Structural convergence and water-mediated substrate mimicry enable broad neuraminidase inhibition by human antibodies
Abstract Influenza has been responsible for multiple global pandemics and seasonal epidemics and claimed millions of lives. The imminent threat of a panzootic outbreak of avian influenza H5N1 virus underscores the urgent need for pandemic preparedness and effective countermeasures, including monoclo...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62339-z |
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| author | Julia Lederhofer Andrew J. Borst Lam Nguyen Rebecca A. Gillespie Connor J. Williams Emma L. Walker Julie E. Raab Christina Yap Daniel Ellis Adrian Creanga Hyon-Xhi Tan Thi H. T. Do Michelle Ravichandran Adrian B. McDermott Valerie Le Sage Sarah F. Andrews Barney S. Graham Adam K. Wheatley Douglas S. Reed Neil P. King Masaru Kanekiyo |
| author_facet | Julia Lederhofer Andrew J. Borst Lam Nguyen Rebecca A. Gillespie Connor J. Williams Emma L. Walker Julie E. Raab Christina Yap Daniel Ellis Adrian Creanga Hyon-Xhi Tan Thi H. T. Do Michelle Ravichandran Adrian B. McDermott Valerie Le Sage Sarah F. Andrews Barney S. Graham Adam K. Wheatley Douglas S. Reed Neil P. King Masaru Kanekiyo |
| author_sort | Julia Lederhofer |
| collection | DOAJ |
| description | Abstract Influenza has been responsible for multiple global pandemics and seasonal epidemics and claimed millions of lives. The imminent threat of a panzootic outbreak of avian influenza H5N1 virus underscores the urgent need for pandemic preparedness and effective countermeasures, including monoclonal antibodies (mAbs). Here, we characterize human mAbs that target the highly conserved catalytic site of viral neuraminidase (NA), termed NCS mAbs, and the molecular basis of their broad specificity. Cross-reactive NA-specific B cells were isolated by using stabilized NA probes of non-circulating subtypes. We found that NCS mAbs recognized multiple NAs of influenza A as well as influenza B NAs and conferred prophylactic protections in mice against H1N1, H5N1, and influenza B viruses. Cryo-electron microscopy structures of two NCS mAbs revealed that they rely on structural mimicry of sialic acid, the substrate of NA, by coordinating not only amino acid side chains but also water molecules, enabling inhibition of NA activity across multiple influenza A and B viruses, including avian influenza clade 2.3.4.4b H5N1 viruses. Our results provide a molecular basis for the broad reactivity and inhibitory activity of NCS mAbs targeting the catalytic site of NA through substrate mimicry. |
| format | Article |
| id | doaj-art-10602569ec1b463e8e695c3ee4e5716b |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-10602569ec1b463e8e695c3ee4e5716b2025-08-20T03:46:11ZengNature PortfolioNature Communications2041-17232025-08-0116111510.1038/s41467-025-62339-zStructural convergence and water-mediated substrate mimicry enable broad neuraminidase inhibition by human antibodiesJulia Lederhofer0Andrew J. Borst1Lam Nguyen2Rebecca A. Gillespie3Connor J. Williams4Emma L. Walker5Julie E. Raab6Christina Yap7Daniel Ellis8Adrian Creanga9Hyon-Xhi Tan10Thi H. T. Do11Michelle Ravichandran12Adrian B. McDermott13Valerie Le Sage14Sarah F. Andrews15Barney S. Graham16Adam K. Wheatley17Douglas S. Reed18Neil P. King19Masaru Kanekiyo20Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthInstitute for Protein Design, University of WashingtonVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDepartment of Immunology, Center for Vaccine Research, University of PittsburghDepartment of Immunology, Center for Vaccine Research, University of PittsburghVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthInstitute for Protein Design, University of WashingtonVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDepartment of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of MelbourneDepartment of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of MelbourneVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDepartment of Immunology, Center for Vaccine Research, University of PittsburghVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDepartment of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of MelbourneDepartment of Immunology, Center for Vaccine Research, University of PittsburghInstitute for Protein Design, University of WashingtonVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthAbstract Influenza has been responsible for multiple global pandemics and seasonal epidemics and claimed millions of lives. The imminent threat of a panzootic outbreak of avian influenza H5N1 virus underscores the urgent need for pandemic preparedness and effective countermeasures, including monoclonal antibodies (mAbs). Here, we characterize human mAbs that target the highly conserved catalytic site of viral neuraminidase (NA), termed NCS mAbs, and the molecular basis of their broad specificity. Cross-reactive NA-specific B cells were isolated by using stabilized NA probes of non-circulating subtypes. We found that NCS mAbs recognized multiple NAs of influenza A as well as influenza B NAs and conferred prophylactic protections in mice against H1N1, H5N1, and influenza B viruses. Cryo-electron microscopy structures of two NCS mAbs revealed that they rely on structural mimicry of sialic acid, the substrate of NA, by coordinating not only amino acid side chains but also water molecules, enabling inhibition of NA activity across multiple influenza A and B viruses, including avian influenza clade 2.3.4.4b H5N1 viruses. Our results provide a molecular basis for the broad reactivity and inhibitory activity of NCS mAbs targeting the catalytic site of NA through substrate mimicry.https://doi.org/10.1038/s41467-025-62339-z |
| spellingShingle | Julia Lederhofer Andrew J. Borst Lam Nguyen Rebecca A. Gillespie Connor J. Williams Emma L. Walker Julie E. Raab Christina Yap Daniel Ellis Adrian Creanga Hyon-Xhi Tan Thi H. T. Do Michelle Ravichandran Adrian B. McDermott Valerie Le Sage Sarah F. Andrews Barney S. Graham Adam K. Wheatley Douglas S. Reed Neil P. King Masaru Kanekiyo Structural convergence and water-mediated substrate mimicry enable broad neuraminidase inhibition by human antibodies Nature Communications |
| title | Structural convergence and water-mediated substrate mimicry enable broad neuraminidase inhibition by human antibodies |
| title_full | Structural convergence and water-mediated substrate mimicry enable broad neuraminidase inhibition by human antibodies |
| title_fullStr | Structural convergence and water-mediated substrate mimicry enable broad neuraminidase inhibition by human antibodies |
| title_full_unstemmed | Structural convergence and water-mediated substrate mimicry enable broad neuraminidase inhibition by human antibodies |
| title_short | Structural convergence and water-mediated substrate mimicry enable broad neuraminidase inhibition by human antibodies |
| title_sort | structural convergence and water mediated substrate mimicry enable broad neuraminidase inhibition by human antibodies |
| url | https://doi.org/10.1038/s41467-025-62339-z |
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