A general computational design strategy for stabilizing viral class I fusion proteins.

Publication date: Feb 13, 2024

Many pathogenic viruses rely on class I fusion proteins to fuse their viral membrane with the host cell membrane. To drive the fusion process, class I fusion proteins undergo an irreversible conformational change from a metastable prefusion state to an energetically more stable postfusion state. Mounting evidence underscores that antibodies targeting the prefusion conformation are the most potent, making it a compelling vaccine candidate. Here, we establish a computational design protocol that stabilizes the prefusion state while destabilizing the postfusion conformation. With this protocol, we stabilize the fusion proteins of the RSV, hMPV, and SARS-CoV-2 viruses, testing fewer than a handful of designs. The solved structures of these designed proteins from all three viruses evidence the atomic accuracy of our approach. Furthermore, the humoral response of the redesigned RSV F protein compares to that of the recently approved vaccine in a mouse model. While the parallel design of two conformations allows the identification of energetically sub-optimal positions for one conformation, our protocol also reveals diverse molecular strategies for stabilization. Given the clinical significance of viruses using class I fusion proteins, our algorithm can substantially contribute to vaccine development by reducing the time and resources needed to optimize these immunogens.

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Concepts Keywords
Atomic Class
Destabilizing Computational
Host Conformation
Postfusion Design
Vaccine Evidence
Fusion
Membrane
Postfusion
Prefusion
Proteins
Protocol
Rsv
Vaccine
Viral
Viruses

Semantics

Type Source Name
disease VO Viruses
disease IDO process
disease VO vaccine candidate
disease VO protocol
disease VO vaccine
disease MESH clinical significance
disease IDO algorithm
disease VO time
disease IDO host
disease IDO immunodeficiency
disease MESH Infectious Diseases
disease VO USA
drug DRUGBANK Proline
disease VO effective
disease VO Respiratory syncytial virus
disease MESH parainfluenza
drug DRUGBANK L-Alanine
drug DRUGBANK Isoxaflutole
drug DRUGBANK Amino acids
drug DRUGBANK Pentaerythritol tetranitrate
drug DRUGBANK Angiotensin II
disease IDO production
disease IDO site
disease VO volume
drug DRUGBANK L-Leucine
disease VO vaccination
disease VO vaccinated
disease VO immunization
drug DRUGBANK Coenzyme M
disease VO efficient
disease VO efficiency
disease VO USDA
drug DRUGBANK Aspartame

Original Article

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