Simulation-Driven Design of Stabilized SARS-CoV-2 Spike S2 Immunogens
Abstract 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 S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of the S2 trimer’s opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Moreover, a corroborating set of experiments indicate that the engineered S2 immunogen exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 12. Feb. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nuqui, Xandra [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.10.24.563841 |
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| PPN (Katalog-ID): |
XBI04131848X |
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| 520 | |a Abstract 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 S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of the S2 trimer’s opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Moreover, a corroborating set of experiments indicate that the engineered S2 immunogen exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses. | ||
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| 700 | 1 | |a Casalino, Lorenzo |0 (orcid)0000-0003-3581-1148 |4 aut | |
| 700 | 1 | |a Zhou, Ling |0 (orcid)0000-0003-3402-5719 |4 aut | |
| 700 | 1 | |a Shehata, Mohamed |0 (orcid)0000-0003-0841-4577 |4 aut | |
| 700 | 1 | |a Wang, Albert |0 (orcid)0000-0003-1162-6837 |4 aut | |
| 700 | 1 | |a Tse, Alexandra L. |0 (orcid)0000-0002-1629-6526 |4 aut | |
| 700 | 1 | |a Ojha, Anupam A. |0 (orcid)0000-0001-6588-3092 |4 aut | |
| 700 | 1 | |a Kearns, Fiona L. |0 (orcid)0000-0002-5469-9035 |4 aut | |
| 700 | 1 | |a Rosenfeld, Mia A. |0 (orcid)0000-0002-8961-8231 |4 aut | |
| 700 | 1 | |a Miller, Emily Happy |0 (orcid)0000-0002-0640-5653 |4 aut | |
| 700 | 1 | |a Acreman, Cory M. |0 (orcid)0009-0004-8064-2245 |4 aut | |
| 700 | 1 | |a Ahn, Surl-Hee |0 (orcid)0000-0002-3422-805X |4 aut | |
| 700 | 1 | |a Chandran, Kartik |0 (orcid)0000-0003-0232-7077 |4 aut | |
| 700 | 1 | |a McLellan, Jason S. |0 (orcid)0000-0003-3991-542X |4 aut | |
| 700 | 1 | |a Amaro, Rommie E. |0 (orcid)0000-0002-9275-9553 |4 aut | |
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