Structural convergence and water-mediated substrate mimicry enable broad neuraminidase inhibition by human antibodies

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 Sage, Sarah F. Andrews, Barney S. Graham, Adam K. Wheatley, Douglas S. Reed, Neil P. King () and Masaru Kanekiyo ()
Additional contact information
Julia Lederhofer: National Institutes of Health
Andrew J. Borst: University of Washington
Lam Nguyen: National Institutes of Health
Rebecca A. Gillespie: National Institutes of Health
Connor J. Williams: University of Pittsburgh
Emma L. Walker: University of Pittsburgh
Julie E. Raab: National Institutes of Health
Christina Yap: National Institutes of Health
Daniel Ellis: University of Washington
Adrian Creanga: National Institutes of Health
Hyon-Xhi Tan: University of Melbourne
Thi H. T. Do: University of Melbourne
Michelle Ravichandran: National Institutes of Health
Adrian B. McDermott: National Institutes of Health
Valerie Sage: University of Pittsburgh
Sarah F. Andrews: National Institutes of Health
Barney S. Graham: National Institutes of Health
Adam K. Wheatley: University of Melbourne
Douglas S. Reed: University of Pittsburgh
Neil P. King: University of Washington
Masaru Kanekiyo: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62339-z

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