期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 22, 期 10, 页码 788-794出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3096
关键词
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资金
- Wellcome Trust (WT) [089755]
- Biotechnology and Biological Sciences Research Council Institute Strategic Programme on Livestock Viral Diseases at The Pirbright Institute
- WT Joint Infrastructure Fund award [060208/Z/00/Z]
- WT equipment grant [093305/Z/10/Z]
- WT, UK Medical Research Council (MRC)
- Biotechnology and Biology Research Council
- WT
- UK MRC [0100099]
- WT core award [090532/Z/09/Z]
- BBSRC [BBS/E/I/00001494, BBS/E/I/00001716] Funding Source: UKRI
- MRC [G1000099, MR/N00065X/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [B14732, BBS/E/I/00001494, EGM17691, BBS/E/I/00001716] Funding Source: researchfish
- Medical Research Council [G1100525, MR/N00065X/1, G1000099] Funding Source: researchfish
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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