Severe fever with thrombocytopenia syndrome(SFTS)caused by the SFTS virus(SFTSV)is an emerging disease in East Asia with a fatality rate of up to 30%.However,the viral-host interaction of SFTSV remains largely unknown...Severe fever with thrombocytopenia syndrome(SFTS)caused by the SFTS virus(SFTSV)is an emerging disease in East Asia with a fatality rate of up to 30%.However,the viral-host interaction of SFTSV remains largely unknown.The heat-shock protein 90(Hsp90)family consists of highly conserved chaperones that fold and remodel proteins and has a broad impact on the infection of many viruses.Here,we showed that Hsp90 is an important host factor involved in SFTSV infection.Hsp90 inhibitors significantly reduced SFTSV replication,viral protein expression,and the formation of inclusion bodies consisting of nonstructural proteins(NSs).Among viral proteins,NSs appeared to be the most reduced when Hsp90 inhibitors were used,and further analysis showed that their translation was affected.Co-immunoprecipitation of NSs with four isomers of Hsp90 showed that Hsp90βspecifically interacted with them.Knockdown of Hsp90βexpression also inhibited replication of SFTSV.These results suggest that Hsp90βplays a critical role during SFTSV infection and could be a potential target for the development of drugs against SFTS.展开更多
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 molnupir...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.展开更多
The global COVID-19 coronavirus pandemic has infected over 109 million people,leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment.Here,we screened about 1.8 million s...The global COVID-19 coronavirus pandemic has infected over 109 million people,leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment.Here,we screened about 1.8 million small molecules against the main protease(M^(pro))and papain like protease(PL^(pro)),two major proteases in severe acute respiratory syndrome-coronavirus 2 genome,and identified 1851M^(pro)inhibitors and 205 PL^(pro)inhibitors with low nmol/l activity of the best hits.Among these inhibitors,eight small molecules showed dual inhibition effects on both M^(pro)and PL^(pro),exhibiting potential as better candidates for COVID-19 treatment.The best inhibitors of each protease were tested in antiviral assay,with over 40%of M^(pro)inhibitors and over 20%of PL^(pro)inhibitors showing high potency in viral inhibition with low cytotoxicity.The X-ray crystal structure of SARS-CoV-2 M^(pro)in complex with its potent inhibitor 4a was determined at 1.8Åresolution.Together with docking assays,our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.展开更多
Dear Editor,The global coronavirus disease 2019(COVID-19)pandemic,which is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has brought a profound impact on humanity.SARS-CoV-2 enters host cells th...Dear Editor,The global coronavirus disease 2019(COVID-19)pandemic,which is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has brought a profound impact on humanity.SARS-CoV-2 enters host cells through the interaction of its spike glycoprotein with angiotensin-converting enzyme 2(ACE2)of the host and releases its viral RNA genome.^(1)展开更多
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)....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).展开更多
In our recent review of the article[1],the author noticed that the dots(red squares)in Fig 1m were accidentally removed from its original location during figure formatting,and the related data analysis is correct.Furt...In our recent review of the article[1],the author noticed that the dots(red squares)in Fig 1m were accidentally removed from its original location during figure formatting,and the related data analysis is correct.Furthermore,we checked this paper again and this situation only occurred in Fig 1m.In addition,in Fig 1c,a legend for SARS-CoV-1 is missing and we have supplemented it.For the text section,no modifications are required.The correct data are provided as follows.The key findings of the article are not affected by these corrections.The original article has been corrected.We regret any inconvenience this has caused.展开更多
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide,such as the on-going outbreak of the novel coronavirus SARS-CoV-2.Herein,we identified two potent inhibitors of human DHODH,S31...Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide,such as the on-going outbreak of the novel coronavirus SARS-CoV-2.Herein,we identified two potent inhibitors of human DHODH,S312 and S416,with favorable drug-likeness and pharmacokinetic profiles,which all showed broad-spectrum antiviral effects against various RNA viruses,including influenza A virus,Zika virus,Ebola virus,and particularly against SARS-CoV-2.Notably,S416 is reported to be the most potent inhibitor so far with an EC5o of 17 nmol/L and an SI value of 10,505.88 in infec-ted cells.Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells.This work demonstrates that both S312/S416 and old drugs(Leflunomide/Teriflunomide)with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide,no matter such viruses are mutated or not.展开更多
Dear Editor,Since December 2019,the pandemic of coronavirus disease 2019(COVID-19)has taken a heavy toll on global health,creating an urgent need to develop effective strategies for prevention and treatment.The etiolo...Dear Editor,Since December 2019,the pandemic of coronavirus disease 2019(COVID-19)has taken a heavy toll on global health,creating an urgent need to develop effective strategies for prevention and treatment.The etiological agent,known as severe acute respiratory syndrome coronavirus 2(SARSCoV-2),has infected nearly 229.2 million people worldwide with more than 4.7 million deaths as of September 15,2021.Older age and preexisting health conditions are associated with worse clinical prognosis including higher mortality rates(Zhou et al.,2020).The global race to combat this pandemic has led to rapid deployment of numerous effective vaccines against SARS-CoV-2(Tregoning et al.,2021).However,the emergence of viral variants,including the Delta variant(B.1.617.2),compromised vaccine effectiveness with resurgence of SARS-CoV-2 infection among highly vaccinated population(Keehner et al.,2021).Therefore,development of therapeutics against the more conserved viral targets would be essential to contain the spread of COVID-19 and reduce mortality.展开更多
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 g...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.展开更多
A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 outbreak.Currently,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identif...A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 outbreak.Currently,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identify new anti-COVID-19 agents.In this study,we screened over 6,000 compounds that included approved drugs,drug candidates in clinical trials,and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease(PLpro).Together with main protease(Mpro),PLpro is responsible for processing the viral replicase polyprotein into functional units.There-fore,it is an attractive target for antiviral drug develop-ment.Here we discovered four compounds,YM155,cryptotanshinone,tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 pmol/L.These compounds also exhibit strong antiviral activities in cell-based assays.YM155,an anti-cancer drug candidate in clinical trials,has the most potent antiviral activity with an EC50 value of 170 nmol/L.In addition,we have determined the crystal structures of this enzyme and its complex with YM155,revealing a unique binding mode.YM155 simultaneously targets three"hot"spots on PLpro,including the substrate-binding pocket,the interferon stimulating gene product 15(ISG15)binding site and zinc finger motif.Our results demonstrate the efficacy of this screening and repur-posing strategy,which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.展开更多
Dear Editor,Coronaviruses (Co Vs) are large enveloped non-segmented positive-strand RNA viruses that broadly distribute among humans and other animal species, including bats, mice and birds. SARS-Co V-2 infections can...Dear Editor,Coronaviruses (Co Vs) are large enveloped non-segmented positive-strand RNA viruses that broadly distribute among humans and other animal species, including bats, mice and birds. SARS-Co V-2 infections can cause diseases, named the 2019 novel coronavirus disease (COVID-19). The symptoms of COVID-19 range from mild symptoms to severe respiratory syndromes, including pneumonia, and even death(Chen et al., 2020b;Jiang and Shi, 2020;Xia et al., 2020).展开更多
Swine acute diarrhea syndrome coronavirus(SADS‐CoV)is a recently discovered coronavirus that causes severe and acute diarrhea and rapid weight loss in piglets.SADS‐CoV was reported to be capable of infecting cell li...Swine acute diarrhea syndrome coronavirus(SADS‐CoV)is a recently discovered coronavirus that causes severe and acute diarrhea and rapid weight loss in piglets.SADS‐CoV was reported to be capable of infecting cell lines derived from diverse species,including bats,mice,hamsters,rats,chickens,pigs,nonhuman primates,and humans,implying its high risk of cross‐species infection.However,its receptor is still unknown.In this study,the receptor‐binding domain of the SADS‐CoV spike(S)protein was purified and then subjected to affinity purification(AP)‐coupled mass spectrometry(MS)‐based proteomic analysis to identify the interactors of the SADS‐CoV S protein.Forty‐three host proteins were identified,and a Gene Ontology analysis indicated that these interactors can be grouped into categories such as“cell‐cell adhesion”,“translation”“viral transcription”,suggesting that these processes may participate in the SADS‐CoV life cycles.RNA interference‐based screening of these interactors indicated that PPIB and vimentin can affect SADS‐CoV replication.Our study provides an overarching view into the host interactome of the SADS‐CoV S protein and highlights potential targets for the development of therapeutics against SADS‐CoV.展开更多
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 deat...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.展开更多
The recent outbreak of novel coronavirus pneumonia(COVID-19)caused by a new coronavirus has posed a great threat to public health.Identifying safe and effective antivirals is of urgent demand to cure the huge number o...The recent outbreak of novel coronavirus pneumonia(COVID-19)caused by a new coronavirus has posed a great threat to public health.Identifying safe and effective antivirals is of urgent demand to cure the huge number of patients.Virusencoded proteases are considered potential drug targets.The human immunodeficiency virus protease inhibitors(lopinavir/ritonavir)has been recommended in the global Solidarity Trial in March launched by World Health Organization.However,there is currently no experimental evidence to support or against its clinical use.We evaluated the antiviral efficacy of lopinavir/ritonavir along with other two viral protease inhibitors in vitro,and discussed the possible inhibitory mechanism in silico.The in vitro to in vivo extrapolation was carried out to assess whether lopinavir/ritonavir could be effective in clinical.Among the four tested compounds,lopinavir showed the best inhibitory effect against the novel coronavirus infection.However,further in vitro to in vivo extrapolation of pharmacokinetics suggested that lopinavir/ritonavir could not reach effective concentration under standard dosing regimen[marketed as Kaletraò,contained lopinavir/ritonavir(200 mg/50 mg)tablets,recommended dosage is 400 mg/10 mg(2 tablets)twice daily].This research concluded that lopinavir/ritonavir should be stopped for clinical use due to the huge gap between in vitro IC50 and free plasma concentration.Nevertheless,the structure–activity relationship analysis of the four inhibitors provided further information for de novel design of future viral protease inhibitors of SARS-CoV-2.展开更多
Figure 1.Discovery of novel and potent DHODHi and their anti-influenza A virus activities.(A)The discovery and design of S312 and S416.The detailed descriptions of the discovery workflow are in Method.Binding analysis...Figure 1.Discovery of novel and potent DHODHi and their anti-influenza A virus activities.(A)The discovery and design of S312 and S416.The detailed descriptions of the discovery workflow are in Method.Binding analysis of S312(B)and S416(C).Thermodynamic analysis of the binding of S312 and S416 to DHODH was carried out at 25 C on a MicroCal iTC200 instrument.Kinetic analysis of the binding of S312 and S416 to DHODH was performed with a Biacore T200 instrument.展开更多
CORRECTION TO:PROTEIN CELL 2020,11(10):723–739 HTTPS://DOI.ORG/10.1007/S13238-020-00768-W In the original publication the author’s name‘Dimitri Lavillete’is published incorrectly.The correct author name should be ...CORRECTION TO:PROTEIN CELL 2020,11(10):723–739 HTTPS://DOI.ORG/10.1007/S13238-020-00768-W In the original publication the author’s name‘Dimitri Lavillete’is published incorrectly.The correct author name should be spelt as‘Dimitri Lavillette’is provided in this correction.OPEN ACCESS This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons licence,and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence,unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use,you will need to obtain permission directly from the copyright holder.To view a copy of this licence,visit http://creativecommons.org/licenses/by/4.0/.展开更多
Dear Editor,Since the beginning of 2020,the Coronavirus(CoV)Disease 2019(COVID-19)pandemic has posed formidable challenges to public health security.The main protease(Mpro,3CLpro)of CoVs plays essential roles in viral...Dear Editor,Since the beginning of 2020,the Coronavirus(CoV)Disease 2019(COVID-19)pandemic has posed formidable challenges to public health security.The main protease(Mpro,3CLpro)of CoVs plays essential roles in viral replication,making them attractive targets for antiviral drug development.展开更多
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 th...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.展开更多
基金supported by grants from the National Natural Science Foundation of China(31900146)the key Biosafety Science and Technology Program of Hubei Jiangxia Laboratory(JXBS001)+1 种基金the Hubei Natural Science Foundation for Distinguished Young Scholars(2021CFA050)the Creative Research Group Program of Natural Science Foundation of Hubei Province(2022CFA021).
文摘Severe fever with thrombocytopenia syndrome(SFTS)caused by the SFTS virus(SFTSV)is an emerging disease in East Asia with a fatality rate of up to 30%.However,the viral-host interaction of SFTSV remains largely unknown.The heat-shock protein 90(Hsp90)family consists of highly conserved chaperones that fold and remodel proteins and has a broad impact on the infection of many viruses.Here,we showed that Hsp90 is an important host factor involved in SFTSV infection.Hsp90 inhibitors significantly reduced SFTSV replication,viral protein expression,and the formation of inclusion bodies consisting of nonstructural proteins(NSs).Among viral proteins,NSs appeared to be the most reduced when Hsp90 inhibitors were used,and further analysis showed that their translation was affected.Co-immunoprecipitation of NSs with four isomers of Hsp90 showed that Hsp90βspecifically interacted with them.Knockdown of Hsp90βexpression also inhibited replication of SFTSV.These results suggest that Hsp90βplays a critical role during SFTSV infection and could be a potential target for the development of drugs against SFTS.
基金This work was supported by grants from the National Natural Science Foundation of China(U22A20379,31970165)the National Key Research and Development Plan of China(2021YFC2300700,2022YFC2303300)+1 种基金the Special Foundation of the Chinese Academy of Sciences(2022000025)Shanghai Science and Technology Committee in China(Number:21S11903100).
文摘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.
基金supported by the National Key R&D Program of China 2018YFA0507000(B.W,Q.Z.),2018ZX09735001(Y.J.)and 2020YFC0844500(J.L.),the National Science Foundation of China grants 31825010(B.W.),81525024(Q.Z.),81673489(J.L),the Key Research Program of Frontier Sciences,CAS grants QYZDB-SSWSMC024(B.W.)and QYZDB-SSW-SMC054(Q.Z.),Fund of Chinese Academy of Sciences 2020YJFK0105(J.L.),Chinese Academy of Engineering and Jack Ma Foundation 2020-CMKYGG-05(J.D.),the Shanghai Science and Technology Development Funds 20431900200(J.L.)and K.C.Wong Education Foundation(J.L.),Fund of Youth Innovation Promotion Association 2018319(X.C.),and the Hubei Science and Technology Project 2020FCA003(G.X.).Fund of Chinese Academy of Sciences 2020YJFK0105(J.L.)。
文摘The global COVID-19 coronavirus pandemic has infected over 109 million people,leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment.Here,we screened about 1.8 million small molecules against the main protease(M^(pro))and papain like protease(PL^(pro)),two major proteases in severe acute respiratory syndrome-coronavirus 2 genome,and identified 1851M^(pro)inhibitors and 205 PL^(pro)inhibitors with low nmol/l activity of the best hits.Among these inhibitors,eight small molecules showed dual inhibition effects on both M^(pro)and PL^(pro),exhibiting potential as better candidates for COVID-19 treatment.The best inhibitors of each protease were tested in antiviral assay,with over 40%of M^(pro)inhibitors and over 20%of PL^(pro)inhibitors showing high potency in viral inhibition with low cytotoxicity.The X-ray crystal structure of SARS-CoV-2 M^(pro)in complex with its potent inhibitor 4a was determined at 1.8Åresolution.Together with docking assays,our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
基金supported by the National Natural Science Foundation of China(82151219,82130105)the Strategic Priority Research Program of the Chinese Academy of Sciences(SIMM010109,SIMM010111)the Qiusuo Outstanding Youth Project of Lingang Laboratory(LG-QS-202205-02).
文摘Dear Editor,The global coronavirus disease 2019(COVID-19)pandemic,which is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has brought a profound impact on humanity.SARS-CoV-2 enters host cells through the interaction of its spike glycoprotein with angiotensin-converting enzyme 2(ACE2)of the host and releases its viral RNA genome.^(1)
基金facility support.This work was supported by the National Natural Science Foundation of China(32188101 and U20A20135)the National Program on Key Research Project of China(2020YFA0707500),and Tsinghua University Spring Breeze Fund.
文摘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).
文摘In our recent review of the article[1],the author noticed that the dots(red squares)in Fig 1m were accidentally removed from its original location during figure formatting,and the related data analysis is correct.Furthermore,we checked this paper again and this situation only occurred in Fig 1m.In addition,in Fig 1c,a legend for SARS-CoV-1 is missing and we have supplemented it.For the text section,no modifications are required.The correct data are provided as follows.The key findings of the article are not affected by these corrections.The original article has been corrected.We regret any inconvenience this has caused.
基金This work was supported in part by the National Key Research and Development Program Grants(2018FYA0900801 and 2018ZX10101004003001 to K.X.2016YFA0502304 to H.L.)the National Natural Science Foundation of China(Grants 31922004 and 81772202 to K.X.,81825020 to H.L.)+2 种基金the National Science&Technology Major Project"Key New Drug Creation and Manufac-turing Program"of China(Grant 2018ZX09711002 to H.L.)Appli-cation&Frontier Research Program of Wuhan Govemment(2019020701011463 to K.X.).Honglin Li is also sponsored by the National Program for Special Supports of Eminent Professionals and National Program for Support of Top-Notch Young ProfessionalsWe are grateful to Taikang Insurance Group Co,Ltd,Beiing Taikang Yicai Foundation,and Special Fund for COVID-19 Research of Wuhan University for their great supports to this work.
文摘Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide,such as the on-going outbreak of the novel coronavirus SARS-CoV-2.Herein,we identified two potent inhibitors of human DHODH,S312 and S416,with favorable drug-likeness and pharmacokinetic profiles,which all showed broad-spectrum antiviral effects against various RNA viruses,including influenza A virus,Zika virus,Ebola virus,and particularly against SARS-CoV-2.Notably,S416 is reported to be the most potent inhibitor so far with an EC5o of 17 nmol/L and an SI value of 10,505.88 in infec-ted cells.Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells.This work demonstrates that both S312/S416 and old drugs(Leflunomide/Teriflunomide)with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide,no matter such viruses are mutated or not.
基金from National Key R&D Program of China(Grant No.2017YFC0840300 to Z.R.)National Key R&D Program of China(Grant No.2020YFA0707500 to H.Y.)+1 种基金Science and Technology Commission of Shanghai Municipality(Grant Nos.20431900200 and 20XD1422900)Department of Science and Technology of Guangxi Zhuang Autonomous Region(Grant No.5602020AB40007).
文摘Dear Editor,Since December 2019,the pandemic of coronavirus disease 2019(COVID-19)has taken a heavy toll on global health,creating an urgent need to develop effective strategies for prevention and treatment.The etiological agent,known as severe acute respiratory syndrome coronavirus 2(SARSCoV-2),has infected nearly 229.2 million people worldwide with more than 4.7 million deaths as of September 15,2021.Older age and preexisting health conditions are associated with worse clinical prognosis including higher mortality rates(Zhou et al.,2020).The global race to combat this pandemic has led to rapid deployment of numerous effective vaccines against SARS-CoV-2(Tregoning et al.,2021).However,the emergence of viral variants,including the Delta variant(B.1.617.2),compromised vaccine effectiveness with resurgence of SARS-CoV-2 infection among highly vaccinated population(Keehner et al.,2021).Therefore,development of therapeutics against the more conserved viral targets would be essential to contain the spread of COVID-19 and reduce mortality.
文摘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.
基金National Key R&D Program of China grants 2017YFC0840300(Z.R.)and 2020YFA0707500(H.Y.)Project of International Cooperation and Exchanges NSFC(Grant No.81520108019 to Z.R.)+3 种基金Science and Technology Commission of Shanghai Municipality(Grant No.20431900200 to H.Y.)Department of Science and Technology of Guangxi Zhuang Autonomous Region(Grant No.2020AB40007 to X.Y.)Hubei Science and Technology Project(Grant No.2020FCA003 to L.Z.)Youth Program of NSFC(Grant No.81900729 to L.S.).
文摘A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 outbreak.Currently,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identify new anti-COVID-19 agents.In this study,we screened over 6,000 compounds that included approved drugs,drug candidates in clinical trials,and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease(PLpro).Together with main protease(Mpro),PLpro is responsible for processing the viral replicase polyprotein into functional units.There-fore,it is an attractive target for antiviral drug develop-ment.Here we discovered four compounds,YM155,cryptotanshinone,tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 pmol/L.These compounds also exhibit strong antiviral activities in cell-based assays.YM155,an anti-cancer drug candidate in clinical trials,has the most potent antiviral activity with an EC50 value of 170 nmol/L.In addition,we have determined the crystal structures of this enzyme and its complex with YM155,revealing a unique binding mode.YM155 simultaneously targets three"hot"spots on PLpro,including the substrate-binding pocket,the interferon stimulating gene product 15(ISG15)binding site and zinc finger motif.Our results demonstrate the efficacy of this screening and repur-posing strategy,which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.
基金supported by the Strategic Priority Research Program of CAS(XDB29010300 to X.Z.)the National Natural Science Foundation of China(31800140 to J.M.,81873964 to Y.Q.,and 31670161 to X.Z.)+1 种基金the National Science and Technology Major Project(2018ZX10101004 to X.Z.)the Yunde Hou Academician Fund from National Institute for Viral Disease Control and Prevention(2019HYDQNJJ10 to J.M.)。
文摘Dear Editor,Coronaviruses (Co Vs) are large enveloped non-segmented positive-strand RNA viruses that broadly distribute among humans and other animal species, including bats, mice and birds. SARS-Co V-2 infections can cause diseases, named the 2019 novel coronavirus disease (COVID-19). The symptoms of COVID-19 range from mild symptoms to severe respiratory syndromes, including pneumonia, and even death(Chen et al., 2020b;Jiang and Shi, 2020;Xia et al., 2020).
基金supported by National Natural Science Foundation of China(31830096)the Open Research Fund Program of Wuhan National Bio‐Safety Level 4 Lab of CAS(2020ACCP‐MS01)the Youth Innovation Promotion Association CAS(grants 2018367 to L.‐K.Z).
文摘Swine acute diarrhea syndrome coronavirus(SADS‐CoV)is a recently discovered coronavirus that causes severe and acute diarrhea and rapid weight loss in piglets.SADS‐CoV was reported to be capable of infecting cell lines derived from diverse species,including bats,mice,hamsters,rats,chickens,pigs,nonhuman primates,and humans,implying its high risk of cross‐species infection.However,its receptor is still unknown.In this study,the receptor‐binding domain of the SADS‐CoV spike(S)protein was purified and then subjected to affinity purification(AP)‐coupled mass spectrometry(MS)‐based proteomic analysis to identify the interactors of the SADS‐CoV S protein.Forty‐three host proteins were identified,and a Gene Ontology analysis indicated that these interactors can be grouped into categories such as“cell‐cell adhesion”,“translation”“viral transcription”,suggesting that these processes may participate in the SADS‐CoV life cycles.RNA interference‐based screening of these interactors indicated that PPIB and vimentin can affect SADS‐CoV replication.Our study provides an overarching view into the host interactome of the SADS‐CoV S protein and highlights potential targets for the development of therapeutics against SADS‐CoV.
基金We thank Xuefang An,Fan Zhang in the Core Facility and Technical Support Facility of the Wuhan Institute of Virology for their technical assistance.This work was partially supported by the National Natural Science Foundation of China(31970165 to L.Z.)the National Key Research and Development Program of China(2021YFC2300700)the Shanghai Municipal Science and Technology Major Project,and the Youth Innovation Promotion Association CAS(2018367 to L.Z.).
文摘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.
基金supported by Beijing Natural Science Foundation(M21016)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-003 and 2021-CAMS-JZ004)+1 种基金Tsinghua-Peking Center for Life Sciences (045-61020100122)Beijing Advanced Innovation Center for Structural Biology
基金supported in part by grants from the National Science and Technology Major Projects(Grant Number 2018ZX09711003)National Key Research and Development Project(2020YFC0841700)+1 种基金the National Natural Science Foundation of China(Grant Number 31621061)the Hubei Science and Technology Project(Grant Number 2020FCA003)。
文摘The recent outbreak of novel coronavirus pneumonia(COVID-19)caused by a new coronavirus has posed a great threat to public health.Identifying safe and effective antivirals is of urgent demand to cure the huge number of patients.Virusencoded proteases are considered potential drug targets.The human immunodeficiency virus protease inhibitors(lopinavir/ritonavir)has been recommended in the global Solidarity Trial in March launched by World Health Organization.However,there is currently no experimental evidence to support or against its clinical use.We evaluated the antiviral efficacy of lopinavir/ritonavir along with other two viral protease inhibitors in vitro,and discussed the possible inhibitory mechanism in silico.The in vitro to in vivo extrapolation was carried out to assess whether lopinavir/ritonavir could be effective in clinical.Among the four tested compounds,lopinavir showed the best inhibitory effect against the novel coronavirus infection.However,further in vitro to in vivo extrapolation of pharmacokinetics suggested that lopinavir/ritonavir could not reach effective concentration under standard dosing regimen[marketed as Kaletraò,contained lopinavir/ritonavir(200 mg/50 mg)tablets,recommended dosage is 400 mg/10 mg(2 tablets)twice daily].This research concluded that lopinavir/ritonavir should be stopped for clinical use due to the huge gap between in vitro IC50 and free plasma concentration.Nevertheless,the structure–activity relationship analysis of the four inhibitors provided further information for de novel design of future viral protease inhibitors of SARS-CoV-2.
文摘Figure 1.Discovery of novel and potent DHODHi and their anti-influenza A virus activities.(A)The discovery and design of S312 and S416.The detailed descriptions of the discovery workflow are in Method.Binding analysis of S312(B)and S416(C).Thermodynamic analysis of the binding of S312 and S416 to DHODH was carried out at 25 C on a MicroCal iTC200 instrument.Kinetic analysis of the binding of S312 and S416 to DHODH was performed with a Biacore T200 instrument.
文摘CORRECTION TO:PROTEIN CELL 2020,11(10):723–739 HTTPS://DOI.ORG/10.1007/S13238-020-00768-W In the original publication the author’s name‘Dimitri Lavillete’is published incorrectly.The correct author name should be spelt as‘Dimitri Lavillette’is provided in this correction.OPEN ACCESS This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons licence,and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence,unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use,you will need to obtain permission directly from the copyright holder.To view a copy of this licence,visit http://creativecommons.org/licenses/by/4.0/.
基金M.L.was funded by the NSFC(82073292,81622002,81861130368)the SJTU Trans-med Awards Research,the Gaofeng Clinical Medicine Grant(828318)+6 种基金the Shanghai Excellent Youth Academic Leader Program(20XD1422700)the Shanghai Medical and Health Excellent Discipline Leader Development Plan(2018BR36)Shanghai Collaborative Innovation Center for Translational Medicine(TM201902)the Foundation of the National Facility for Translational Medicine(Shanghai)(TMSK-2020-003)the Newton Advanced Fellowship,and the Samuel Waxman Cancer Research Foundation.H.Y.was funded by the Science and Technology Commission of Shanghai Municipality(20431900200)the Department of Science and Technology of Guangxi Zhuang Autonomous Region(2020AB40007)L.Z.was funded by the NSFC(31970165).
文摘Dear Editor,Since the beginning of 2020,the Coronavirus(CoV)Disease 2019(COVID-19)pandemic has posed formidable challenges to public health security.The main protease(Mpro,3CLpro)of CoVs plays essential roles in viral replication,making them attractive targets for antiviral drug development.
基金supported by the National Natural Science Foundation of China (Nos.82130105 to H.L.,82121005 to H.L.,92169112 to S.J.,82041036 to L.L.,T2225002 to M.Z.,82002142 to S.X.,82341093 to F.B.,and 32200131 to Y.Z.)the National Program on Key Research Project of China (2021YFC2300703 to L.L.)+4 种基金National Key R&D Program of China (2022YFC0868900 and 2021YFC0864900 to H.L.,2021YFC2300700 to L.Z.)Shanghai Municipal Science and Technology Major Project,Shanghai Science and Technology Development Funds (20QA1406400 to F.B.)Lingang Laboratory (LG202101-01-07 to H.Y.,LG202103-04-03 to W.D.)Youth Innovation Promotion Association CAS (2023296 to S.Z)the Science and Technology Commission of Shanghai Municipality (YDZX20213100001556 to H.Y.).
文摘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.