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

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Authors

Kotecha, Abhay
Seago, Julian
Scott, Katherine Anne
Burman, Alison
Loureiro, Silvia
Ren, Jingshan
Porta, Claudine
Ginn, Helen M.
Jackson, Terry
Perez-Martin, Eva

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Publisher

Nature Publishing Group

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.

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Keywords

Foot-and-mouth disease virus (FMDV), Protein interfaces guides, Structural analyses, Stability

Sustainable Development Goals

Citation

Kotecha, K, Seago, J, Scott, KA, Burman, A, Loureiro, S, Ren, J, Porta, C, Ginn, HM, Jackson, T, Perez-Martin, E, Siebert, CA, Paul, G, Huiskonen, JT, Jones, IM, Esnouf, RM, Fry, EE, Maree, FF, Charleston, B & Stuart, D 2015, 'Structure-based energetics of protein interfaces guides foot-and-mouth disease virus vaccine design', Nature Structural and Molecular Biology, vol. 22, no. 10, pp. 1-10.