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Human coronavirus HKU1 neutralization by glycan receptor mimicry

Feng, Z.; Kose, N.; Moreira, F. R.; Kimpel, A. L. M.; Copps, J.; Suryadevara, N.; Jackson, D. J.; Gern, J. E.; Wilson, I. A.; Li, S.; de Vries, R. P.; Baric, R. S.; Bangaru, S.; Crowe, J. E.; Ward, A. B.

2025-11-07 immunology
10.1101/2025.11.05.686863 bioRxiv
Show abstract

Entry of seasonal human coronavirus HKU1 (HCoV-HKU1) into host cells is facilitated by sequential binding to sialoglycans and transmembrane serine protease 2 (TMPRSS2) receptors. However, the neutralizing capacity of antibodies disrupting these receptor interactions have not been examined. Here, we describe the isolation and characterization of a human monoclonal antibody (mAb) HKU1-2 that recognizes the HCoV-HKU1 spike protein and exhibits dose-dependent neutralization of the virus. Epitope mapping and structural analysis revealed that HKU1-2 mAb targets the sialoglycan binding site in the N-terminal domain of the spike protein. A cryo-electron microscopy (cryo-EM) structure of the spike-Fab complex further demonstrated the ability of HKU1-2 to mimic sialic acid binding thereby effectively blocking sialoglycan receptor engagement. HKU1-2 binding is primarily mediated by CDRH3 recognition of NTD residues K80 and W89 that are known to be critical for sialic acid engagement. Overall, our results demonstrate antibody recognition and neutralization of HCoV-HKU1 by receptor mimicry.

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