Dear Editor,Enterovirus 71(EV71)is the main pathogen of hand,foot,and mouth disease(HFMD),which is a serious public health threat,especially in the Asia-Pacific region(Wu et al.,2013).Due to the lack of effective anti...Dear Editor,Enterovirus 71(EV71)is the main pathogen of hand,foot,and mouth disease(HFMD),which is a serious public health threat,especially in the Asia-Pacific region(Wu et al.,2013).Due to the lack of effective antivirals for treatment,supportive therapy remains to be the primary measure for severe infections of EV71.EV71 belongs to the genus Enterovirus in the family of Picornavirridae.EV71 encodes a polyprotein that is proteolytically cleaved into four structural proteins and seven nonstructural proteins,i.e.,VP1 to VP4,2A to 2C,and 3A to 3D.Moreover,an alternative encoding strategy of harboring a novel open reading frame encoding a short peptide has been recently reported in gut epithelial cells infected with some enteroviruses(Lulla et al.,2019).Structural proteins play a key role in the packaging and maturation of virus particles,while non-structural proteins are mainly involved in the replication process of virus.Among them,the 3D polymerase(3Dpol)protein functions as an RNA-dependent RNA polymerase(RdRP)that is essential for viral RNA synthesis(Wu et al.,2010).展开更多
Hand,foot,and mouth disease(HFMD)is a common pediatric illness mainly caused by enteroviruses,which are important human pathogens.Currently,there are no available antiviral agents for the therapy of enterovirus infect...Hand,foot,and mouth disease(HFMD)is a common pediatric illness mainly caused by enteroviruses,which are important human pathogens.Currently,there are no available antiviral agents for the therapy of enterovirus infection.In this study,an excellent high-content antiviral screening system utilizing the EV-A71-eGFP reporter virus was developed.Using this screening system,we screened a drug library containing 1042 natural compounds to identify potential EV-A71 inhibitors.Fangchinoline(FAN),a bis-benzylisoquinoline alkaloid,exhibits potential inhibitory effects against various enteroviruses that cause HFMD,such as EV-A71,CV-A10,CV-B3 and CV-A16.Further investigations revealed that FAN targets the early stage of the enterovirus life cycle.Through the selection of FAN-resistant EV-A71 viruses,we demonstrated that the VP1 protein could be a potential target of FAN,as two mutations in VP1(E145G and V258I)resulted in viral resistance to FAN.Our research suggests that FAN is an efficient inhibitor of EV-A71 and has the potential to be a broad-spectrum antiviral drug against human enteroviruses.展开更多
Dear editor,Ebola virus(EBOV)is a member of the genus Orthoebolavirus within the family of Filoviridae.It's the causative agent of Ebola virus disease(EVD),characterized by general malaise,severe gastrointestinal ...Dear editor,Ebola virus(EBOV)is a member of the genus Orthoebolavirus within the family of Filoviridae.It's the causative agent of Ebola virus disease(EVD),characterized by general malaise,severe gastrointestinal illness,febrile,coagulopathy,multi-organs dysfunction,and high mortality(up to 90%)in humans and nonhuman primates(NHPs)(Jacob et al.,2020).Since its discovery in 1976,EBOV has grabbed the global concerns,especially after the West African epidemic from 2014 to 2016,which resulted in 30,000 cases and over 11,000 deaths(Feldmann et al.,2020;Jacob et al.,2020).From 2018 to 2022,there have been thousands of infections primarily in the Democratic Republic of the Congo(DRC),resulting in over 2000 deaths.This highlights the importance of continued attention and ongoing surveillance(www.who.int/emergenci es/disease-outbreak-news).展开更多
Chikungunya virus(CHIKV) is a mosquito-borne alphavirus. As an emerging virus, CHIKV imposes a threat to public health. Currently, there are no vaccines or antivirals available for the prevention of CHIKV infection. L...Chikungunya virus(CHIKV) is a mosquito-borne alphavirus. As an emerging virus, CHIKV imposes a threat to public health. Currently, there are no vaccines or antivirals available for the prevention of CHIKV infection. Lycorine, an alkaloid from Amaryllidaceae plants, has antiviral activity against a number of viruses such as coronavirus, flavivirus and enterovirus. In this study, we found that lycorine could inhibit CHIKV in cell culture at a concentration of 10 lmol/L without apparent cytotoxicity. In addition, it exhibited broad-spectrum anti-alphavirus activity, including Sindbis virus(SINV),Semliki Forest virus(SFV), and Venezuelan equine encephalomyelitis virus(VEEV). The time of addition studies indicated that lycorine functions at an early post-entry stage of CHIKV life cycle. The results based on two different CHIKV replicons provided further evidence that lycorine exerts its antiviral activity mainly by inhibiting CHIKV translation.Overall, our study extends the antiviral spectrum of lycorine.展开更多
The lung is the prophylaxis target against SARS-CoV-2 infection,and neutralizing antibodies are a leading class of biological products against various infectious viral pathogen.In this study,we develop a safe and cost...The lung is the prophylaxis target against SARS-CoV-2 infection,and neutralizing antibodies are a leading class of biological products against various infectious viral pathogen.In this study,we develop a safe and cost-effective platform to express neutralizing antibody in the lung with replicating mRNA basing on alphavirus replicon particle(VRP)delivery system,to prevent SARS-CoV-2 infections.First,a modified VEEV replicon with two subgenomic(sg)promoters was engineered to translate the light and heavy chains of antibody simultaneously,for expression and assembly of neutralizing anti-SARS-CoV-2 antibody CB6.Second,the feasibility and protective efficacy of replicating mRNA against SARS-CoV-2 infection were demonstrated through both in vitro and in vivo assays.The lung target delivery with the help of VRP system resulted in efficiently block SARS-CoV-2 infection with reducing viral titer and less tissue damage in the lung of mice.Overall,our data suggests that expressing neutralizing antibodies in the lungs with the help of self-replicating mRNA could potentially be a promising prophylaxis approach against SARS-CoV-2 infection.展开更多
The evolution of coronaviruses,such as SARS-CoV-2,makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after.Here we report a human angiotensin-converting enzyme 2(ACE2)-targeting mo...The evolution of coronaviruses,such as SARS-CoV-2,makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after.Here we report a human angiotensin-converting enzyme 2(ACE2)-targeting monoclonal antibody,3E8,blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2,SARS-CoV-2 mutant variants(SARS-CoV-2-D614G,B.1.1.7,B.1.351,B.1.617.1,and P.1).展开更多
Dear Editor,Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread rapidly and developed into a global pandemic since its outbreak in December 2019.Currentl...Dear Editor,Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread rapidly and developed into a global pandemic since its outbreak in December 2019.Currently,there is no antiviral treatment available for human use.Numerous compounds,such as remdesivir and chloroquine,have been reported to inhibit SARS-CoV-2 replication effectively in vitro,but for most of them,the in vivo efficacies against SARS-CoV-2 are still under clinical studies,and for chloroquine,a drug with prominent in vitro antiviral activity,it has been found no beneficial effect for COVID-19 patients in the recent largest study.It is thus urgent to speed up large-scale screening to discover drug candidates to treat COVID-19.展开更多
Stimulator of interferon genes,namely STING,an adaptor protein located in the endoplasmic reticulum,has been recognized as a shining target for cancer and infection research.However,STING agonists cyclic dinucleotides...Stimulator of interferon genes,namely STING,an adaptor protein located in the endoplasmic reticulum,has been recognized as a shining target for cancer and infection research.However,STING agonists cyclic dinucleotides(CDNs)have shown almost zero efficacy in phase I clinical trials as a monotherapy,likely due to poor cellular permeability and rapid diffusion despite intratumoral injection.These deficiencies further affect other applications of CDNs,such as pandemic SARS-CoV-2 prevention and therapy.Here,we rationally design a supramolecular cytosolic delivery system based on controllable recognition of calixarene,namely CASTING(CAlixarene-STING),to improve CDN druggability,including degradation stability,cellular permeability,and tissue retention.CASTING efficiently enhances the immunostimulatory potency of CDGSF[a chemically modified cyclic di-GMP(CDG)]to generate an immunogenic microenvironment for melanoma regression,anti-PD-1 response rate increase,and durable memory formation against tumor recurrence.More importantly,CASTING displays a superior adjuvant activity on SARSCoV-2 recombinant spike/receptor binding domain vaccines,inducing robust and coordinated T-cell and antibody responses against SARS-CoV-2 infection in vivo.Collectively,the CASTING design represents an innovative advancement to facilitate the clinical translational capability of STING agonists.展开更多
Dear Editor,The prolonged outbreak and spread of coronavirus disease 2019(COVID-19),caused by SARS-CoV-2 poses a great threat to global economic and public health.The protective efficacy of the vaccines based on the s...Dear Editor,The prolonged outbreak and spread of coronavirus disease 2019(COVID-19),caused by SARS-CoV-2 poses a great threat to global economic and public health.The protective efficacy of the vaccines based on the spike protein(S)of SARS-CoV-2 has been compromised by the emergence of variants of concern(VOC).展开更多
Dear Editor,The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continues to disrupt global public health since its first report in December 2019,resulting in more than 380 billi...Dear Editor,The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continues to disrupt global public health since its first report in December 2019,resulting in more than 380 billion confirmed cases including nearly 5.7 billion deaths worldwide(https://covidl9.who.int).展开更多
基金supported by Hubei Provincial Natural Science Foundation of China(2025AFB822)National Key Research and Development Program of China(No.2022YFD1800100)National Natural Science Foundation of China(32100110).
文摘Dear Editor,Enterovirus 71(EV71)is the main pathogen of hand,foot,and mouth disease(HFMD),which is a serious public health threat,especially in the Asia-Pacific region(Wu et al.,2013).Due to the lack of effective antivirals for treatment,supportive therapy remains to be the primary measure for severe infections of EV71.EV71 belongs to the genus Enterovirus in the family of Picornavirridae.EV71 encodes a polyprotein that is proteolytically cleaved into four structural proteins and seven nonstructural proteins,i.e.,VP1 to VP4,2A to 2C,and 3A to 3D.Moreover,an alternative encoding strategy of harboring a novel open reading frame encoding a short peptide has been recently reported in gut epithelial cells infected with some enteroviruses(Lulla et al.,2019).Structural proteins play a key role in the packaging and maturation of virus particles,while non-structural proteins are mainly involved in the replication process of virus.Among them,the 3D polymerase(3Dpol)protein functions as an RNA-dependent RNA polymerase(RdRP)that is essential for viral RNA synthesis(Wu et al.,2010).
基金funded by Guangzhou Municipal Science and Technology Project(202102020241)the National Natural Science Foundation of China(32100110 and 32300132)the National Key Research and Development Program of China(2021YFC2701800,2021YFC2701801).
文摘Hand,foot,and mouth disease(HFMD)is a common pediatric illness mainly caused by enteroviruses,which are important human pathogens.Currently,there are no available antiviral agents for the therapy of enterovirus infection.In this study,an excellent high-content antiviral screening system utilizing the EV-A71-eGFP reporter virus was developed.Using this screening system,we screened a drug library containing 1042 natural compounds to identify potential EV-A71 inhibitors.Fangchinoline(FAN),a bis-benzylisoquinoline alkaloid,exhibits potential inhibitory effects against various enteroviruses that cause HFMD,such as EV-A71,CV-A10,CV-B3 and CV-A16.Further investigations revealed that FAN targets the early stage of the enterovirus life cycle.Through the selection of FAN-resistant EV-A71 viruses,we demonstrated that the VP1 protein could be a potential target of FAN,as two mutations in VP1(E145G and V258I)resulted in viral resistance to FAN.Our research suggests that FAN is an efficient inhibitor of EV-A71 and has the potential to be a broad-spectrum antiviral drug against human enteroviruses.
文摘Dear editor,Ebola virus(EBOV)is a member of the genus Orthoebolavirus within the family of Filoviridae.It's the causative agent of Ebola virus disease(EVD),characterized by general malaise,severe gastrointestinal illness,febrile,coagulopathy,multi-organs dysfunction,and high mortality(up to 90%)in humans and nonhuman primates(NHPs)(Jacob et al.,2020).Since its discovery in 1976,EBOV has grabbed the global concerns,especially after the West African epidemic from 2014 to 2016,which resulted in 30,000 cases and over 11,000 deaths(Feldmann et al.,2020;Jacob et al.,2020).From 2018 to 2022,there have been thousands of infections primarily in the Democratic Republic of the Congo(DRC),resulting in over 2000 deaths.This highlights the importance of continued attention and ongoing surveillance(www.who.int/emergenci es/disease-outbreak-news).
基金This work was supported by the National Key Research and Development Program of China(2018YFA0507201)。
文摘Chikungunya virus(CHIKV) is a mosquito-borne alphavirus. As an emerging virus, CHIKV imposes a threat to public health. Currently, there are no vaccines or antivirals available for the prevention of CHIKV infection. Lycorine, an alkaloid from Amaryllidaceae plants, has antiviral activity against a number of viruses such as coronavirus, flavivirus and enterovirus. In this study, we found that lycorine could inhibit CHIKV in cell culture at a concentration of 10 lmol/L without apparent cytotoxicity. In addition, it exhibited broad-spectrum anti-alphavirus activity, including Sindbis virus(SINV),Semliki Forest virus(SFV), and Venezuelan equine encephalomyelitis virus(VEEV). The time of addition studies indicated that lycorine functions at an early post-entry stage of CHIKV life cycle. The results based on two different CHIKV replicons provided further evidence that lycorine exerts its antiviral activity mainly by inhibiting CHIKV translation.Overall, our study extends the antiviral spectrum of lycorine.
基金This work was supported by the National Key Research and Development Program of China(2018YFA0507201)The funders had no role in study design,data collection,and interpretation,or the decision to submit the work for publication.
文摘The lung is the prophylaxis target against SARS-CoV-2 infection,and neutralizing antibodies are a leading class of biological products against various infectious viral pathogen.In this study,we develop a safe and cost-effective platform to express neutralizing antibody in the lung with replicating mRNA basing on alphavirus replicon particle(VRP)delivery system,to prevent SARS-CoV-2 infections.First,a modified VEEV replicon with two subgenomic(sg)promoters was engineered to translate the light and heavy chains of antibody simultaneously,for expression and assembly of neutralizing anti-SARS-CoV-2 antibody CB6.Second,the feasibility and protective efficacy of replicating mRNA against SARS-CoV-2 infection were demonstrated through both in vitro and in vivo assays.The lung target delivery with the help of VRP system resulted in efficiently block SARS-CoV-2 infection with reducing viral titer and less tissue damage in the lung of mice.Overall,our data suggests that expressing neutralizing antibodies in the lungs with the help of self-replicating mRNA could potentially be a promising prophylaxis approach against SARS-CoV-2 infection.
基金This work was supported by the China National Major Scientific and Technological Special Project for"Significant New Drugs Innovation and Development"(2019ZX09732002-006)the Strategic Priority Research Program of the Chinese Academy of Sciences(CAS)(XDA12020223 and XDA12020330)+7 种基金the National Natural Science Foundation of China(81872785,81673347,31971123,32022037,81920108015,and 31930059)Shanghai Municipal Commission of Science and Technology of China(17431904400 and 19YF1457400)Institutes for Drug Discovery and Development,Chinese Academy of Sciences(CASIMM0120202008 and CASIMM0120202007)the National Key R&D Program(2020YFA0509303)Major Scientific and Technological Special Project of Zhongshan City(191022172638719 and 210205143867019)the Key R&D Program of Zhejiang Province(2020C04001)the SARS-CoV-2 emergency project of the Science and Technology Department of Zhejiang Province(2020C03129)the Leading Innovative and Entrepreneur Team Introduction Program of Hangzhou,Westlake Education Foundation and Tencent Foundation.
文摘The evolution of coronaviruses,such as SARS-CoV-2,makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after.Here we report a human angiotensin-converting enzyme 2(ACE2)-targeting monoclonal antibody,3E8,blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2,SARS-CoV-2 mutant variants(SARS-CoV-2-D614G,B.1.1.7,B.1.351,B.1.617.1,and P.1).
基金supported by the National Key Research and Development Program of China(2018YFA0507201).
文摘Dear Editor,Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread rapidly and developed into a global pandemic since its outbreak in December 2019.Currently,there is no antiviral treatment available for human use.Numerous compounds,such as remdesivir and chloroquine,have been reported to inhibit SARS-CoV-2 replication effectively in vitro,but for most of them,the in vivo efficacies against SARS-CoV-2 are still under clinical studies,and for chloroquine,a drug with prominent in vitro antiviral activity,it has been found no beneficial effect for COVID-19 patients in the recent largest study.It is thus urgent to speed up large-scale screening to discover drug candidates to treat COVID-19.
基金supported by the National Key R&D Program of China(nos.2019YFA0904200 and 2018YFA0507600)the Tsinghua University Spring Breeze Fund(no.2020Z99CFY042)+1 种基金the National Natural Science Foundation of China(nos.92053108 and 31961143004)NCC Fund(no.NCC2020FH04).
文摘Stimulator of interferon genes,namely STING,an adaptor protein located in the endoplasmic reticulum,has been recognized as a shining target for cancer and infection research.However,STING agonists cyclic dinucleotides(CDNs)have shown almost zero efficacy in phase I clinical trials as a monotherapy,likely due to poor cellular permeability and rapid diffusion despite intratumoral injection.These deficiencies further affect other applications of CDNs,such as pandemic SARS-CoV-2 prevention and therapy.Here,we rationally design a supramolecular cytosolic delivery system based on controllable recognition of calixarene,namely CASTING(CAlixarene-STING),to improve CDN druggability,including degradation stability,cellular permeability,and tissue retention.CASTING efficiently enhances the immunostimulatory potency of CDGSF[a chemically modified cyclic di-GMP(CDG)]to generate an immunogenic microenvironment for melanoma regression,anti-PD-1 response rate increase,and durable memory formation against tumor recurrence.More importantly,CASTING displays a superior adjuvant activity on SARSCoV-2 recombinant spike/receptor binding domain vaccines,inducing robust and coordinated T-cell and antibody responses against SARS-CoV-2 infection in vivo.Collectively,the CASTING design represents an innovative advancement to facilitate the clinical translational capability of STING agonists.
基金supported by the National Key Research and Development Program of China(2018YFA0507201).
文摘Dear Editor,The prolonged outbreak and spread of coronavirus disease 2019(COVID-19),caused by SARS-CoV-2 poses a great threat to global economic and public health.The protective efficacy of the vaccines based on the spike protein(S)of SARS-CoV-2 has been compromised by the emergence of variants of concern(VOC).
基金We thank the National Key Research and Development Program of China(2018YFA0507201)for grant support.We thank the National Virus Resource center for making Omicron available.
文摘Dear Editor,The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continues to disrupt global public health since its first report in December 2019,resulting in more than 380 billion confirmed cases including nearly 5.7 billion deaths worldwide(https://covidl9.who.int).
