2023年第9期14卷 703-707页

作者： Lu Liu Panpan Wang Aijun Liu Leike Zhang Liming Yan Yu Guo Gengfu Xiao zihe rao Zhiyong Lou MOE Key Laboratory of Protein Science School of MedicineTsinghua UniversityBeijing 100084China School of Life Sciences Peking UniversityBeijing 100080China Kobilka Institute of Innovative Drug Discovery School of Life and Health SciencesThe Chinese University of Hong KongShenzhen 518100China State key laboratory of Virology and National Virus Resource Center Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan430071China State Key Laboratory of Medicinal Chemical Biology College of Life Sciences and College of PharmacyNankai UniversityTianjin 300350China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100105China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 200120China Innovation Center for Pathogen Research Guangzhou LaboratoryGuangzhou 510005China

DearEditor,The Arenaviridae family(recently assigned to the Bunyavirales order)is a group of emerging viruses that include causative agents of severe hemorrhagic fevers with high mortality in humans(de la Torre,2009).Lymphocytic choriomeningitis virus(LCMV)is the prototypic member of the Arenaviridae family and belongs to the Old World(OW)arenavirus together with Lassa virus(LASV),which are distinct from the New World(NW)arenavirus[*** virus(MACV)and Junin virus(JUNV)].LCMV infection in the fetus and newborm results in severe impairment of brain development associated with sensory loss and mental retardation and is also known to be associated with severe systemic infection with high mortality in transplantation patients(Palacios et al.,2008).

关键词： lymphocytic mortality fetus

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Architecture of severe fever with thrombocytopenia syndromevirus

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Protein & Cell 2023年第12期14卷 914-918页

作者： Zixian Sun Jing Cheng Yuan Bai Lin Cao Daoxin Xie Fei Deng Xinzheng Zhang zihe rao Zhiyong Lou Department of Basic Research Guangzhou LaboratoryGuangzhou 510005China MOE Key Laboratory of Protein Science School of MedicineTsinghua UniversityBeijing 100084China University of Chinese Academy of Sciences Beijing100049China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China National Virus Resource Center Wuhan Institute of VirologyChinese Academy of SciencesWuhan 430071China State Key Laboratory of Medicinal Chemical Biology and College of Life Science and Pharmacy Nankai UniversityTianjin 300350China

Dear Editor,Severe fever with thrombocytopenia syndrome(SFTS)is an acute infectious disease caused by severe fever with thrombocytopenia syndrome virus(SFTSV)and is characterized by rapid onset,high mortality and widespread *** fatality rate can be as high as 10%-30%,which is significantly higher than that of the hemorrhagic fever caused by Hantavirus in the same area(Song et al.,2018).However,no effective treatments or vaccines are available yet,and the underlying pathogenic mechanisms of the virus are poorly understood.

关键词： fever mortality

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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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Cryo-EM structures for the Mycobacterium tuberculosis iron-loaded siderophore transporter IrtAB

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Protein & Cell 2023年第6期14卷 448-458页

作者： Shan Sun Yan Gao Xiaolin Yang Xiuna Yang Tianyu Hu Jingxi Liang Zhiqi Xiong Yuting Ran Pengxuan Ren Fang Bai Luke WGuddat Haitao Yang zihe rao Bing Zhang Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State Key Laboratory of Medicinal Chemical Biology Nankai UniversityTianjin 300353China Laboratory of Structural Biology Tsinghua UniversityBeijing 100084China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China School of Chemistry and Molecular Biosciences The University of QueenslandBrisbaneQueensland 4072Australia CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China University of Chinese Academy of Sciences Beijing 100101China Shanghai Clinical Research and Trial Center Shanghai 201210China

The adenosine 5'-triphosphate(ATP)-binding cassette(ABC)transporter,IrtAB,plays a vital role in the replication and viability of Mycobacterium tuberculosis(Mtb),where its function is to import iron-loaded ***,it adopts the canonical type IV exporter ***,we report the structure of unliganded Mtb IrtAB and its structure in complex with ATP,ADP,or ATP analogue(AMP-PNP)at resolutions ranging from 2.8 to 3.5Å.The structure of IrtAB bound ATP-Mg2+shows a“head-to-tail”dimer of nucleotide-binding domains(NBDs),a closed amphipathic cavity within the transmembrane domains(TMDs),and a metal ion liganded to three histidine residues of IrtA in the ***-electron microscopy(Cryo-EM)structures and ATP hydrolysis assays show that the NBD of IrtA has a higher affinity for nucleotides and increased ATPase activity compared with ***,the metal ion located in the TM region of IrtA is critical for the stabilization of the conformation of IrtAB during the transport *** study provides a structural basis to explain the ATP-driven conformational changes that occur in IrtAB.

关键词： ABC exporter-like importer iron-loaded siderophore IrtAB Mycobacterium tuberculosis ABC transporter

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加紧实施“战略性基础研究计划”

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科技导报 2022年第6期40卷 1-2页

作者：饶子和清华大学北京100084

基础研究是科技创新的源泉。党的十八大以来,习近平总书记多次强调基础研究的重要意义,提出“基础研究是整个科学体系的源头,是所有技术问题的总机关”的重要论断,为发展基础研究指明了方向。特别是《中共中央关于制定国民经济和社会发... 详细信息

基础研究是科技创新的源泉。党的十八大以来,习近平总书记多次强调基础研究的重要意义,提出“基础研究是整个科学体系的源头,是所有技术问题的总机关”的重要论断,为发展基础研究指明了方向。特别是《中共中央关于制定国民经济和社会发展第十四个五年规划和二〇三五年远景目标的建议》,把“坚持创新”放在“十四五”工作的首位,是“五年规划建议”历史上第一次以专章部署“创新”。

关键词：远景目标五年规划党的十八大以来坚持创新战略性基础研究习近平总书记

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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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