The ongoing outbreak of Coronavirus Disease 2019(COVID-19)has become a global public health emergency.SARScoronavirus-2(SARS-CoV-2),the causative pathogen of COVID-19,is a positive-sense single-stranded RNA virus belo...The ongoing outbreak of Coronavirus Disease 2019(COVID-19)has become a global public health emergency.SARScoronavirus-2(SARS-CoV-2),the causative pathogen of COVID-19,is a positive-sense single-stranded RNA virus belonging to the family Coronaviridae.For RNA viruses,virus-encoded RNA helicases have long been recognized to play pivotal roles during viral life cycles by facilitating the correct folding and replication of viral RNAs.Here,our studies show that SARS-CoV-2-encoded nonstructural protein 13(nsp13)possesses the nucleoside triphosphate hydrolase(NTPase)and RNA helicase activities that can hydrolyze all types of NTPs and unwind RNA helices dependently of the presence of NTP,and further characterize the biochemical characteristics of these two enzymatic activities associated with SARS-CoV-2 nsp13.Moreover,we found that some bismuth salts could effectively inhibit both the NTPase and RNA helicase activities of SARS-CoV-2 nsp13 in a dose-dependent manner.Thus,our findings demonstrate the NTPase and helicase activities of SARS-CoV-2 nsp13,which may play an important role in SARS-CoV-2 replication and serve as a target for antivirals.展开更多
丙型肝炎病毒(hepatitis C virus,HCV)感染是全球性的公共卫生问题之一,全世界有1.3亿至1.5亿人长期感染,其中四分之一的患者会产生肝硬化、肝细胞癌甚至肝功能衰竭等并发症。完全清除病毒是研究者不断进行抗丙肝新药物研发的目标与动...丙型肝炎病毒(hepatitis C virus,HCV)感染是全球性的公共卫生问题之一,全世界有1.3亿至1.5亿人长期感染,其中四分之一的患者会产生肝硬化、肝细胞癌甚至肝功能衰竭等并发症。完全清除病毒是研究者不断进行抗丙肝新药物研发的目标与动力。本综述精选近几年具代表性的研究实例,从药物化学的视角总结了抗丙肝小分子抑制剂的前沿进展。展开更多
The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity.Here,we show that carrimycin,a new macrolide antibiotic in the...The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity.Here,we show that carrimycin,a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials,decreases the efficiency of programmed–1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum fashion.Carrimycin binds directly to the coronaviral frameshift-stimulatory element(FSE)RNA pseudoknot,interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription complexes.Combined carrimycin with known viral replicase inhibitors yielded a synergistic inhibitory effect on coronaviruses.Because the FSE mechanism is essential in all coronaviruses,carrimycin could be a new broad-spectrum antiviral drug for human coronaviruses by directly targeting the conserved coronaviral FSE RNA.This finding may open a new direction in antiviral drug discovery for coronavirus variants.展开更多
Hepatitis C virus(HCV)infection is a global health problem,with an estimated 170 million people being chronically infected.HCV cell entry is a complex multi-step process,involving several cellular factors that trigger...Hepatitis C virus(HCV)infection is a global health problem,with an estimated 170 million people being chronically infected.HCV cell entry is a complex multi-step process,involving several cellular factors that trigger virus uptake into the hepatocytes.The high-density lipoprotein receptor scavenger receptor class B type I,tetraspanin CD81,tight junction protein claudin-1,and occludin are the main receptors that mediate the initial step of HCV infection.In addition,the virus uses cell receptor tyrosine kinases as entry regulators,such as epidermal growth factor receptor and ephrin receptor A2.This review summarizes the current understanding about how cell surface molecules are involved in HCV attachment,internalization,and membrane fusion,and how host cell kinases regulate virus entry.The advances of the potential antiviral agents targeting this process are introduced.展开更多
丙型肝炎病毒(hepatitis C virus,HCV)是血液传播的球形包膜病毒,编码单正链RNA,是黄病毒科成员。目前,全世界约有1.7亿患者感染丙型肝炎病毒,每年有300万的新增感染病例,我国HCV感染者近4 000万。HCV慢性化程度高,约80%的急性感染者将...丙型肝炎病毒(hepatitis C virus,HCV)是血液传播的球形包膜病毒,编码单正链RNA,是黄病毒科成员。目前,全世界约有1.7亿患者感染丙型肝炎病毒,每年有300万的新增感染病例,我国HCV感染者近4 000万。HCV慢性化程度高,约80%的急性感染者将发展为慢性肝脏疾病,其中又有约20%将最终进展到肝硬化。展开更多
Chronic hepatitis B(CHB) remains a significant unmet medical need, with 240 million chronically infected persons worldwide. It can be controlled effectively with either nucleoside/nucleotide-based or interferonbased t...Chronic hepatitis B(CHB) remains a significant unmet medical need, with 240 million chronically infected persons worldwide. It can be controlled effectively with either nucleoside/nucleotide-based or interferonbased therapies. However, most patients receiving these therapies will relapse after treatment withdrawal. During recent years, the advances in molecular biology and immunology have enabled a better understanding of the viral-host interaction and inspired new treatment approaches to achieve either elimination of the virus from the liver or durable immune control of the infection. This review aims to provide a brief overview on the potential new therapies that may overcome the challenge of persistent CHB infection in the near future.展开更多
Currently,there is no effective antiviral medication for coronavirus disease 2019(COVID-19)and the knowledge on the potential therapeutic target is in great need.Guided by a time-course transmission electron microscop...Currently,there is no effective antiviral medication for coronavirus disease 2019(COVID-19)and the knowledge on the potential therapeutic target is in great need.Guided by a time-course transmission electron microscope(TEM)imaging,we analyzed early phosphorylation dynamics within the first 15 min during severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)viral entry.Based on alterations in the phosphorylation events,we found that kinase activities such as protein kinase C(PKC),interleukin-1 receptor-associated kinase 4(IRAK4),MAP/microtubule affinity-regulating kinase 3(MARK3),and TANK-binding kinase 1(TBK1)were affected within 15 min of infection.Application of the corresponding kinase inhibitors of PKC,IRAK4,and p38 showed significant inhibition of SARS-CoV-2 replication.Additionally,proinflammatory cytokine production was reduced by applying PKC and p38 inhibitors.By an acquisition of a combined image data using positiveand negative-sense RNA probes,as well as pseudovirus entry assay,we demonstrated that PKC contributed to viral entry into the host cell,and therefore,could be a potential COVID-19 therapeutic target.展开更多
基金supported by the Strategic Priority Research Program of CAS(XDB29010300 to X.Z.)National Natural Science Foundation of China(81873964 to Y.Q.,31800140 to J.M.and 31670161 to X.Z.)+1 种基金National Science and Technology Major Project(2018ZX10101004 to X.Z.)the Science and Technology Development Fund,Macao SAR(0007/2020/A to R.W)。
文摘The ongoing outbreak of Coronavirus Disease 2019(COVID-19)has become a global public health emergency.SARScoronavirus-2(SARS-CoV-2),the causative pathogen of COVID-19,is a positive-sense single-stranded RNA virus belonging to the family Coronaviridae.For RNA viruses,virus-encoded RNA helicases have long been recognized to play pivotal roles during viral life cycles by facilitating the correct folding and replication of viral RNAs.Here,our studies show that SARS-CoV-2-encoded nonstructural protein 13(nsp13)possesses the nucleoside triphosphate hydrolase(NTPase)and RNA helicase activities that can hydrolyze all types of NTPs and unwind RNA helices dependently of the presence of NTP,and further characterize the biochemical characteristics of these two enzymatic activities associated with SARS-CoV-2 nsp13.Moreover,we found that some bismuth salts could effectively inhibit both the NTPase and RNA helicase activities of SARS-CoV-2 nsp13 in a dose-dependent manner.Thus,our findings demonstrate the NTPase and helicase activities of SARS-CoV-2 nsp13,which may play an important role in SARS-CoV-2 replication and serve as a target for antivirals.
文摘丙型肝炎病毒(hepatitis C virus,HCV)感染是全球性的公共卫生问题之一,全世界有1.3亿至1.5亿人长期感染,其中四分之一的患者会产生肝硬化、肝细胞癌甚至肝功能衰竭等并发症。完全清除病毒是研究者不断进行抗丙肝新药物研发的目标与动力。本综述精选近几年具代表性的研究实例,从药物化学的视角总结了抗丙肝小分子抑制剂的前沿进展。
基金supported by grants from the National Natural Science Foundation,China(82151525)the National key research and development program,China(2022YFC0869000)the CAMS Innovation Fund for Medical Sciences(2022-I2M-JB-013,2021-I2M-1-028 and 2022-I2M-2-002,China).
文摘The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity.Here,we show that carrimycin,a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials,decreases the efficiency of programmed–1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum fashion.Carrimycin binds directly to the coronaviral frameshift-stimulatory element(FSE)RNA pseudoknot,interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription complexes.Combined carrimycin with known viral replicase inhibitors yielded a synergistic inhibitory effect on coronaviruses.Because the FSE mechanism is essential in all coronaviruses,carrimycin could be a new broad-spectrum antiviral drug for human coronaviruses by directly targeting the conserved coronaviral FSE RNA.This finding may open a new direction in antiviral drug discovery for coronavirus variants.
基金Supported by Research Grants from National S and T Major Project for Infectious Diseases Control,No.2012ZX10002003-004-010National Natural Science Foundation of China,No.81171564,No.81273557 and No.81302812+2 种基金Medical Youth Science Program,No.13QNP100Shanghai Municipal Natural Science Foundation,No.13ZR1449300Shanghai LAD Project,No.B901
文摘Hepatitis C virus(HCV)infection is a global health problem,with an estimated 170 million people being chronically infected.HCV cell entry is a complex multi-step process,involving several cellular factors that trigger virus uptake into the hepatocytes.The high-density lipoprotein receptor scavenger receptor class B type I,tetraspanin CD81,tight junction protein claudin-1,and occludin are the main receptors that mediate the initial step of HCV infection.In addition,the virus uses cell receptor tyrosine kinases as entry regulators,such as epidermal growth factor receptor and ephrin receptor A2.This review summarizes the current understanding about how cell surface molecules are involved in HCV attachment,internalization,and membrane fusion,and how host cell kinases regulate virus entry.The advances of the potential antiviral agents targeting this process are introduced.
文摘丙型肝炎病毒(hepatitis C virus,HCV)是血液传播的球形包膜病毒,编码单正链RNA,是黄病毒科成员。目前,全世界约有1.7亿患者感染丙型肝炎病毒,每年有300万的新增感染病例,我国HCV感染者近4 000万。HCV慢性化程度高,约80%的急性感染者将发展为慢性肝脏疾病,其中又有约20%将最终进展到肝硬化。
文摘Chronic hepatitis B(CHB) remains a significant unmet medical need, with 240 million chronically infected persons worldwide. It can be controlled effectively with either nucleoside/nucleotide-based or interferonbased therapies. However, most patients receiving these therapies will relapse after treatment withdrawal. During recent years, the advances in molecular biology and immunology have enabled a better understanding of the viral-host interaction and inspired new treatment approaches to achieve either elimination of the virus from the liver or durable immune control of the infection. This review aims to provide a brief overview on the potential new therapies that may overcome the challenge of persistent CHB infection in the near future.
基金This research was made possible because of a generous grant from the National Key R&D Program,Ministry of Science and Technology,China(no.2017YFC1600500)the National Natural Science Foundation of China(no.21705137)+2 种基金the Theme-Based Research Scheme(no.T11/707/15)General Research Fund(no.17107019)the Research Grants Council,Hong Kong Special Administrative Region,and the Sanming-Project of Medicine in Shenzhen,China(nos.SZSM201911014 and SZSM201811070).
文摘Currently,there is no effective antiviral medication for coronavirus disease 2019(COVID-19)and the knowledge on the potential therapeutic target is in great need.Guided by a time-course transmission electron microscope(TEM)imaging,we analyzed early phosphorylation dynamics within the first 15 min during severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)viral entry.Based on alterations in the phosphorylation events,we found that kinase activities such as protein kinase C(PKC),interleukin-1 receptor-associated kinase 4(IRAK4),MAP/microtubule affinity-regulating kinase 3(MARK3),and TANK-binding kinase 1(TBK1)were affected within 15 min of infection.Application of the corresponding kinase inhibitors of PKC,IRAK4,and p38 showed significant inhibition of SARS-CoV-2 replication.Additionally,proinflammatory cytokine production was reduced by applying PKC and p38 inhibitors.By an acquisition of a combined image data using positiveand negative-sense RNA probes,as well as pseudovirus entry assay,we demonstrated that PKC contributed to viral entry into the host cell,and therefore,could be a potential COVID-19 therapeutic target.
