Human Claudin-Derived Peptides Block the Membrane Fusion Process of Zika Virus and Are Broad Flavivirus Inhibitors
ABSTRACT Zika virus (ZIKV) is a mosquito-borne flavivirus that emerged in the Pacific islands in 2007 and spread to the Americas in 2015. The infection remains asymptomatic in most cases but can be associated with severe neurological disorders. Despite massive efforts, no specific drug or vaccine ag...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-10-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.02989-22 |
| _version_ | 1811329751634149376 |
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| author | Jim Zoladek Julien Burlaud-Gaillard Maxime Chazal Sophie Desgraupes Patricia Jeannin Antoine Gessain Nathalie Pardigon Mathieu Hubert Philippe Roingeard Nolwenn Jouvenet Philippe V. Afonso |
| author_facet | Jim Zoladek Julien Burlaud-Gaillard Maxime Chazal Sophie Desgraupes Patricia Jeannin Antoine Gessain Nathalie Pardigon Mathieu Hubert Philippe Roingeard Nolwenn Jouvenet Philippe V. Afonso |
| author_sort | Jim Zoladek |
| collection | DOAJ |
| description | ABSTRACT Zika virus (ZIKV) is a mosquito-borne flavivirus that emerged in the Pacific islands in 2007 and spread to the Americas in 2015. The infection remains asymptomatic in most cases but can be associated with severe neurological disorders. Despite massive efforts, no specific drug or vaccine against ZIKV infection is available to date. Claudins are tight-junction proteins that favor the entry of several flaviviruses, including ZIKV. In this study, we identified two peptides derived from the N-terminal sequences of claudin-7 and claudin-1, named CL7.1 and CL1.1, respectively, that inhibited ZIKV infection in a panel of human cell lines. Using cell-to-cell fusion assays, we demonstrated that these peptides blocked the ZIKV E-mediated membrane fusion. A comparison of the antiviral efficacy of CL1.1 and CL7.1 pointed to the importance of the peptide amphipathicity. Electron microscopic analysis revealed that CL1.1 altered the ultrastructure of the viral particles likely by binding the virus lipid envelope. However, amphipathicity could not fully explain the antiviral activity of CL1.1. In silico docking simulations suggested that CL1.1 may also interact with the E protein, near its stem region. Overall, our data suggested that claudin-derived peptides inhibition may be linked to simultaneous interaction with the E protein and the viral lipid envelope. Finally, we found that CL1.1 also blocked infection by yellow fever and Japanese encephalitis viruses but not by HIV-1 or SARS-CoV-2. Our results provide a basis for the future development of therapeutics against a wide range of endemic and emerging flaviviruses. IMPORTANCE Zika virus (ZIKV) is a flavivirus transmitted by mosquito bites that have spread to the Pacific Islands and the Americas over the past decade. The infection remains asymptomatic in most cases but can cause severe neurological disorders. ZIKV is a major public health threat in areas of endemicity, and there is currently no specific antiviral drug or vaccine available. We identified two antiviral peptides deriving from the N-terminal sequences of claudin-7 and claudin-1 with the latter being the most effective. These peptides block the envelope-mediated membrane fusion. Our data suggested that the inhibition was likely achieved by simultaneously interacting with the viral lipid envelope and the E protein. The peptides also inhibited other flaviviruses. These results could provide the basis for the development of therapies that might target a wide array of flaviviruses from current epidemics and possibly future emergences. |
| first_indexed | 2024-04-13T15:49:27Z |
| format | Article |
| id | doaj.art-1f981db521e8490bb3322c0d8de4783b |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-13T15:49:27Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-1f981db521e8490bb3322c0d8de4783b2022-12-22T02:40:53ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-10-0110510.1128/spectrum.02989-22Human Claudin-Derived Peptides Block the Membrane Fusion Process of Zika Virus and Are Broad Flavivirus InhibitorsJim Zoladek0Julien Burlaud-Gaillard1Maxime Chazal2Sophie Desgraupes3Patricia Jeannin4Antoine Gessain5Nathalie Pardigon6Mathieu Hubert7Philippe Roingeard8Nolwenn Jouvenet9Philippe V. Afonso10Unité Épidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Paris, FranceInserm U1259 MAVIVH, Université de Tours and CHRU de Tours, Tours, FranceUnité Signalisation Antivirale, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Paris, FranceUnité Épidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Paris, FranceUnité Épidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Paris, FranceUnité Épidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Paris, FranceGroupe Arbovirus, Unité Environnement et Risques Infectieux, Institut Pasteur, Université Paris Cité, Paris, FranceUnité Virus et Immunité, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Paris, FranceInserm U1259 MAVIVH, Université de Tours and CHRU de Tours, Tours, FranceUnité Signalisation Antivirale, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Paris, FranceUnité Épidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Paris, FranceABSTRACT Zika virus (ZIKV) is a mosquito-borne flavivirus that emerged in the Pacific islands in 2007 and spread to the Americas in 2015. The infection remains asymptomatic in most cases but can be associated with severe neurological disorders. Despite massive efforts, no specific drug or vaccine against ZIKV infection is available to date. Claudins are tight-junction proteins that favor the entry of several flaviviruses, including ZIKV. In this study, we identified two peptides derived from the N-terminal sequences of claudin-7 and claudin-1, named CL7.1 and CL1.1, respectively, that inhibited ZIKV infection in a panel of human cell lines. Using cell-to-cell fusion assays, we demonstrated that these peptides blocked the ZIKV E-mediated membrane fusion. A comparison of the antiviral efficacy of CL1.1 and CL7.1 pointed to the importance of the peptide amphipathicity. Electron microscopic analysis revealed that CL1.1 altered the ultrastructure of the viral particles likely by binding the virus lipid envelope. However, amphipathicity could not fully explain the antiviral activity of CL1.1. In silico docking simulations suggested that CL1.1 may also interact with the E protein, near its stem region. Overall, our data suggested that claudin-derived peptides inhibition may be linked to simultaneous interaction with the E protein and the viral lipid envelope. Finally, we found that CL1.1 also blocked infection by yellow fever and Japanese encephalitis viruses but not by HIV-1 or SARS-CoV-2. Our results provide a basis for the future development of therapeutics against a wide range of endemic and emerging flaviviruses. IMPORTANCE Zika virus (ZIKV) is a flavivirus transmitted by mosquito bites that have spread to the Pacific Islands and the Americas over the past decade. The infection remains asymptomatic in most cases but can cause severe neurological disorders. ZIKV is a major public health threat in areas of endemicity, and there is currently no specific antiviral drug or vaccine available. We identified two antiviral peptides deriving from the N-terminal sequences of claudin-7 and claudin-1 with the latter being the most effective. These peptides block the envelope-mediated membrane fusion. Our data suggested that the inhibition was likely achieved by simultaneously interacting with the viral lipid envelope and the E protein. The peptides also inhibited other flaviviruses. These results could provide the basis for the development of therapies that might target a wide array of flaviviruses from current epidemics and possibly future emergences.https://journals.asm.org/doi/10.1128/spectrum.02989-22antimicrobial peptidesclaudinflavivirusZika |
| spellingShingle | Jim Zoladek Julien Burlaud-Gaillard Maxime Chazal Sophie Desgraupes Patricia Jeannin Antoine Gessain Nathalie Pardigon Mathieu Hubert Philippe Roingeard Nolwenn Jouvenet Philippe V. Afonso Human Claudin-Derived Peptides Block the Membrane Fusion Process of Zika Virus and Are Broad Flavivirus Inhibitors Microbiology Spectrum antimicrobial peptides claudin flavivirus Zika |
| title | Human Claudin-Derived Peptides Block the Membrane Fusion Process of Zika Virus and Are Broad Flavivirus Inhibitors |
| title_full | Human Claudin-Derived Peptides Block the Membrane Fusion Process of Zika Virus and Are Broad Flavivirus Inhibitors |
| title_fullStr | Human Claudin-Derived Peptides Block the Membrane Fusion Process of Zika Virus and Are Broad Flavivirus Inhibitors |
| title_full_unstemmed | Human Claudin-Derived Peptides Block the Membrane Fusion Process of Zika Virus and Are Broad Flavivirus Inhibitors |
| title_short | Human Claudin-Derived Peptides Block the Membrane Fusion Process of Zika Virus and Are Broad Flavivirus Inhibitors |
| title_sort | human claudin derived peptides block the membrane fusion process of zika virus and are broad flavivirus inhibitors |
| topic | antimicrobial peptides claudin flavivirus Zika |
| url | https://journals.asm.org/doi/10.1128/spectrum.02989-22 |
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