IgG Fc-Binding Peptide-Conjugated Pan-CoV Fusion Inhibitor Exhibits Extended In Vivo Half-Life and Synergistic Antiviral Effect When Combined with Neutralizing Antibodies
The peptide-based pan-coronavirus fusion inhibitor EK1 is in phase III clinical trials, and it has, thus far, shown good clinical application prospects against SARS-CoV-2 and its variants. To further improve its in vivo long-acting property, we herein developed an Fc-binding strategy by conjugating...
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MDPI AG
2023-08-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/9/1283 |
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| author | Xiaojie Su Ziqi Huang Wei Xu Qian Wang Lixiao Xing Lu Lu Shibo Jiang Shuai Xia |
| author_facet | Xiaojie Su Ziqi Huang Wei Xu Qian Wang Lixiao Xing Lu Lu Shibo Jiang Shuai Xia |
| author_sort | Xiaojie Su |
| collection | DOAJ |
| description | The peptide-based pan-coronavirus fusion inhibitor EK1 is in phase III clinical trials, and it has, thus far, shown good clinical application prospects against SARS-CoV-2 and its variants. To further improve its in vivo long-acting property, we herein developed an Fc-binding strategy by conjugating EK1 with human immunoglobulin G Fc-binding peptide (IBP), which can exploit the long half-life advantage of IgG in vivo. The newly engineered peptide IBP-EK1 showed potent and broad-spectrum inhibitory activity against SARS-CoV-2 and its variants, including various Omicron sublineages and other human coronaviruses (HCoVs) with low cytotoxicity. In mouse models, IBP-EK1 possessed potent prophylactic and therapeutic efficacy against lethal HCoV-OC43 challenge, and it showed good safety profile and low immunogenicity. More importantly, IBP-EK1 exhibited a significantly extended in vivo half-life in rhesus monkeys of up to 37.7 h, which is about 20-fold longer than that reported for EK1. Strikingly, IBP-EK1 displayed strong in vitro or ex vivo synergistic anti-HCoV effect when combined with monoclonal neutralizing antibodies, including REGN10933 or S309, suggesting that IBP-conjugated EK1 can be further developed as a long-acting, broad-spectrum anti-HCoV agent, either alone or in combination with neutralizing antibodies, to combat the current COVID-19 pandemic or future outbreaks caused by emerging and re-emerging highly pathogenic HCoVs. |
| first_indexed | 2024-03-10T22:59:06Z |
| format | Article |
| id | doaj.art-2a14433b72be44108c052f6733977343 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T22:59:06Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-2a14433b72be44108c052f67339773432023-11-19T09:44:47ZengMDPI AGBiomolecules2218-273X2023-08-01139128310.3390/biom13091283IgG Fc-Binding Peptide-Conjugated Pan-CoV Fusion Inhibitor Exhibits Extended In Vivo Half-Life and Synergistic Antiviral Effect When Combined with Neutralizing AntibodiesXiaojie Su0Ziqi Huang1Wei Xu2Qian Wang3Lixiao Xing4Lu Lu5Shibo Jiang6Shuai Xia7Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai 200032, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai 200032, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai 200032, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai 200032, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai 200032, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai 200032, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai 200032, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai 200032, ChinaThe peptide-based pan-coronavirus fusion inhibitor EK1 is in phase III clinical trials, and it has, thus far, shown good clinical application prospects against SARS-CoV-2 and its variants. To further improve its in vivo long-acting property, we herein developed an Fc-binding strategy by conjugating EK1 with human immunoglobulin G Fc-binding peptide (IBP), which can exploit the long half-life advantage of IgG in vivo. The newly engineered peptide IBP-EK1 showed potent and broad-spectrum inhibitory activity against SARS-CoV-2 and its variants, including various Omicron sublineages and other human coronaviruses (HCoVs) with low cytotoxicity. In mouse models, IBP-EK1 possessed potent prophylactic and therapeutic efficacy against lethal HCoV-OC43 challenge, and it showed good safety profile and low immunogenicity. More importantly, IBP-EK1 exhibited a significantly extended in vivo half-life in rhesus monkeys of up to 37.7 h, which is about 20-fold longer than that reported for EK1. Strikingly, IBP-EK1 displayed strong in vitro or ex vivo synergistic anti-HCoV effect when combined with monoclonal neutralizing antibodies, including REGN10933 or S309, suggesting that IBP-conjugated EK1 can be further developed as a long-acting, broad-spectrum anti-HCoV agent, either alone or in combination with neutralizing antibodies, to combat the current COVID-19 pandemic or future outbreaks caused by emerging and re-emerging highly pathogenic HCoVs.https://www.mdpi.com/2218-273X/13/9/1283human coronavirusfusion inhibitorIgG-binding peptidelong-acting strategyhalf-lifeneutralizing antibodies |
| spellingShingle | Xiaojie Su Ziqi Huang Wei Xu Qian Wang Lixiao Xing Lu Lu Shibo Jiang Shuai Xia IgG Fc-Binding Peptide-Conjugated Pan-CoV Fusion Inhibitor Exhibits Extended In Vivo Half-Life and Synergistic Antiviral Effect When Combined with Neutralizing Antibodies Biomolecules human coronavirus fusion inhibitor IgG-binding peptide long-acting strategy half-life neutralizing antibodies |
| title | IgG Fc-Binding Peptide-Conjugated Pan-CoV Fusion Inhibitor Exhibits Extended In Vivo Half-Life and Synergistic Antiviral Effect When Combined with Neutralizing Antibodies |
| title_full | IgG Fc-Binding Peptide-Conjugated Pan-CoV Fusion Inhibitor Exhibits Extended In Vivo Half-Life and Synergistic Antiviral Effect When Combined with Neutralizing Antibodies |
| title_fullStr | IgG Fc-Binding Peptide-Conjugated Pan-CoV Fusion Inhibitor Exhibits Extended In Vivo Half-Life and Synergistic Antiviral Effect When Combined with Neutralizing Antibodies |
| title_full_unstemmed | IgG Fc-Binding Peptide-Conjugated Pan-CoV Fusion Inhibitor Exhibits Extended In Vivo Half-Life and Synergistic Antiviral Effect When Combined with Neutralizing Antibodies |
| title_short | IgG Fc-Binding Peptide-Conjugated Pan-CoV Fusion Inhibitor Exhibits Extended In Vivo Half-Life and Synergistic Antiviral Effect When Combined with Neutralizing Antibodies |
| title_sort | igg fc binding peptide conjugated pan cov fusion inhibitor exhibits extended in vivo half life and synergistic antiviral effect when combined with neutralizing antibodies |
| topic | human coronavirus fusion inhibitor IgG-binding peptide long-acting strategy half-life neutralizing antibodies |
| url | https://www.mdpi.com/2218-273X/13/9/1283 |
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