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LitCovid-PubTator

LitCovid-PD-FMA-UBERON

LitCovid-PD-UBERON

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T16","span":{"begin":1966,"end":1971},"obj":"Body_part"}],"attributes":[{"id":"A16","pred":"uberon_id","subj":"T16","obj":"http://purl.obolibrary.org/obo/UBERON_0002488"}],"text":"3 Research and development of therapeutics and prophylactics\nAt the present, no specific antiviral therapy has been approved for treatment of infection by human CoVs. As development of vaccines and compounds for prevention and treatment of infection have been brought to priority status by WHO and governments [56], numerous drug studies have been done or are moving forward. Some of them focus on the CoV fusion/entry process either by inhibition of S1 mediated virus attachment or by blocking of S2 mediated virus-cell membrane fusion, and some of them interfere with viral replication [57].\n\n3.1 CoV fusion/entry inhibitors\nBased on the previous experience in developing the HIV-1 fusion inhibitor SJ-2176 [58], Jiang et al. discovered the first anti-SARS-CoV peptide (SC-1) from the HR2 domain of SARS-CoV S protein S2 subunit. SC-1 could bind onto the HR1 domain to form a six-helical bundle (6-HB), blocking S protein-mediated membrane fusion and inhibiting SARS-CoV infection [59]. When MERS-CoV was circulating in human populations in 2012, following similar mechanistic design, Jiang’s research group developed another peptide, designated HR2P, which was derived from the virus HR2 region as well and effectively inhibited MERS-CoV infection [60]. The further modified version of HR2P, HR2P-M2, presented even better anti-MERS-CoV activity and pharmaceutical properties.\nDevelopment of broad-spectrum pan-CoV fusion inhibitors would be an ideal way to cope with epidemics or pandemics caused by emerging HCoVs. The conservative amino acid sequence of the HR1 region across different CoVs has the potential to be a target domain for development of an inhibitor. Continuing to work on the HR1 and HR2 domains, Jiang’s group discovered that the peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, broadly inhibited fusion by multiple HCoVs. By optimization of this peptide, a pan-CoV fusion inhibitor, EK1, was generated. It could form a stable six-helix bundle (6-HB) structure with HR1s and showed significantly improved fusion-inhibitory activity and pharmaceutical properties [61]. The alignment of S protein in Fig. 1 exhibited 100% identity at the HR2 domains between the 2019-nCoV and SARS-CoV; however, they found 7 amino acid changes in the fusion core of the HR1, located in the EK1 binding motif. Fortunately, the substitutions were conservative replacements which would not dramatically disrupt the interactions between EK1 and HR1, meaning that EK1 would still have the potential to be an effective inhibitor for 2019-nCoV infection.\n\n3.2 CoV S-RBD-specific neutralizing antibodies\nSo far, most neutralizing antibodies recognize the RBD in the S protein S2 of CoVs. Compared with the high mutation rate in the S1 protein, S2 is much more conservative, thereby decreasing the off-target risk caused by amino acid replacement [62], and also bypassing the special epitopes that may cause ADE [63]. This means that the cocktail of monoclonal antibodies binding to different epitopes of RBD would be more desirable for therapeutic purposes [64]. For treatment, the monoclonal antibodies are from a human source or are humanized antibodies, isolated or generated with various approaches. For example, wild-type mice were immunized with soluble recombinant RBD containing the S protein. Then mouse antibodies were humanized and isolated, or transgenic mice were directly immunized, to express human versions of the antibodies [50,65,66]. However, direct cloning of single B cells from human survivors, used in combination with the phage-display antibody library, could provide authentic human antibodies. Until now, it should be noted that many neutralizing antibodies have been successfully discovered for treatment of SARS-CoV [67] and MERS-CoV infection [45,68,69]. These antibodies have all been described favorably in the literature [29,70,71]. A similar approach is known as single chain fragment variable (scFv) library screening, whereby the use of RBD as a bait protein allows some neutralizing antibodies to be screened out from non-immune humans [72,73].\nAntibodies effective at inhibiting SARS-CoV infection should also have the potential for treatment of 2019-nCoV as well, as long as the binding motif in RBD shares the same sequences. The new neutralizing monoclonal antibodies would also be isolated from the patients using the established techniques.\n\n3.3 CoV replication inhibitors\nSimilar to developing vaccines, drugs effective against other RNA viruses were also repurposed for CoVs. Two major types of drugs being nucleoside analogues and immunomodulators. So far, the most common therapies tried in patients with CoVs are ribavirin, lopinavir/ritonavir, IFN, or their combinations [74]. Despite the antiviral activity observed with in vitro studies, the clinical effect was not consistent [75], in that ribavirin does not prolong the survival of SARS-CoV patients [74,76], while lopinavir/ritonavir plus ribavirin seemed to improve clinical outcomes for SARS patients [77], but the improvement was not confirmed in MERS-CoV patients. IFNs showed effective at inducing antiviral activity against both SARS-CoV and MRES-CoV, but without significant improvement in the outcomes for the patients [78,79]. In addition to the drug regimens used in patients, numerous drugs developed for the treatment of infection with CoVs were thoroughly discussed in the literature [57].\nHowever, replication of an RNA virus usually generates progeny viruses with a highly diverse genome. Recombination also easily takes place between viral genomes [80], and these gene level changes may result in drug resistance if the mutations affect the drug target domain. Development of drugs is also hampered by various evaluation methods and animal models used for testing drug activity among different labs worldwide, which could postpone selection of the best drug for clinical trials."}

LitCovid_AGAC

{"project":"LitCovid_AGAC","denotations":[{"id":"p50304s23","span":{"begin":2047,"end":2066},"obj":"MPA"},{"id":"p50311s20","span":{"begin":2806,"end":2809},"obj":"MPA"},{"id":"p50330s20","span":{"begin":5626,"end":5641},"obj":"MPA"}],"text":"3 Research and development of therapeutics and prophylactics\nAt the present, no specific antiviral therapy has been approved for treatment of infection by human CoVs. As development of vaccines and compounds for prevention and treatment of infection have been brought to priority status by WHO and governments [56], numerous drug studies have been done or are moving forward. Some of them focus on the CoV fusion/entry process either by inhibition of S1 mediated virus attachment or by blocking of S2 mediated virus-cell membrane fusion, and some of them interfere with viral replication [57].\n\n3.1 CoV fusion/entry inhibitors\nBased on the previous experience in developing the HIV-1 fusion inhibitor SJ-2176 [58], Jiang et al. discovered the first anti-SARS-CoV peptide (SC-1) from the HR2 domain of SARS-CoV S protein S2 subunit. SC-1 could bind onto the HR1 domain to form a six-helical bundle (6-HB), blocking S protein-mediated membrane fusion and inhibiting SARS-CoV infection [59]. When MERS-CoV was circulating in human populations in 2012, following similar mechanistic design, Jiang’s research group developed another peptide, designated HR2P, which was derived from the virus HR2 region as well and effectively inhibited MERS-CoV infection [60]. The further modified version of HR2P, HR2P-M2, presented even better anti-MERS-CoV activity and pharmaceutical properties.\nDevelopment of broad-spectrum pan-CoV fusion inhibitors would be an ideal way to cope with epidemics or pandemics caused by emerging HCoVs. The conservative amino acid sequence of the HR1 region across different CoVs has the potential to be a target domain for development of an inhibitor. Continuing to work on the HR1 and HR2 domains, Jiang’s group discovered that the peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, broadly inhibited fusion by multiple HCoVs. By optimization of this peptide, a pan-CoV fusion inhibitor, EK1, was generated. It could form a stable six-helix bundle (6-HB) structure with HR1s and showed significantly improved fusion-inhibitory activity and pharmaceutical properties [61]. The alignment of S protein in Fig. 1 exhibited 100% identity at the HR2 domains between the 2019-nCoV and SARS-CoV; however, they found 7 amino acid changes in the fusion core of the HR1, located in the EK1 binding motif. Fortunately, the substitutions were conservative replacements which would not dramatically disrupt the interactions between EK1 and HR1, meaning that EK1 would still have the potential to be an effective inhibitor for 2019-nCoV infection.\n\n3.2 CoV S-RBD-specific neutralizing antibodies\nSo far, most neutralizing antibodies recognize the RBD in the S protein S2 of CoVs. Compared with the high mutation rate in the S1 protein, S2 is much more conservative, thereby decreasing the off-target risk caused by amino acid replacement [62], and also bypassing the special epitopes that may cause ADE [63]. This means that the cocktail of monoclonal antibodies binding to different epitopes of RBD would be more desirable for therapeutic purposes [64]. For treatment, the monoclonal antibodies are from a human source or are humanized antibodies, isolated or generated with various approaches. For example, wild-type mice were immunized with soluble recombinant RBD containing the S protein. Then mouse antibodies were humanized and isolated, or transgenic mice were directly immunized, to express human versions of the antibodies [50,65,66]. However, direct cloning of single B cells from human survivors, used in combination with the phage-display antibody library, could provide authentic human antibodies. Until now, it should be noted that many neutralizing antibodies have been successfully discovered for treatment of SARS-CoV [67] and MERS-CoV infection [45,68,69]. These antibodies have all been described favorably in the literature [29,70,71]. A similar approach is known as single chain fragment variable (scFv) library screening, whereby the use of RBD as a bait protein allows some neutralizing antibodies to be screened out from non-immune humans [72,73].\nAntibodies effective at inhibiting SARS-CoV infection should also have the potential for treatment of 2019-nCoV as well, as long as the binding motif in RBD shares the same sequences. The new neutralizing monoclonal antibodies would also be isolated from the patients using the established techniques.\n\n3.3 CoV replication inhibitors\nSimilar to developing vaccines, drugs effective against other RNA viruses were also repurposed for CoVs. Two major types of drugs being nucleoside analogues and immunomodulators. So far, the most common therapies tried in patients with CoVs are ribavirin, lopinavir/ritonavir, IFN, or their combinations [74]. Despite the antiviral activity observed with in vitro studies, the clinical effect was not consistent [75], in that ribavirin does not prolong the survival of SARS-CoV patients [74,76], while lopinavir/ritonavir plus ribavirin seemed to improve clinical outcomes for SARS patients [77], but the improvement was not confirmed in MERS-CoV patients. IFNs showed effective at inducing antiviral activity against both SARS-CoV and MRES-CoV, but without significant improvement in the outcomes for the patients [78,79]. In addition to the drug regimens used in patients, numerous drugs developed for the treatment of infection with CoVs were thoroughly discussed in the literature [57].\nHowever, replication of an RNA virus usually generates progeny viruses with a highly diverse genome. Recombination also easily takes place between viral genomes [80], and these gene level changes may result in drug resistance if the mutations affect the drug target domain. Development of drugs is also hampered by various evaluation methods and animal models used for testing drug activity among different labs worldwide, which could postpone selection of the best drug for clinical trials."}

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-PD-GO-BP

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T39","span":{"begin":522,"end":537},"obj":"http://purl.obolibrary.org/obo/GO_0061025"},{"id":"T40","span":{"begin":571,"end":588},"obj":"http://purl.obolibrary.org/obo/GO_0019079"},{"id":"T41","span":{"begin":571,"end":588},"obj":"http://purl.obolibrary.org/obo/GO_0019058"},{"id":"T42","span":{"begin":935,"end":950},"obj":"http://purl.obolibrary.org/obo/GO_0061025"},{"id":"T43","span":{"begin":5626,"end":5641},"obj":"http://purl.obolibrary.org/obo/GO_0042493"}],"text":"3 Research and development of therapeutics and prophylactics\nAt the present, no specific antiviral therapy has been approved for treatment of infection by human CoVs. As development of vaccines and compounds for prevention and treatment of infection have been brought to priority status by WHO and governments [56], numerous drug studies have been done or are moving forward. Some of them focus on the CoV fusion/entry process either by inhibition of S1 mediated virus attachment or by blocking of S2 mediated virus-cell membrane fusion, and some of them interfere with viral replication [57].\n\n3.1 CoV fusion/entry inhibitors\nBased on the previous experience in developing the HIV-1 fusion inhibitor SJ-2176 [58], Jiang et al. discovered the first anti-SARS-CoV peptide (SC-1) from the HR2 domain of SARS-CoV S protein S2 subunit. SC-1 could bind onto the HR1 domain to form a six-helical bundle (6-HB), blocking S protein-mediated membrane fusion and inhibiting SARS-CoV infection [59]. When MERS-CoV was circulating in human populations in 2012, following similar mechanistic design, Jiang’s research group developed another peptide, designated HR2P, which was derived from the virus HR2 region as well and effectively inhibited MERS-CoV infection [60]. The further modified version of HR2P, HR2P-M2, presented even better anti-MERS-CoV activity and pharmaceutical properties.\nDevelopment of broad-spectrum pan-CoV fusion inhibitors would be an ideal way to cope with epidemics or pandemics caused by emerging HCoVs. The conservative amino acid sequence of the HR1 region across different CoVs has the potential to be a target domain for development of an inhibitor. Continuing to work on the HR1 and HR2 domains, Jiang’s group discovered that the peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, broadly inhibited fusion by multiple HCoVs. By optimization of this peptide, a pan-CoV fusion inhibitor, EK1, was generated. It could form a stable six-helix bundle (6-HB) structure with HR1s and showed significantly improved fusion-inhibitory activity and pharmaceutical properties [61]. The alignment of S protein in Fig. 1 exhibited 100% identity at the HR2 domains between the 2019-nCoV and SARS-CoV; however, they found 7 amino acid changes in the fusion core of the HR1, located in the EK1 binding motif. Fortunately, the substitutions were conservative replacements which would not dramatically disrupt the interactions between EK1 and HR1, meaning that EK1 would still have the potential to be an effective inhibitor for 2019-nCoV infection.\n\n3.2 CoV S-RBD-specific neutralizing antibodies\nSo far, most neutralizing antibodies recognize the RBD in the S protein S2 of CoVs. Compared with the high mutation rate in the S1 protein, S2 is much more conservative, thereby decreasing the off-target risk caused by amino acid replacement [62], and also bypassing the special epitopes that may cause ADE [63]. This means that the cocktail of monoclonal antibodies binding to different epitopes of RBD would be more desirable for therapeutic purposes [64]. For treatment, the monoclonal antibodies are from a human source or are humanized antibodies, isolated or generated with various approaches. For example, wild-type mice were immunized with soluble recombinant RBD containing the S protein. Then mouse antibodies were humanized and isolated, or transgenic mice were directly immunized, to express human versions of the antibodies [50,65,66]. However, direct cloning of single B cells from human survivors, used in combination with the phage-display antibody library, could provide authentic human antibodies. Until now, it should be noted that many neutralizing antibodies have been successfully discovered for treatment of SARS-CoV [67] and MERS-CoV infection [45,68,69]. These antibodies have all been described favorably in the literature [29,70,71]. A similar approach is known as single chain fragment variable (scFv) library screening, whereby the use of RBD as a bait protein allows some neutralizing antibodies to be screened out from non-immune humans [72,73].\nAntibodies effective at inhibiting SARS-CoV infection should also have the potential for treatment of 2019-nCoV as well, as long as the binding motif in RBD shares the same sequences. The new neutralizing monoclonal antibodies would also be isolated from the patients using the established techniques.\n\n3.3 CoV replication inhibitors\nSimilar to developing vaccines, drugs effective against other RNA viruses were also repurposed for CoVs. Two major types of drugs being nucleoside analogues and immunomodulators. So far, the most common therapies tried in patients with CoVs are ribavirin, lopinavir/ritonavir, IFN, or their combinations [74]. Despite the antiviral activity observed with in vitro studies, the clinical effect was not consistent [75], in that ribavirin does not prolong the survival of SARS-CoV patients [74,76], while lopinavir/ritonavir plus ribavirin seemed to improve clinical outcomes for SARS patients [77], but the improvement was not confirmed in MERS-CoV patients. IFNs showed effective at inducing antiviral activity against both SARS-CoV and MRES-CoV, but without significant improvement in the outcomes for the patients [78,79]. In addition to the drug regimens used in patients, numerous drugs developed for the treatment of infection with CoVs were thoroughly discussed in the literature [57].\nHowever, replication of an RNA virus usually generates progeny viruses with a highly diverse genome. Recombination also easily takes place between viral genomes [80], and these gene level changes may result in drug resistance if the mutations affect the drug target domain. Development of drugs is also hampered by various evaluation methods and animal models used for testing drug activity among different labs worldwide, which could postpone selection of the best drug for clinical trials."}

LitCovid-PD-HP

{"project":"LitCovid-PD-HP","denotations":[{"id":"T7","span":{"begin":5626,"end":5641},"obj":"Phenotype"}],"attributes":[{"id":"A7","pred":"hp_id","subj":"T7","obj":"http://purl.obolibrary.org/obo/HP_0020174"}],"text":"3 Research and development of therapeutics and prophylactics\nAt the present, no specific antiviral therapy has been approved for treatment of infection by human CoVs. As development of vaccines and compounds for prevention and treatment of infection have been brought to priority status by WHO and governments [56], numerous drug studies have been done or are moving forward. Some of them focus on the CoV fusion/entry process either by inhibition of S1 mediated virus attachment or by blocking of S2 mediated virus-cell membrane fusion, and some of them interfere with viral replication [57].\n\n3.1 CoV fusion/entry inhibitors\nBased on the previous experience in developing the HIV-1 fusion inhibitor SJ-2176 [58], Jiang et al. discovered the first anti-SARS-CoV peptide (SC-1) from the HR2 domain of SARS-CoV S protein S2 subunit. SC-1 could bind onto the HR1 domain to form a six-helical bundle (6-HB), blocking S protein-mediated membrane fusion and inhibiting SARS-CoV infection [59]. When MERS-CoV was circulating in human populations in 2012, following similar mechanistic design, Jiang’s research group developed another peptide, designated HR2P, which was derived from the virus HR2 region as well and effectively inhibited MERS-CoV infection [60]. The further modified version of HR2P, HR2P-M2, presented even better anti-MERS-CoV activity and pharmaceutical properties.\nDevelopment of broad-spectrum pan-CoV fusion inhibitors would be an ideal way to cope with epidemics or pandemics caused by emerging HCoVs. The conservative amino acid sequence of the HR1 region across different CoVs has the potential to be a target domain for development of an inhibitor. Continuing to work on the HR1 and HR2 domains, Jiang’s group discovered that the peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, broadly inhibited fusion by multiple HCoVs. By optimization of this peptide, a pan-CoV fusion inhibitor, EK1, was generated. It could form a stable six-helix bundle (6-HB) structure with HR1s and showed significantly improved fusion-inhibitory activity and pharmaceutical properties [61]. The alignment of S protein in Fig. 1 exhibited 100% identity at the HR2 domains between the 2019-nCoV and SARS-CoV; however, they found 7 amino acid changes in the fusion core of the HR1, located in the EK1 binding motif. Fortunately, the substitutions were conservative replacements which would not dramatically disrupt the interactions between EK1 and HR1, meaning that EK1 would still have the potential to be an effective inhibitor for 2019-nCoV infection.\n\n3.2 CoV S-RBD-specific neutralizing antibodies\nSo far, most neutralizing antibodies recognize the RBD in the S protein S2 of CoVs. Compared with the high mutation rate in the S1 protein, S2 is much more conservative, thereby decreasing the off-target risk caused by amino acid replacement [62], and also bypassing the special epitopes that may cause ADE [63]. This means that the cocktail of monoclonal antibodies binding to different epitopes of RBD would be more desirable for therapeutic purposes [64]. For treatment, the monoclonal antibodies are from a human source or are humanized antibodies, isolated or generated with various approaches. For example, wild-type mice were immunized with soluble recombinant RBD containing the S protein. Then mouse antibodies were humanized and isolated, or transgenic mice were directly immunized, to express human versions of the antibodies [50,65,66]. However, direct cloning of single B cells from human survivors, used in combination with the phage-display antibody library, could provide authentic human antibodies. Until now, it should be noted that many neutralizing antibodies have been successfully discovered for treatment of SARS-CoV [67] and MERS-CoV infection [45,68,69]. These antibodies have all been described favorably in the literature [29,70,71]. A similar approach is known as single chain fragment variable (scFv) library screening, whereby the use of RBD as a bait protein allows some neutralizing antibodies to be screened out from non-immune humans [72,73].\nAntibodies effective at inhibiting SARS-CoV infection should also have the potential for treatment of 2019-nCoV as well, as long as the binding motif in RBD shares the same sequences. The new neutralizing monoclonal antibodies would also be isolated from the patients using the established techniques.\n\n3.3 CoV replication inhibitors\nSimilar to developing vaccines, drugs effective against other RNA viruses were also repurposed for CoVs. Two major types of drugs being nucleoside analogues and immunomodulators. So far, the most common therapies tried in patients with CoVs are ribavirin, lopinavir/ritonavir, IFN, or their combinations [74]. Despite the antiviral activity observed with in vitro studies, the clinical effect was not consistent [75], in that ribavirin does not prolong the survival of SARS-CoV patients [74,76], while lopinavir/ritonavir plus ribavirin seemed to improve clinical outcomes for SARS patients [77], but the improvement was not confirmed in MERS-CoV patients. IFNs showed effective at inducing antiviral activity against both SARS-CoV and MRES-CoV, but without significant improvement in the outcomes for the patients [78,79]. In addition to the drug regimens used in patients, numerous drugs developed for the treatment of infection with CoVs were thoroughly discussed in the literature [57].\nHowever, replication of an RNA virus usually generates progeny viruses with a highly diverse genome. Recombination also easily takes place between viral genomes [80], and these gene level changes may result in drug resistance if the mutations affect the drug target domain. Development of drugs is also hampered by various evaluation methods and animal models used for testing drug activity among different labs worldwide, which could postpone selection of the best drug for clinical trials."}

LitCovid-sentences

2_test

PMC:7102556 / 14583-20490 JSONTXT

Annnotations TAB JSON ListView MergeView

PMC:7102556 / 14583-20490 JSON TXT