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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

Peptidic defective interfering gene nanoparticles against Omicron,Delta SARS-CoV-2 variants and influenza A virus in vivo

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Signal Transduction and Targeted Therapy 2022年第9期7卷 3484-3493页

作者： Hanjun Zhao Chuyuan Zhang Hoiyan Lam Xinjie Meng Zheng Peng Man Lung Yeung Jasper Fuk-Woo Chan Kelvin Kai-Wang To kwok-yung yuen State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong Special Administrative RegionChina Department of Microbiology School of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong Special Administrative RegionChina Centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong Special Administrative RegionChina Department of Infectious Disease and Microbiology The University of Hong Kong-Shenzhen HospitalShenzhenGuangdong ProvinceChina Carol Yu Centre for Infection The University of Hong KongPokfulamHong Kong Special Administrative RegionChina Guangzhou Laboratory GuangzhouGuangdong ProvinceChina

Defective interfering genes(DIGs)are short viral genomes and interfere with wild-type viral ***,we demonstrate that the new designed SARS-CoV-2 DIG(CD3600)can significantly inhibit the replication of SARS-CoV-2 including Alpha,Delta,Kappa and Omicron variants in human HK-2 cells and influenza DIG(PAD4)can significantly inhibit influenza virus replication in human A549 *** dose of influenza DIGs prophylactically protects 90%mice from lethal challenge of A(H1N1)pdm09 virus and CD3600 inhibits SARS-CoV-2 replication in hamster lungs when DIGs are administrated to lungs one day before viral *** further investigate the gene delivery vector in the respiratory tract,a peptidic TAT2-P1&LAH4,which can package genes to form small spherical nanoparticles with high endosomal escape ability,is demonstrated to dramatically increase gene expression in the lung ***2-P1&LAH4,with the dual-functional TAT2-P1(gene-delivery and antiviral),can deliver CD3600 to significantly inhibit the replication of Delta and Omicron SARS-CoV-2 in hamster *** peptide-based nanoparticle system can effectively transfect genes in lungs and deliver DIGs to inhibit SARS-CoV-2 variants and influenza virus in vivo,which provides the new insight into the drug delivery system for gene therapy against respiratory viruses.

关键词： influenza vivo Delta

Pathogenesis of pandemic H1N1 2009 influenza virusinfection and the implication on management

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Frontiers of Medicine 2010年第2期4卷 147-156页

作者： Kelvin Kai-Wang TO Iris Wai-Sum LI Ivan Fan-Ngai HUNG Vincent Chi-Chung CHENG kwok-yung yuen Carol Yu Center for Infection Department of MicrobiologyThe University of Hong KongHong Kong SARChina

The pandemic H1N12009 inﬂuenza virus has caused theﬁrst inﬂuenza pandemic of the 21st century,leading to disproportionate fatalities in the low-risk population despite the generally mild nature of the *** in science and technology have allowed very detailed study on the pathogenesis of this novel virus,and many have already been published in less than a year after the start of the *** generated from cell lines,animal models,and clinical data analysis has provided us with greater understanding of the behavior of this virus and the associated host *** new knowledge will allow us to formulate scientiﬁcally sound and evidence-based management plans.

关键词： inﬂuenza A virus,H1N1 subtype pandemic pathogenesis virulence factors immunity management,antiviral

A critical role of IL-17 in modulating the B-cell response during H5N1 influenza virus infection

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Cellular & Molecular Immunology 2011年第6期8卷 462-468页

作者： Xiaohui Wang Chris CS Chan Min Yang Jun Deng Vincent KM Poon Virtual HC Leung King-Hung Ko Jie Zhou kwok yung yuen Bo-Jian Zheng Liwei Lu Department of Pathology The University of Hong KongHong KongChina Department of Microbiology The University of Hong KongHong KongChina Center of Infection and Immunology The University of Hong KongHong KongChina

Interleukin-17(IL-17),a member of the IL-17 cytokine family,plays a crucial role in mediating the immune response against extracellular bacteria and fungi in the *** there is increasing evidence that IL-17 is involved in protective immunity against H1 and H3 influenza virus infections,little is known about the role of IL-17 in the highly pathogenic H5N1 influenza virus *** this study,we show that H5N1-infected IL-17 knockout(KO)mice exhibit markedly increased weight loss,more pronounced lung immunopathology and significantly reduced survival rates as compared with infected wild-type ***,the frequency of B cells in the lung were substantially decreased in IL-17 KO mice after virus infection,which correlated with reduced CXCR5 expression in B cells and decreased CXCL13 production in the lung tissue of IL-17 KO *** with this observation,B cells from IL-17 KO mice exhibited a significant reduction in chemokine-mediated migration in *** together,these findings demonstrate a critical role for IL-17 in mediating the recruitment of B cells to the site of pulmonary influenza virus infection in mice.

关键词： B cell H5N1 influenza virus IL-17 lung infection

Analogous comparison unravels heightened antiviral defense and boosted viral infection upon immunosuppression in bat organoids

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Signal Transduction and Targeted Therapy 2023年第1期8卷 276-287页

作者： Xiaojuan Liu Cun Li Zhixin Wan Man Chun Chiu Jingjing Huang Yifei Yu Lin Zhu Jian-Piao Cai Lei Rong You-qiang Song Hin Chu Zongwei Cai Shibo Jiang kwok-yung yuen Jie Zhou Department of Microbiology School of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina State Key Laboratory of Environmental and Biological Analysis Department of ChemistryHong Kong Baptist UniversityHong KongChina Department of Medicine The University of Hong KongShenzhen HospitalShenzhenGuangdongChina School of Biomedical Sciences State Key Laboratory of Brain and Cognitive SciencesThe University of HongkongHong KongChina State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for InfectionThe University of Hong KongHong KongChina Centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong KongChina Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS) Institute of Infectious Disease and BiosecuritySchool of Basic Medical SciencesFudan UniversityShanghaiChina

Horseshoe bats host numerous SARS-related coronaviruses without overt disease *** intestinal organoids,a unique model of bat intestinal epithelium,allow direct comparison with human intestinal *** sought to unravel the cellular mechanism(s)underlying bat tolerance of coronaviruses by comparing the innate immunity in bat and human *** optimized the culture medium,which enabled a consecutive passage of bat intestinal organoids for over one *** expression levels of IFNs and IFN-stimulated genes were higher in bat organoids than in their human ***,bat organoids mounted a more rapid,robust and prolonged antiviral defense than human organoids upon Poly(I:C)***3 and RLR might be the conserved pathways mediating antiviral response in bat and human intestinal *** susceptibility of bat organoids to a bat coronavirus CoV-HKU4,but resistance to EV-71,an enterovirus of exclusive human origin,indicated that bat organoids adequately recapitulated the authentic susceptibility of bats to certain ***,TLR3/RLR inhibition in bat organoids significantly boosted viral growth in the early phase after SARS-CoV-2 or CoV-HKU4 ***,the higher basal expression of antiviral genes,especially more rapid and robust induction of innate immune response,empowered bat cells to curtail virus propagation in the early phase of infection.

关键词： boost comparison mounted

A six-year descriptive epidemiological study of human coronavirus infections in hospitalized patients in Hong Kong

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Virologica Sinica 2016年第1期31卷 41-48页

作者： Cyril C.Y.Yip Carol S.F.Lam Hayes K.H.Luk Emily Y.M.Wong Rodney A.Lee Lok-Yee So kwok-Hung Chan Vincent C.C.Cheng kwok-yung yuen Patrick C.Y.Woo Susanna K.P.Lau Department of Microbiology The University of Hong Kong Department of Microbiology Pamela Youde Nethersole Eastern Hospital Department of Paediatrics and Adolescent Medicine Pamela Youde Nethersole Eastern Hospital Research Centre of Infection and Immunology The University of Hong Kong State Key Laboratory of Emerging Infectious Diseases The University of Hong Kong

We conducted a six-year epidemiological study on human coronaviruses（HCoVs） circulating in Hong Kong, using 8275 nasopharyngeal samples from patients with acute respiratory tract infections. HCoVs were detected in 77（0.93%） of the samples by a pan-HCoV RT-PCR assay. The most frequently detected HCoV species was HCoV-OC43（0.58%）, followed by HCoV-229E（0.15%）,HCoV-HKU1（0.13%） and HCoV-NL63（0.07%）. HCoVs were detected throughout the study period（September 2008–August 2014）, with the highest detection rate from September 2010 to August2011（22/1500, 1.47%）. Different seasonal patterns of each HCoV species in Hong Kong were ***-OC43 was predominant in the fall and winter, whereas HCoV-HKU1 showed peak activity in winter, with a few cases occurred in spring and summer. HCoV-229 E mainly occurred in winter and spring, while HCoV-NL63 was predominant in summer and autumn. HCoVs most commonly infect the elderly and young children, with median age of 79.5 years（range, 22 days to 95 years）.Intriguingly, the detection rate of HCoV-OC43 in the age group of ＆gt; 80 years（26/2380, 1.09%） was significantly higher than that in the age group of 0–10 years（12/2529, 0.47%）（P 〈 0.05）. These data provides new insight into the epidemiology of coronaviruses.

关键词： epidemiology human coronaviruses respiratory tract infections

Leptotrichia hongkongensis ***.,a novel Leptotrichia species with the oral cavity as its natural reservoir

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2010年第6期11卷 391-401页

作者： Patrick C. Y. WOO Samson S. Y. WONG Jade L. L. TENG Kit-Wah LEUNG Antonio H. Y. NGAN Dong-qing ZHAO Herman TSE Susanna K. P. LAU kwok-yung yuen State Key Laboratory of Emerging Infectious Diseases The University of Hong Kong Hong Kong China Research Centre of Infection and Immunology The University of Hong Kong Hong Kong China Department of Microbiology The University of Hong Kong Hong Kong China Carol Yu Centre for Infection The University of Hong Kong Hong Kong China

A straight, non-sporulating, Gram-variable bacillus (HKU24T) was recovered from the blood culture of a patient with metastatic breast carcinoma. After repeated subculturing in BACTEC Plus Anaerobic/F blood culture broth, HKU24T grew on brucella agar as non-hemolytic, pinpoint colonies after 96 h of incubation at 37 °C in an anaerobic environment and aerobic environment with 5% CO2. Growth was enhanced with a streak of Staphylococcus aureus. HKU24T was non-motile and catalase-negative, but positive for alkaline phosphatase, β-glucosidase, and α-glucosidase. It hydrolyzed phenylphosphonate and reduced resazurin. 16S rRNA, groEL, gyrB, recA, and rpoB sequencing showed that HKU24T occupies a distinct phylogenetic position among the Leptotrichia species, being most closely related to Leptotrichia trevisanii. Using HKU24T groEL, gyrB, recA, and rpoB gene-specific primers, fragments of these genes were amplified from one of 20 oral specimens. Based on phenotypic and genotypic characteristics, we propose a new species, Leptotrichia hongkongensis sp. nov., to describe this bacterium.

关键词： Leptotrichia hongkongensis Bacterium Blood culture Anaerobic bacteria Novel species

Cellular response to influenza virus infection: a potential role for autophagy in CXCL10 and interferon-alpha induction

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Cellular & Molecular Immunology 2010年第4期7卷 263-270页

作者： Anna Hing-Yee Law Davy Chun-Wai Lee kwok-yung yuen Malik Peiris Allan Sik-Yin Lau Cytokine Biology Group Department of Paediatrics and Adolescent MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina Department of Microbiology Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina

Historically,influenza pandemics have arisen from avian influenza *** influenza viruses H5N1 and H9N2 are potential pandemic *** of humans with the highly pathogenic avian influenza H5N1 virus is associated with a mortality in excess of 60%,which has been attributed to dysregulation of the cytokine *** macrophages and epithelial cells infected with some genotypes of H5N1 and H9N2 viruses express markedly elevated cytokine and chemokine levels when compared with seasonal influenza A subtype H1N1 *** mechanisms underlying this cytokine and chemokine hyperinduction are not fully *** the present study,we demonstrate that autophagy,a tightly regulated homeostatic process for self-digestion of unwanted cellular subcomponents,plays a role in cytokine *** is induced to a greater extent by H9N2/G1,in association with cytokine hyperinduction,compared with H1N1 and the novel pandemic swine-origin influenza A/H1N1 *** 3-methyladenine to inhibit autophagy and small interfering RNA to silence the autophagy gene,Atg5,we further show that autophagic responses play a role in influenza virus-induced CXCL10 and interferon-a expression in primary human blood *** results provide new insights into the pathogenic mechanisms of avian influenza viruses.

关键词： autophagy CXCL10 influenza interferon

The persistent prevalence and evolution of cross-family recombinant coronavirus GCCDC1 among a bat population:a two-year follow-up

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Science China(Life Sciences) 2017年第12期60卷 1357-1363页

作者： Joseph O.Obameso Hong Li Hao Jia Min Han Shiyan Zhu Canping Huang Yuhui Zhao Min Zhao Yu Bai Fei Yuan Honglan Zhao Xia Peng Wen Xu Wenjie Tan Yingze Zhao kwok-yung yuen William J.Liu Lin Lu George F.Gao CAS Key Laboratory of Pathogenic Microbiology and Immunology Institute of MicrobiologyChinese Academy of SciencesBeijing 100101China Yunnan Provincial Center for Disease Control and Prevention Kunming 650022China University of Chinese Academy of Sciences Beijing 100049China College of Laboratory Medicine and Life Sciences Wenzhou Medical UniversityWenzhou 325035China Key Laboratory of Medical Virology and Viral Diseases Ministry of Health of People's Republic of ChinaNational Institute for Viral Disease Control and PreventionChinese Center for Disease Control and PreventionBeijing 102206China State Key Laboratory of Emerging Infectious Diseases The University of Hong KongHong Kong Special Administrative RegionHong KongChina

Bats are connected with the increasing numbers of emerging and re-emerging viruses that may break the species barrier and spread into the human population. Coronaviruses are one of the most common viruses discovered in bats, which were considered as the natural source of recent human-susceptible coronaviruses, i.e. SARS-COV and MERS-CoV. Our previous study reported the discovery of a bat-derived putative cross-family recombinant coronavirus with a reovirus gene p10, named as Ro-BatCoV GCCDC1. In this report, through a two-year follow-up of a special bat population in one specific cave of south China, we illustrate that Ro-BatCoV GCCDC1 persistently circulates among bats. Notably, through the longitudinal observation, we identified the dynamic evolution of Ro-BatCoV GCCDC1 in bats represented by continuously recombination events. Our study provides the first glimpse of the virus evolution in one longitudinally observed bat population cohort and underlines the surveillance and pre-warning of potential interspecies transmittable viruses in bats.

关键词： coronavirus bat population evolution