Simulation-driven design of stabilized SARS-CoV-2 spike S2 immunogens DOI Creative Commons
Xandra Nuqui, Lorenzo Casalino, Ling Zhou

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 27, 2024

The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants concern that accumulate most sequence modifications in immunodominant S1 subunit. S2, contrast, evolutionarily conserved region and can elicit broadly neutralizing protective antibodies. Yet, S2's usage as an alternative vaccine strategy hampered its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized closed prefusion conformation. Molecular simulations provide mechanistic characterization S2 trimer's opening, informing tryptophan substitutions impart kinetic thermodynamic stabilization. Structural via cryo-EM shows molecular basis stabilization Informed corroborated experiments, report engineered immunogen exhibits increased protein expression, superior thermostability, preserved immunogenicity against sarbecoviruses.

Language: Английский

Simulation-driven design of stabilized SARS-CoV-2 spike S2 immunogens DOI Creative Commons
Xandra Nuqui, Lorenzo Casalino, Ling Zhou

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 27, 2024

The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants concern that accumulate most sequence modifications in immunodominant S1 subunit. S2, contrast, evolutionarily conserved region and can elicit broadly neutralizing protective antibodies. Yet, S2's usage as an alternative vaccine strategy hampered its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized closed prefusion conformation. Molecular simulations provide mechanistic characterization S2 trimer's opening, informing tryptophan substitutions impart kinetic thermodynamic stabilization. Structural via cryo-EM shows molecular basis stabilization Informed corroborated experiments, report engineered immunogen exhibits increased protein expression, superior thermostability, preserved immunogenicity against sarbecoviruses.

Language: Английский

Citations

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