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SARS-CoV-2 ORF10 hijacking ubiquitination machinery reveals potential unique drug targeting sites

Acta Pharmaceutica Sinica B 2024年第9期14卷 4164-4173页

作者： kaixiang Zhu lili Song linyue Wang Lei Hua Ziyu Luo Tongyun Wang Bo Qin Shuofeng Yuan Xiaopan Gao Wenyi Mi Sheng Cui NHC Key Laboratory of Systems Biology of Pathogens National Institute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Key Laboratory of Pathogen Infection Prevention and Control(Peking Union Medical College) Ministry of EducationBeijing 100730China The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease(Ministry of Education)Tianjin Medical University General HospitalDepartment of ImmunologyTianjin Medical UniversityTianjin 300070China Medical School Yan’an UniversityShaanxi ProvinceYan’an 716000China State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SARChina department of microbiology Li Ka ShingFaculty of Medicinethe University of Hong KongPokfulamHong Kong SARChina

Viruses often manipulate ubiquitination pathways to facilitate their replication and ***2ZYG11B known as the substrate receptor of cullin-2 RING E3 ligase,is bound by SARS-CoV-2 ORF10 to increase its E3 ligase activity,leading to degradation of IFT46,a protein component of the intraflagellar transport(IFT)complex *** results in dysfunctional cilia,which explains certain symptoms that are specific to ***,the precise molecular mechanism of how ORF10 recognizes CUL2ZYG11B remains ***,we determined the crystal structure of CUL2ZYG11B complexed with the N-terminal extension(NTE)of SARS-CoV-2 ORF10(2.9 A°).The structure reveals that the ORF10 N-terminal heptapeptide(NTH)mimics the Gly/N-degron to bind *** studies identified key residues within ORF10 that are key players in its interaction with CUL2ZYG11B both in ITC assay and in vivo *** addition,we prove that enhancement of CUL2ZYG11B activity for IFT46 degradation by which ORF10-mediated correlates with the binding affinity between ORF10 and ***,we used a Global Protein Stability system to show that the NTH of ORF10 mimics the Gly/N-degron motif,thereby binding competitively to CUL2ZYG11B and inhibiting the degradation of target substrates bearing the Gly/N-degron ***,this study sheds light on how SARS-CoV-2 ORF10 exploits the ubiquitination machinery for proteasomal degradation,and offers valuable insights for optimizing PROTAC-based drug design based on NTH CUL2ZYG11B interaction,while pinpointing a promising target for the development of treatments for COVID-19.

关键词： SARS-CoV-2 ORF10 Crystal structure cullin-2 RING E3 ligase Drug design

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Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4028-4044页

作者： Chris Chun-Yiu Chan Qian Guo Jasper Fuk-Woo Chan kaiming Tang Jian-Piao Cai Kenn ka-Heng Chik Yixin Huang Mei Dai Bo Qin Chon Phin Ong Allen Wing-Ho Chu Wan-Mui Chan Jonathan Daniel Ip Lei Wen Jessica Oi-ling Tsang Tong-Yun Wang Yubin Xie Zhenzhi Qin Jianli Cao Zi-Wei Ye Hin Chu Kelvin kai-Wang To Xing-Yi Ge Tao Ni Dong-Yan Jin Sheng Cui Kwok-Yung Yuen Shuofeng Yuan State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for InfectionDepartment of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China department of Infectious Diseases and microbiology the University of Hong Kong-Shenzhen HospitalShenzhen 518000China Centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong SAR 999077China Academician Workstation of Hainan Province Hainan Medical University-the University of Hong Kong Joint Laboratory of Tropical Infectious DiseasesHaikou 571100China School of Biomedical Sciences Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen Biology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China College of Biology Hunan Provincial Key Laboratory of Medical VirologyHunan UniversityChangsha 410082China

There are only eight approved small molecule antiviral drugs for treating *** them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous *** there is a dearth of new treatment options for *** this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 *** compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of *** studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3CLpro)by binding to an allosteric site and reduces 3CLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in *** vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 ***,this study identified an alternative druggable site on the SARS-CoV-23CLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

关键词： SARS-CoV-2 High throughput screening Broad-spectrum antiviral treatment 3CLpro inhibitor Allosteric-site inhibitor Animal models Chemical genetics Reverse genetics

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Multi-omics analysis of attenuated variant reveals potential evaluation marker of host damaging for SARS-CoV-2 variants

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Science China(life Sciences) 2024年第1期67卷 83-95页

作者： Guangshan Xie lin Zhu Siwen liu Cun li Xin Diao Yanhao Zhang Xiuli Su Yuanyuan Song Guodong Cao li Zhong Pui Wang Xiaojuan liu Bobo Wing-Yee Mok Shusheng Zhang Dong-Yan Jin Jie Zhou Honglin Chen Zongwei Cai State Key Laboratory of Environmental and Biological Analysis Hong Kong Baptist UniversityHong Kong SARChina State Key Laboratory for Emerging Infectious Diseases and Department of MicrobiologyLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina College of Chemistry Zhengzhou UniversityZhengzhou 450001China School of Biomedical Sciences The University of Hong KongHong Kong SARChina HKBU Shenzhen institute of Research and Continuing Education Shenzhen 518000China

SARS-CoV-2 continues to threaten human society by generating novel variants via mutation and *** high number of mutations that appeared in emerging variants not only enhanced their immune-escaping ability but also made it difficult to predict the pathogenicity and virulence based on viral nucleotide *** markers for evaluating the pathogenicity of new variants are therefore *** comparing host responses to wild-type and variants with attenuated pathogenicity at proteome and metabolome levels,six key molecules on the polyamine biosynthesis pathway including putrescine,SAM,dc-SAM,ODC1,SAMS,and SAMDC were found to be differentially upregulated and associated with pathogenicity of *** validate our discovery,human airway organoids were subsequently used which recapitulates SARS-CoV-2 replication in the airway epithelial cells of COVID-19 *** ODC1 as a proof-ofconcept,differential activation of polyamine biosynthesis was found to be modulated by the renin-angiotensin system(RAS)and positively associated with ACE2 *** experiments demonstrated that ODC1 expression could be differentially activated upon a panel of SARS-CoV-2 variants of concern(VOCs)and was found to be correlated with each VOCs’pathogenic ***,the presented study revealed the discriminative ability of key molecules on polyamine biosynthesis as a predictive marker for virulence evaluation and assessment of SARS-CoV-2 variants in cell or organoid *** work,therefore,presented a practical strategy that could be potentially applied as an evaluation tool for the pathogenicity of current and emerging SARS-CoV-2 variants.

关键词： SARS-CoV-2 multi-omics attenuated variant predictive pathogenic marker polyamine biosynthesis

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The development of anti-HIV-1 drugs

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药学学报 2010年第2期45卷 165-176页

作者： LU Xiao-fan CHEN Zhi-wei aids institute Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina department of microbiology and Research Center of Infection and Immunology Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China

Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency disease syndrome (aids).After over 26 years of efforts,there is still not a therapeutic cure or an effective vaccine against HIV/*** clinical management of HIV-1 infected people largely relies on antiretroviral therapy (ART).Although highly active antiretroviral therapy (HAART) has provided an effective way to treat aids patients,the huge burden of ART in developing countries,together with the increasing incidence of drug resistant viruses among treated people,calls for continuous efforts for the development of anti-HIV-1 ***,four classes of over 30 licensed antiretrovirals (ARVs) and combination regimens of these ARVs are in use clinically including:reverse transcriptase inhibitors (RTIs) (*** reverse transcriptase inhibitors,NRTIs;and non-nucleoside reverse transcriptase inhibitors,NNRTIs),protease inhibitors (PIs),integrase inhibitors and entry inhibitors (*** inhibitors and CCR5 antagonists).Here,we intend to provide updated information of currently available antiretroviral drugs for ART to promote the development of novel anti-HIV-1 drugs.

关键词：人类免疫缺陷病毒艾滋病临床分析诊断方法

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Closing the door to human immunodeficiency virus

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Protein & Cell 2013年第2期4卷 86-102页

作者： Yuanxi kang Jia Guo Zhiwei Chen aids institute and department of microbiology of li ka shing faculty of medicine The University of Hong Kong21 Sassoon RoadPokfulamHong Kong SARChina Research Center for Infection and Immunity The University of Hong Kong21 Sassoon RoadPokfulamHong Kong SARChina

The pandemic of human immunodeficiency virus type one(HIV-1),the major etiologic agent of acquired immunodeficiency disease(aids),has led to over 33 million people living with the virus,among which 18 million are women and *** now,there is neither an effective vaccine nor a therapeutic cure despite over 30 years of *** the Thai RV144 vaccine trial has demonstrated an efficacy of 31.2%,an effective vaccine will likely rely on a break-through discovery of immunogens to elicit broadly reactive neutralizing antibodies,which may take years to ***,there is an urgency of exploring other prophylactic ***,antiretroviral treatment as prevention is an exciting area of pro-gress in HIV-1 *** effective,the im-plementation of such strategy faces great financial,political and social challenges in heavily affected re-gions such as developing countries where drug re-sistant viruses have already been found with growing *** latently infected cells for thera-peutic cure is another area of *** it is greatly difficult to eradicate HIV-1 after the establish-ment of viral latency,it is necessary to investigate strategies that may close the door to ***,we review studies on non-vaccine strategies in targeting viral entry,which may have critical implications for HIV-1 prevention.

关键词： HIV-1 entry inhibitor vaccine antiretrovi-ral antibody

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Urban recreational water – potential breeding ground for antibiotic resistant bacteria?

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Journal of Environmental Sciences 2019年第7期31卷 1-3页

作者： Jing Yang Xu Connie Le Baowei Chen Hongquan Zhang Division of Analytical and Environmental Toxicology Department of Laboratory Medicine and Pathology Faculty of Medicine & DentistryUniversity of Alberta li ka shing institute of Virology Department of Medical Microbiology and Immunology University of Alberta Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering School of Marine Sciences Sun Yat-Sen University

The emergence of multidrug-resistant bacteria, or'superbugs,' has become an urgent and worldwide ***-resistant bacteria (ARB) cause significant morbidity and mortality (O’Neill, 2016). It has been estimated that ARB cause at least 23,000 deaths annually in the United States alone and hundreds of thousands of deaths in developing countries (Bougnom and Piddock, 2017).

关键词： Antibiotic resistance genes (ARGs) Multidrug resistance in bacteria Microbial pathogens Lake water and sediment

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Naturally occurring spike mutations influence the infectivity and immunogenicity of SARS-CoV-2

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Cellular & Molecular Immunology 2022年第11期19卷 1302-1310页

作者： Qiaoli Peng Runhong Zhou Na liu Hui Wang Haoran Xu Meiqing Zhao Dawei Yang ka-Kit Au Haode Huang li liu Zhiwei Chen aids institute Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong Special Administrative RegionPR China National Clinical Research Center for Infectious Diseases HKU AIDS Institute Shenzhen Research LaboratoryThe Third People’s Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and TechnologyShenzhenGuangdongPR China department of microbiology Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong Special Administrative RegionPR China Centre for Virology Vaccinology and Therapeutics LimitedThe University of Hong KongHong Kong Special Administrative RegionPR China HKU aids institute Joint Laboratory Department of Clinical Microbiology and Infection ControlThe University of Hong Kong-Shenzhen HospitalShenzhenGuangdongPR China State Key Laboratory of Emerging Infectious Disease The University of Hong KongHong Kong Special Administrative RegionPR China

Mutations in SARS-CoV-2 variants of concern(VOCs)have enhanced transmissibility and immune evasion with respect to current vaccines and neutralizing antibodies(NAbs).How naturally occurring spike mutations affect the infectivity and antigenicity of VOCs remains to be *** entry efficiency of individual spike mutations was determined in vitro using pseudotyped ***/c mice were immunized with 2-dose DNA vaccines encoding B.1.1.7,B.1.351,B.1.1.529 and their single *** and humoral immune responses were then compared to determine the impact of individual mutations on *** the B.1.1.7 lineage,Del69–70 and Del 144 in NTD,A570D and P681H in SD1 and S982A and D1118H in S2 significantly increased viral entry,whereas T716I resulted in a *** the B.1.351 lineage,L18F and Del 242–244 in the NTD,K417N in the RBD and A701V in S2 also increased viral entry.S982A weakened the generation of binding *** sera showed reduced cross-neutralization activity against B.1.351,B.1.617.2(Delta)and B.1.1.529(Omicron BA.1).S982A,L18F,and Del 242–244 hindered the induction of cross-NAbs,whereas Del 69–70,Del144,R246I,and K417N showed the opposite effects.B.1.351 elicited adequate broad cross-NAbs against both B.1.351 and *** immunogens tested,however,showed low neutralization against circulating *** addition,T-cell responses were unlikely affected by mutations tested in the *** conclude that individual spike mutations influence viral infectivity and vaccine *** VOC-targeted vaccines is likely necessary to overcome immune evasion from current vaccines and neutralizing antibodies.

关键词： SARS-CoV-2 Variants of Concern Single mutation neutralizing antibody T cell responses vaccine immunogenicity

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Antibiotic Treatment Drives the Diversification of the Human Gut Resistome

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Genomics, Proteomics & Bioinformatics 2019年第1期17卷 39-51页

作者： Jun li Elizabeth A.Rettedal Eric van der Helm Mostafa Ellabaan Gianni Panagiotou Morten O.A.Sommer department of Infectious Diseases and Public Health Colleague of Veterinary Medicine and Life Sciences City Univerity of Hong Kong School of Data Science City Univerity of Hong Kong Novo Nordisk Foundation Center for Biosustainability Systems Biology and Bioinformatics Unit Leibniz Institute for Natural Product Research and Infection Biology – Hans Kn?ll Institute Systems Biology and Bioinformatics Group School of Biological Sciences Faculty of Sciences The University of Hong Kong department of microbiology Li Ka Shing Faculty of Medicine The University of Hong Kong

Despite the documented antibiotic-induced disruption of the gut microbiota, the impact of antibiotic intake on strain-level dynamics, evolution of resistance genes, and factors influencing resistance dissemination potential remains poorly understood. To address this gap we analyzed public metagenomic datasets from 24 antibiotic treated subjects and controls, combined with an in-depth prospective functional study with two subjects investigating the bacterial community dynamics based on cultivation-dependent and independent methods. We observed that shortterm antibiotic treatment shifted and diversified the resistome composition, increased the average copy number of antibiotic resistance genes, and altered the dominant strain genotypes in an individual-specific manner. More than 30% of the resistance genes underwent strong differentiation at the single nucleotide level during antibiotic treatment. We found that the increased potential for horizontal gene transfer, due to antibiotic administration, was ～3-fold stronger in the differentiated resistance genes than the non-differentiated ones. This study highlights how antibiotic treatment has individualized impacts on the resistome and strain level composition, and drives the adaptive evolution of the gut microbiota.

关键词： Antibiotics Resistome Gut microbiome Strain Evolution Horizontal gene transfer

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A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicron in vivo

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Protein & Cell 2023年第1期14卷 37-50页

作者： Daming Zuo Yu Chen Jian-piaoCai Hao-Yang Yuan Jun-Qi Wu Yue Yin Jing-Wen Xie Jing-Min lin Jia Luo Yang Feng Long-Jiao Ge Jia Zhou Ronald JQuinn San-Jun Zhao Xing Tong Dong-Yan Jin Shuofeng Yuan Shao-Xing Dai Min Xu Center for Pharmaceutical Sciences Faculty of Life Science and TechnologyKunming University of Science and TechnologyKunming 650500China department of Medical Laboratory School of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhou 510515China State Key Laboratory of Primate Biomedical Research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunming 650500China department of microbiology Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong 999077China department of Immunology School of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China Griffith institute for Drug Discovery Griffith UniversityBrisbane 4111Australia School of life Sciences Yunnan Normal UniversityKunming 650500China School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong 999077China Microbiome medicine Center Department of Laboratory medicineZhujiang HospitalSouthern Medical UniversityGuangzhou 510515China

The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease,including the devastating *** effective antivirals with broad-spectrum coverage are urgently ***,we reported a novel broad-spectrum antiviral compound *** administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV ***,oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron(BA.1)infection significantly decreases viral loads and attenuates lung ***,PAC5 binds to a pocket near Asp49 in the RNA recognition motif of ***5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway,leading to the production of type I IFNs with antiviral *** results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1,which may have a role in dealing with emerging infectious diseases now and in the future.

关键词： hnRNPA2B1 PAC5 HBV SARS-CoV-2 omicron TBK1-IRF3 pathway type I IFNs

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Targeting papain-like protease for broad-spectrum coronavirus inhibition

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Protein & Cell 2022年第12期13卷 940-953页

作者： Shuofeng Yuan Xiaopan Gao kaiming Tang Jian-Piao Cai Menglong Hu Peng Luo Lei Wen Zi-Wei Ye Cuiting Luo Jessica Oi-ling Tsang Chris Chun-Yiu Chan Yaoqiang Huang Jianli Cao Ronghui liang Zhenzhi Qin Bo Qin Feifei Yin Hin Chu Dong-Yan Jin Ren Sun Jasper Fuk-Woo Chan Sheng Cui Kwok-Yung Yuen State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina department of microbiology Li Ka ShingFaculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina department of Molecular and Medical Pharmacology David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCAUSA Key Laboratory of Tropical Translational medicine of Ministry of Education Hainan Medical UniversityHaikou 571199China Academician Workstation of Hainan Province Hainan Medical UniversityHaikou 571199China Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases The University of Hong KongPokfulamHong Kong Special Administrative RegionChina Guangzhou Laboratory Guangzhou 510320China department of Clinical microbiology and Infection Control The University of Hong Kong-Shenzhen HospitalShenzhen 518053China

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral *** the multi-functional papain-like protease(PLpro)domain of the viral nsp3 holds ***,none of the known coronavirus PLpro inhibitors has been shown to be in vivo ***,we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity,including against the Sarbecoviruses(SARSCoV-1 and SARS-CoV-2),Merbecovirus(MERS-CoV),as well as the Alphacoronavirus(hCoV-229E and hCoVOC43).Importantly,F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice.F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage,as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase *** the significant difference of substrate recognition,mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue,whereas an allosteric inhibitor of MERSPLpro interacting with its 271E *** proof-ofconcept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anticoronavirus *** orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.

关键词： protease inhibitor coronavirus Nsp3 antiviral

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