Inhibition of VP2-mediated entry: a potential antiviral strategy to treat or prevent calicivirus disease

Lewis, C. B.; Sherry, L.; McGrory, R.; Gould, E.; Freitag, M.; Sasvari, H.; Southall, J.; Petrov, F.; Meir, A.; Govindan, N.; Spiri, A.; Bordicchia, M.; Hofmann-Lehmann, R.; Barrs, V. R.; Grove, J.; Jamieson, A.; Hosie, M. J.; Bhella, D. J.

doi:10.64898/2026.05.10.723473

bioRxiv · 10.64898/2026.05.10.723473

Inhibition of VP2-mediated entry: a potential antiviral strategy to treat or prevent calicivirus disease

Lewis, C. B.·Sherry, L.·McGrory, R.·Gould, E.·Freitag, M.·Sasvari, H.·Southall, J.·Petrov, F.·Meir, A.·Govindan, N.·Spiri, A.·Bordicchia, M.·Hofmann-Lehmann, R.·Barrs, V. R.·Grove, J.·Jamieson, A.·Hosie, M. J.·Bhella, D. J.

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Abstract

The Caliciviridae include many notable human and animal pathogens, including norovirus and sapovirus, which cause outbreaks of acute gastroenteritis. We previously demonstrated that, following receptor engagement, feline calicivirus (FCV) assembles a portal structure at a unique capsid three-fold axis. This comprises twelve copies of the minor capsid protein VP2 and is essential for genome delivery. We designed a short peptide based on our structure data that occludes the VP2 binding sites on the capsid surface, to prevent assembly of the VP2 portal and thereby halt the viral entry mechanism. Incubation with low micromolar concentrations of the peptide considerably reduced the infectivity of two laboratory strains and four clinical isolates of FCV associated with respiratory or virulent-systemic disease. Cryo-electron microscopy structures of FCV virions complexed with the peptide confirmed that the peptide occupies the VP2 binding site on the major capsid protein VP1, preventing portal assembly and subsequent genome delivery. Our data show that targeting VP2 is a viable antiviral approach to preventing calicivirus infection, with potential for the treatment or prevention of norovirus disease.

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Lewis, C. B., Sherry, L., McGrory, R., Gould, E., Freitag, M., Sasvari, H., Southall, J., Petrov, F., Meir, A., Govindan, N., Spiri, A., Bordicchia, M., Hofmann-Lehmann, R., Barrs, V. R., Grove, J., Jamieson, A., Hosie, M. J., Bhella, D. J.. 2026-05-10. Inhibition of VP2-mediated entry: a potential antiviral strategy to treat or prevent calicivirus disease. https://doi.org/10.64898/2026.05.10.723473

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