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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 crisis.Although 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 compromised.Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses.Cathepsin L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response.Here,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and CAPN1.The 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 CAPN1.Both 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 cells.Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance.Moreover,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in mice.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 model.And 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 pneumonia.Taken together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

关键词： calpain overcome entrance

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A viral RNA-dependent RNA polymerase inhibitor VV116 broadly inhibits human coronaviruses and has synergistic potency with 3CLpro inhibitor nirmatrelvir

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Signal Transduction and Targeted Therapy 2023年第10期8卷 5036-5045页

作者： Yumin Zhang Yuan Sun Yuanchao Xie Wejuan Shang Zhen Wang Hualiang Jiang Jingshan Shen gengfu xiao Leike Zhang State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of Sciences430071 WuhanChina University of Chinese Academy of Sciences 100049 BeijingChina Lingang Laboratory 200031 ShanghaiChina Shanghai Institute of Materia Medica Chinese Academy of Sciences201203 ShanghaiChina Hubei Jiangxia Laboratory 430200 WuhanChina

During the ongoing pandemic,providing treatment consisting of effective,low-cost oral antiviral drugs at an early stage of SARSCoV-2 infection has been a priority for controling COVID-19.Although Paxlovid and molnupiravir have received emergency approval from the FDA,some side effect concerns have emerged,and the possible oral agents are stillimited,resulting in optimized drug development becoming an urgent requirement.

关键词： drugs approval synergistic

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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[e.g.Machupo 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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Ebola virus VP35 perturbs type I interferon signaling to facilitate viral replication

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Virologica Sinica 2023年第6期38卷 922-930页

作者： Zengguo Cao Chenchen Liu Cheng Peng Yong Ran Yulin Yao gengfu xiao Entao Li Zixi Chen Xia Chuai Sandra Chiu Key Laboratory of Special Pathogens and Biosafety Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan430071China University of Chinese Academy of Sciences Beijing100190China National Biosafety Laboratory Chinese Academy of SciencesWuhan430020China Division of Life Sciences and Medicine University of Science and Technology of Chin1Hefei230026China Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science Shenzhen Engineering Laboratory for Marine Algal BiotechnologyGuangdong Provincial Key Laboratory for Plant EpigeneticsCollege of Life Sciences and OceanographyShenzhen UniversityShenzhen 518060China

As one of the deadliest viruses,Ebola virus(EBOV)causes lethal hemorrhagic fevers in humans and nonhuman primates.The suppression of innate immunity leads to robust systemic virus replication of EBOV,leading to enhanced transmission.However,the mechanism of EBOV-host interaction is not fully understood.Here,we identified multiple dysregulated genes in early stage of EBOV infection through transcriptomic analysis,which are highly clustered to Jak-STAT signaling.EBOV VP35 and VP30 were found to inhibit type I interferon(IFN)signaling.Moreover,exogenous expression of VP35 blocks the phosphorylation of endogenous STAT1,and suppresses nuclear translocation of STAT1.Using serial truncated mutations of VP35,N-terminal 1–220amino acid residues of VP35 were identified to be essential for blocking on type I IFN signaling.Remarkably,VP35 of EBOV suppresses type I IFN signaling more efficiently than those of Bundibugyo virus(BDBV)and Marburg virus(MARV),resulting in stable replication to facilitate the pathogenesis.Altogether,this study enriches understanding on EBOV evasion of innate immune response,and provides insights into the interplay between filoviruses and host.

关键词： Ebola virus(EBOV) Type I interferon(IFN)signaling Viral replication

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Deletion of the first glycosylation site promotes Lassa virus glycoprotein-mediated membrane fusion

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Virologica Sinica 2023年第3期38卷 380-386页

作者： Siqi Dong Wenting Mao Yang Liu xiaoying Jia Yueli Zhang Minmin Zhou Yuxia Hou gengfu xiao Wei Wang State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan430207China University of the Chinese Academy of Sciences Beijing100049China College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology Nankai UniversityTianjin300071China

The Lassa virus(LASV)is endemic in West Africa and causes severe hemorrhagic Lassa fever in humans.The glycoprotein complex(GPC)of LASV is highly glycosylation-modified,with 11 N-glycosylation sites.All 11 N-linked glycan chains play critical roles in GPC cleavage,folding,receptor binding,membrane fusion,and immune evasion.In this study,we focused on the first glycosylation site because its deletion mutant(N79Q)results in an unexpected enhanced membrane fusion,whereas it exerts little effect on GPC expression,cleavage,and receptor binding.Meanwhile,the pseudotype virus bearing GPC_(N79Q)was more sensitive to the neutralizing antibody 37.7H and was attenuated in virulence.Exploring the biological functions of the key glycosylation site on LASV GPC will help elucidate the mechanism of LASV infection and provide strategies for the development of attenuated vaccines against LASV infection.

关键词： Lassa virus(LASV) Glycoprotein complex(GPC) Glycosylation site Membrane fusion

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Assembly of long DNA sequences using a new synthetic Escherichia coli-yeast shuttle vector

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Virologica Sinica 2016年第2期31卷 160-167页

作者： Zheng Hou Zheng Zhou Zonglin Wang gengfu xiao State Key Laboratory of Virology Wuhan Institute of Virology Chinese Academy of Sciences

Synthetic biology is a newly developed field of research focused on designing and rebuilding novel biomolecular components, circuits, and networks. Synthetic biology can also help understand biological principles and engineer complex artificial metabolic systems. DNA manipulation on a large genome-wide scale is an inevitable challenge, but a necessary tool for synthetic biology. To improve the methods used for the synthesis of long DNA fragments, here we constructed a novel shuttle vector named p GF(plasmid Genome Fast) for DNA assembly in vivo. The BAC plasmid p CC1 BAC, which can accommodate large DNA molecules, was chosen as the backbone. The sequence of the yeast artificial chromosome(YAC) regulatory element CEN6-ARS4 was synthesized and inserted into the plasmid to enable it to replicate in yeast. The selection sequence HIS3, obtained by polymerase chain reaction(PCR) from the plasmid p BS313, was inserted for screening. This new synthetic shuttle vector can mediate the transformation-associated recombination(TAR) assembly of large DNA fragments in yeast, and the assembled products can be transformed into Escherichia coli for further amplification. We also conducted in vivo DNA assembly using p GF and yeast homologous recombination and constructed a 31-kb long DNA sequence from the cyanophage PP genome. Our findings show that this novel shuttle vector would be a useful tool for efficient genome-scale DNA reconstruction.

关键词：酵母人工染色体 DNA序列合成生物学穿梭载体大肠杆菌组装 DNA片段生物分子元件

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Oral remdesivir derivative VV116 is a potent inhibitor of respiratory syncytial virus with efficacy in mouse model

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Signal Transduction and Targeted Therapy 2022年第5期7卷 1386-1388页

作者： Ruxue Zhang Yumin Zhang Wei Zheng Weijuan Shang Yan Wu Ning Li Jun Xiong Hualiang Jiang Jingshan Shen gengfu xiao Yuanchao Xie Leike Zhang State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China University of Chinese Academy of Sciences Beijing 100049China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China Shanghai Junshi Biosciences Co. Ltd.Shanghai 200126China Lingang Laboratory Shanghai 200031China

Dear Editor,Respiratory syncytial virus(RSV)is the leading cause of serious lower respiratory tract disease in children under 5 years of age worldwide,causing an estimated 3.2 million hospitalizations and 120,000 deaths in children globally per year.Furthermore,nearly all children can be infected with RSV by 2 years of age,and individuals can be repeatedly re-infected with RSV throughout life,which poses great threats to infants,the elderly.

关键词： respiratory syncytial repeatedly

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Structure-function relationship of the mammarenavirus envelope glycoprotein

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Virologica Sinica 2016年第5期31卷 380-394页

作者： Wei Wang Zheng Zhou Leike Zhang Shaobo Wang gengfu xiao State Key Laboratory of Virology Wuhan Institute of Virology Chinese Academy of Sciences

Mammarenaviruses, including lethal pathogens such as Lassa virus and Junín virus, can cause severe hemorrhagic fever in humans. Entry is a key step for virus infection, which starts with binding of the envelope glycoprotein(GP) to receptors on target cells and subsequent fusion of the virus with target cell membranes. The GP precursor is synthesized as a polypeptide, and maturation occurs by two cleavage events, yielding a tripartite GP complex(GPC) formed by a stable signal peptide(SSP), GP1 and GP2. The unique retained SSP interacts with GP2 and plays essential roles in virion maturation and infectivity. GP1 is responsible for binding to the cell receptor, and GP2 is a class I fusion protein. The native structure of the tripartite GPC is unknown.GPC is critical for the receptor binding, membrane fusion and neutralization antibody recognition.Elucidating the molecular mechanisms underlining the structure–function relationship of the three subunits is the key for understanding their function and can facilitate novel avenues for combating virus infections. This review summarizes the basic aspects and recent research of the structure–function relationship of the three subunits. We discuss the structural basis of the receptor-binding domain in GP1, the interaction between SSP and GP2 and its role in virion maturation and membrane fusion, as well as the mechanism by which glycosylation stabilizes the GPC structure and facilitates immune evasion. Understanding the molecular mechanisms involved in these aspects will contribute to the development of novel vaccines and treatment strategies against mammarenaviruses infection.

关键词： Mammarenaviruses glycoprotein 建筑群(GPC ) 稳定的信号肽(SSP ) 膜熔化 glycosylation

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Structure and function of bak gene and its apoptosis-inducing mechanism

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Chinese Science Bulletin 1999年第7期44卷 605-609页

作者： Yan Li Yipeng Qi gengfu xiao Wuhan Univ Inst Virol Wuhan 430072 Peoples R China

The Bcl-2 family plays an important role in the regulation of apoptosis. Some members in the family prevent apoptosis while others promote it. The newly discovered bcl-2 homolog,bak, promotes the apoptosis induced by a variety of stimuli. It can interact with the anti-apoptotic members through its BH3 domain and antagonize their activity. Investigation results suggest that the expression of bak gene becomes altered in some diseases, such as cancer. The preferential stimulation of Bak-induced apoptosis, therefore, may be involved in the mechanisms of some antitumor drugs.

关键词： programmed cell death apoptosis Bcl-2 family bak.

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Characterizing the Lassa Virus Envelope Glycoprotein Membrane Proximal External Region for Its Role in Fusogenicity

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Virologica Sinica 2021年第2期36卷 273-280页

作者： Junyuan Cao Guangshun Zhang Minmin Zhou Yang Liu gengfu xiao Wei Wang State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China University of the Chinese Academy of Sciences Beijing 100049China College of Life Sciences Nankai UniversityTianjin 300353China

The membrane-proximal external region(MPER)of Lassa virus(LASV)glycoprotein complex(GPC)is critical in modulating its functionality.Till now,the high-resolution structure of the intact GPC,including MPER is not available.In this study,we used alanine substitution to scan all 16 residues located in LASV MPER.Western blotting and quantification fusion assay showed that the residues located at the C terminus of the HR2(M414 and L415)and N terminus of the MPER(K417 and Y419)are critical for GPC-mediated membrane fusion function.Furthermore,cell surface biotinylation experiments revealed that M414 A,K417 A and Y419 A expressed similar levels as WT,whereas L415 A mutant led to a reduction of mature GPC on the cell surface.Moreover,substitution of these residues with the similar residue such as M414 L,L415 I,K417 R and Y419 F would partly compensate the loss of the fusion activity caused by the alanine mutant in these sites.Results from this study showed that several key residues in the MPER region are indispensable to promote the conformational changes that drive fusion events and shed light on the structure analysis of LASV GPC and anti-LASV therapeutics.

关键词： Lassa virus(LASV) Arenavirus Glycoprotein complex(GPC) Membrane-proximal external region(MPER) Membrane fusion

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