The spike protein(S)of SARS-CoV-2 is responsible for viral attachment and entry,thus a major factor for host suscep-tibility,tissue tropism,virulence and pathogenicity.The S is divided with S1 and S2 region,and the S1...The spike protein(S)of SARS-CoV-2 is responsible for viral attachment and entry,thus a major factor for host suscep-tibility,tissue tropism,virulence and pathogenicity.The S is divided with S1 and S2 region,and the S1 contains the receptor-binding domain(RBD),while the S2 contains the hydrophobic fusion domain for the entry into the host cell.Numerous host proteases have been implicated in the activation of SARS-CoV-2 S through various c leavage sites.In this article,we review host proteases including furin,trypsin,transmembrane protease serine 2(TMPRSS2)and cathepsins in the activation of SARS-CoV-2 S.Many betacoronaviruses including SARS-CoV-2 have polybasic residues at the S1/S2 site which is subjected to the cleavage by furin.The S1/S2 cleavage facilitates more assessable RBD to the receptor ACE2,and the binding triggers further conformational changes and exposure of the S2'site to proteases such as type Il transmembrane serine proteases(TTPRs)including TMPRSS2.In the presence of TMPRSS2 on the target cells,SARS-CoV-2 can utilize a direct entry route by fusion of the viral envelope to the cellular membrane.In the absence of TMPRSS2,SARS-CoV-2 enter target cells via endosomes where multiple cathepsins cleave the S for the successful entry.Additional host proteases involved in the cleavage of the S were discussed.This article also includes roles of 3C-like protease inhibitors which have inhibitory activity against cathepsin L in the entry of SARS-CoV-2,and discussed the dual roles of such inhibitors in virus replication.展开更多
Despite the global decline in the severity of the coronavirus disease 2019 (COVID-19) cases, the disease stillrepresents a major concern to the relevant scientific and medical communities. The primary concern of drug ...Despite the global decline in the severity of the coronavirus disease 2019 (COVID-19) cases, the disease stillrepresents a major concern to the relevant scientific and medical communities. The primary concern of drug scientists,virologists, and other concerned specialists in this respect is to find ready-to-use suitable and potent anticoronaviraltherapies that are broadly effective against the different species/strains of the coronaviruses in general, not only againstthe current and previous coronaviruses (e.g., the recently-appeared severe acute respiratory syndrome coronavirus 2“SARS-CoV-2”), i.e., effective antiviral agents for treatment and/or prophylaxis of any coronaviral infections, includingthose of the coming ones from the next species and strains (if any). As an expert in this field, I tried, in this up-to-dateperspective “viewpoint” article, to evaluate the suitability and applicability of using the currently-availableanticoronaviral agents for the next coronavirus diseases (COVIDs) and coronaviral pandemics, highlighting the mostimportant general guidelines that should be considered in the next pandemics from the therapeutic points of view.展开更多
COVID-19 is caused by the SARS-CoV-2 virus. Current RNA vaccines Pfizer/BioNTech’s BNT162b2 and Moderna’s mRNA-1273 are more than 94% successful in preventing infection. The spike protein of the virus is essential f...COVID-19 is caused by the SARS-CoV-2 virus. Current RNA vaccines Pfizer/BioNTech’s BNT162b2 and Moderna’s mRNA-1273 are more than 94% successful in preventing infection. The spike protein of the virus is essential for the interaction and internalization of the virus in the host cell and is considered a prime target for vaccine development against the SARS virus. This study aims to identify highly conserved sequences in spike protein or other sections of the viral genome that can potentially be used to develop a universal coronavirus vaccine. Bioinformatic analysis of 258,269 full-length SARS-CoV-2 genomic sequences in the NCBI database was carried out using a custom Perl Script. All sequences were compared to the spike protein and full-length viral genome reference to find 100 nucleotide-long segments that were at least 99% conserved across SARS-CoV-2 sequences. The analysis resulted in a >99.5% conserved 114-nucleotide segment on the spike protein and a 99.49% conserved 104-nucleotide segment on the non-spike protein section of the viral genome. The conserved sequences from this study may be useful in developing an RNA or protein vaccine that may be effective against future SARS-CoV-2 strains or could act as a universal vaccine if these sequences are present in other coronavirus families.展开更多
Meanwhile the outbreak of the Covid-19 since December, 2019 in China, it has killed more than a hundred thousand of people of all ages and sex across the globe in a short span of time. On the bases of this study the n...Meanwhile the outbreak of the Covid-19 since December, 2019 in China, it has killed more than a hundred thousand of people of all ages and sex across the globe in a short span of time. On the bases of this study the nearest family member of the virus and its receptor binding domain of S protein including its model structure and function of its active sites were naked through Multiple Sequence Alignment, modelling and molecular docking software accordingly its repository genome databases. The virus was genetically associated and molecular evolutionary related with (<em>RaTG</em>13) and it scores 96.12% homology with 99% query coverage followed by <em>bat-SL-CoVZC</em>45 and<em> bat-SL-CoVZXC</em>21 notch 89.12% and 88.65% respectively. However, SARS and MERS corona type virus those outbreak earlier respectively less likely family members of 2019-nCoV. Though the virus has a close genetic association with those previous SARS coronaviruses, and certainly the spike protein used as a binding receptor to fight against human receptor protein of ACE 2, but on the basis of FRODOC and HDOCK server analysis multi favorable active sites of S protein was discovered such GLN493 shown as a finest key in both model and possessed a unique traits on it resulting unexpected rate of transmission and number of people died while compared to the previous one. TYR500, ASN501, GLN498 and others residues preferably contemplate site also. In particular, the diversity of the virus in the world may be due to the genome structure of the virus and S gene changed over the time, across the world against to host of human genetic diversity, which may be more robust, and may be a new and unique feature. This is because it is characterized close to contact with distance divergence between wild type novel coronavirus which was risen from China against to the genomes from Lebanon, India, Italy, and USA and so on. Thus, the World Health Organization and its researchers should focus on immunologic research and effective drug and vaccine development that will help to address the epidemiology of the virus, which can provide a long-term solution.展开更多
The present pandemic has posed a crisis to the economy of the world and the health sector.Therefore,the race to expand research to understand some good molecular targets for vaccine and therapeutic development for SAR...The present pandemic has posed a crisis to the economy of the world and the health sector.Therefore,the race to expand research to understand some good molecular targets for vaccine and therapeutic development for SARS-CoV-2 is inevitable.The newly discovered coronavirus 2019(COVID-19)is a positive sense,single-stranded RNA,and enveloped virus,assigned to the beta CoV genus.The virus(SARS-CoV-2)is more infectious than the previously detected coronaviruses(MERS and SARS).Findings from many studies have revealed that S protein and RdRp are good targets for drug repositioning,novel therapeutic development(antibodies and small molecule drugs),and vaccine discovery.Therapeutics such as chloroquine,convalescent plasma,monoclonal antibodies,spike binding peptides,and small molecules could alter the ability of S protein to bind to the ACE-2 receptor,and drugs such as remdesivir(targeting SARS-CoV-2 RdRp),favipir,and emetine could prevent SASR-CoV-2 RNA synthesis.The novel vaccines such as mRNA1273(Moderna),3LNP-mRNAs(Pfizer/BioNTech),and ChAdOx1-S(University of Oxford/Astra Zeneca)targeting S protein have proven to be effective in combating the present pandemic.Further exploration of the potential of S protein and RdRp is crucial in fighting the present pandemic.展开更多
基金National Institutes of Health(NIH)(grants R01 A/130092 and Al161085).
文摘The spike protein(S)of SARS-CoV-2 is responsible for viral attachment and entry,thus a major factor for host suscep-tibility,tissue tropism,virulence and pathogenicity.The S is divided with S1 and S2 region,and the S1 contains the receptor-binding domain(RBD),while the S2 contains the hydrophobic fusion domain for the entry into the host cell.Numerous host proteases have been implicated in the activation of SARS-CoV-2 S through various c leavage sites.In this article,we review host proteases including furin,trypsin,transmembrane protease serine 2(TMPRSS2)and cathepsins in the activation of SARS-CoV-2 S.Many betacoronaviruses including SARS-CoV-2 have polybasic residues at the S1/S2 site which is subjected to the cleavage by furin.The S1/S2 cleavage facilitates more assessable RBD to the receptor ACE2,and the binding triggers further conformational changes and exposure of the S2'site to proteases such as type Il transmembrane serine proteases(TTPRs)including TMPRSS2.In the presence of TMPRSS2 on the target cells,SARS-CoV-2 can utilize a direct entry route by fusion of the viral envelope to the cellular membrane.In the absence of TMPRSS2,SARS-CoV-2 enter target cells via endosomes where multiple cathepsins cleave the S for the successful entry.Additional host proteases involved in the cleavage of the S were discussed.This article also includes roles of 3C-like protease inhibitors which have inhibitory activity against cathepsin L in the entry of SARS-CoV-2,and discussed the dual roles of such inhibitors in virus replication.
文摘Despite the global decline in the severity of the coronavirus disease 2019 (COVID-19) cases, the disease stillrepresents a major concern to the relevant scientific and medical communities. The primary concern of drug scientists,virologists, and other concerned specialists in this respect is to find ready-to-use suitable and potent anticoronaviraltherapies that are broadly effective against the different species/strains of the coronaviruses in general, not only againstthe current and previous coronaviruses (e.g., the recently-appeared severe acute respiratory syndrome coronavirus 2“SARS-CoV-2”), i.e., effective antiviral agents for treatment and/or prophylaxis of any coronaviral infections, includingthose of the coming ones from the next species and strains (if any). As an expert in this field, I tried, in this up-to-dateperspective “viewpoint” article, to evaluate the suitability and applicability of using the currently-availableanticoronaviral agents for the next coronavirus diseases (COVIDs) and coronaviral pandemics, highlighting the mostimportant general guidelines that should be considered in the next pandemics from the therapeutic points of view.
文摘COVID-19 is caused by the SARS-CoV-2 virus. Current RNA vaccines Pfizer/BioNTech’s BNT162b2 and Moderna’s mRNA-1273 are more than 94% successful in preventing infection. The spike protein of the virus is essential for the interaction and internalization of the virus in the host cell and is considered a prime target for vaccine development against the SARS virus. This study aims to identify highly conserved sequences in spike protein or other sections of the viral genome that can potentially be used to develop a universal coronavirus vaccine. Bioinformatic analysis of 258,269 full-length SARS-CoV-2 genomic sequences in the NCBI database was carried out using a custom Perl Script. All sequences were compared to the spike protein and full-length viral genome reference to find 100 nucleotide-long segments that were at least 99% conserved across SARS-CoV-2 sequences. The analysis resulted in a >99.5% conserved 114-nucleotide segment on the spike protein and a 99.49% conserved 104-nucleotide segment on the non-spike protein section of the viral genome. The conserved sequences from this study may be useful in developing an RNA or protein vaccine that may be effective against future SARS-CoV-2 strains or could act as a universal vaccine if these sequences are present in other coronavirus families.
文摘Meanwhile the outbreak of the Covid-19 since December, 2019 in China, it has killed more than a hundred thousand of people of all ages and sex across the globe in a short span of time. On the bases of this study the nearest family member of the virus and its receptor binding domain of S protein including its model structure and function of its active sites were naked through Multiple Sequence Alignment, modelling and molecular docking software accordingly its repository genome databases. The virus was genetically associated and molecular evolutionary related with (<em>RaTG</em>13) and it scores 96.12% homology with 99% query coverage followed by <em>bat-SL-CoVZC</em>45 and<em> bat-SL-CoVZXC</em>21 notch 89.12% and 88.65% respectively. However, SARS and MERS corona type virus those outbreak earlier respectively less likely family members of 2019-nCoV. Though the virus has a close genetic association with those previous SARS coronaviruses, and certainly the spike protein used as a binding receptor to fight against human receptor protein of ACE 2, but on the basis of FRODOC and HDOCK server analysis multi favorable active sites of S protein was discovered such GLN493 shown as a finest key in both model and possessed a unique traits on it resulting unexpected rate of transmission and number of people died while compared to the previous one. TYR500, ASN501, GLN498 and others residues preferably contemplate site also. In particular, the diversity of the virus in the world may be due to the genome structure of the virus and S gene changed over the time, across the world against to host of human genetic diversity, which may be more robust, and may be a new and unique feature. This is because it is characterized close to contact with distance divergence between wild type novel coronavirus which was risen from China against to the genomes from Lebanon, India, Italy, and USA and so on. Thus, the World Health Organization and its researchers should focus on immunologic research and effective drug and vaccine development that will help to address the epidemiology of the virus, which can provide a long-term solution.
文摘The present pandemic has posed a crisis to the economy of the world and the health sector.Therefore,the race to expand research to understand some good molecular targets for vaccine and therapeutic development for SARS-CoV-2 is inevitable.The newly discovered coronavirus 2019(COVID-19)is a positive sense,single-stranded RNA,and enveloped virus,assigned to the beta CoV genus.The virus(SARS-CoV-2)is more infectious than the previously detected coronaviruses(MERS and SARS).Findings from many studies have revealed that S protein and RdRp are good targets for drug repositioning,novel therapeutic development(antibodies and small molecule drugs),and vaccine discovery.Therapeutics such as chloroquine,convalescent plasma,monoclonal antibodies,spike binding peptides,and small molecules could alter the ability of S protein to bind to the ACE-2 receptor,and drugs such as remdesivir(targeting SARS-CoV-2 RdRp),favipir,and emetine could prevent SASR-CoV-2 RNA synthesis.The novel vaccines such as mRNA1273(Moderna),3LNP-mRNAs(Pfizer/BioNTech),and ChAdOx1-S(University of Oxford/Astra Zeneca)targeting S protein have proven to be effective in combating the present pandemic.Further exploration of the potential of S protein and RdRp is crucial in fighting the present pandemic.
