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http://conacyt.repositorioinstitucional.mx/jspui/handle/1000/8336| Simulation-Driven Design of Stabilized SARS-CoV-2 Spike S2 Immunogens | |
| Xandra Nuqui Lorenzo Casalino Ling Zhou Mohamed Shehata Albert Wang Alexandra Tse ANUPAM ANAND OJHA Fiona Kearns Mia Rosenfeld Emily Miller Cory Acreman Surl-Hee (Shirley) Ahn kartik chandran Jason McLellan Rommie Amaro | |
| Acceso Abierto | |
| Atribución-NoComercial-SinDerivadas | |
| https://doi.org/10.1101/2023.10.24.563841 | |
| https://www.biorxiv.org/content/10.1101/2023.10.24.563841v1 | |
| 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 of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, S2’s usage as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design highly stable S2-only antigens retaining a closed prefusion conformation. Weighted ensemble simulations provide mechanistic characterization of the S2 trimer’s opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Alchemical free energy perturbation calculations and a corroborating set of experiments confirm that V991W and T998W in the central helices of S2 stabilize the trimer in the closed prefusion conformation, producing an antigen with increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses. | |
| bioRxiv | |
| 25-10-2023 | |
| Preimpreso | |
| Inglés | |
| Público en general | |
| VIRUS RESPIRATORIOS | |
| Aparece en las colecciones: | Materiales de Consulta y Comunicados Técnicos |
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| Fichero | Tamaño | Formato | |
|---|---|---|---|
| Simulation-Driven Design of Stabilized SARS-CoV-2 Spike S2 Immunogens.pdf | 11.67 MB | Adobe PDF | Visualizar/Abrir |