Simulation-driven design of stabilized SARS-CoV-2 spike S2 immunogens

Xandra Nuqui, Lorenzo Casalino, Ling Zhou, Mohamed Shehata, Albert Wang, Alexandra L. Tse, Anupam A. Ojha, Fiona L. Kearns, Mia A. Rosenfeld, Emily Happy Miller, Cory M. Acreman, Surl-Hee Ahn, Kartik Chandran, Jason S. McLellan and Rommie E. Amaro ()
Additional contact information
Xandra Nuqui: University of California San Diego
Lorenzo Casalino: University of California San Diego
Ling Zhou: The University of Texas at Austin
Mohamed Shehata: University of California San Diego
Albert Wang: Albert Einstein College of Medicine
Alexandra L. Tse: Albert Einstein College of Medicine
Anupam A. Ojha: University of California San Diego
Fiona L. Kearns: University of California San Diego
Mia A. Rosenfeld: University of California San Diego
Emily Happy Miller: Albert Einstein College of Medicine
Cory M. Acreman: The University of Texas at Austin
Surl-Hee Ahn: University of California Davis
Kartik Chandran: Albert Einstein College of Medicine
Jason S. McLellan: The University of Texas at Austin
Rommie E. Amaro: University of California San Diego

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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. Informed by molecular simulations and corroborated by experiments, we report an engineered S2 immunogen that exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-50976-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50976-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-50976-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().