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Nat Struct Mol Biol. 2015 Oct;22(10):788-94. doi: 10.1038/nsmb.3096. Epub 2015 Sep 21.

Structure-based energetics of protein interfaces guides foot-and-mouth disease virus vaccine design.

Author information

1
Division of Structural Biology, University of Oxford, Oxford, UK.
2
Pirbright Institute, Pirbright, UK.
3
Transboundary Animal Disease Programme, Agricultural Research Council-Onderstepoort Veterinary Institute, Onderstepoort, South Africa.
4
Animal and Microbial Sciences, University of Reading, Reading, UK.
5
Merck Sharp &Dohme Animal Health, Cologne, Germany.
6
Department of Microbiology and Plant Pathology, University of Pretoria, Pretoria, South Africa.
7
Diamond Light Source, Didcot, UK.

Abstract

Virus capsids are primed for disassembly, yet capsid integrity is key to generating a protective immune response. Foot-and-mouth disease virus (FMDV) capsids comprise identical pentameric protein subunits held together by tenuous noncovalent interactions and are often unstable. Chemically inactivated or recombinant empty capsids, which could form the basis of future vaccines, are even less stable than live virus. Here we devised a computational method to assess the relative stability of protein-protein interfaces and used it to design improved candidate vaccines for two poorly stable, but globally important, serotypes of FMDV: O and SAT2. We used a restrained molecular dynamics strategy to rank mutations predicted to strengthen the pentamer interfaces and applied the results to produce stabilized capsids. Structural analyses and stability assays confirmed the predictions, and vaccinated animals generated improved neutralizing-antibody responses to stabilized particles compared to parental viruses and wild-type capsids.

PMID:
26389739
PMCID:
PMC5985953
DOI:
10.1038/nsmb.3096
[Indexed for MEDLINE]
Free PMC Article

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