A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
06
12
2021
accepted:
10
05
2022
pubmed:
3
6
2022
medline:
28
9
2022
entrez:
2
6
2022
Statut:
ppublish
Résumé
Protein tertiary structure mimetics are valuable tools to target large protein-protein interaction interfaces. Here, we demonstrate a strategy for designing dimeric helix-hairpin motifs from a previously reported three-helix-bundle miniprotein that targets the receptor-binding domain (RBD) of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Through truncation of the third helix and optimization of the interhelical loop residues of the miniprotein, we developed a thermostable dimeric helix-hairpin. The dimeric four-helix bundle competes with the human angiotensin-converting enzyme 2 (ACE2) in binding to RBD with 2:2 stoichiometry. Cryogenic-electron microscopy revealed the formation of dimeric spike ectodomain trimer by the four-helix bundle, where all the three RBDs from either spike protein are attached head-to-head in an open conformation, revealing a novel mechanism for virus neutralization. The proteomimetic protects hamsters from high dose viral challenge with replicative SARS-CoV-2 viruses, demonstrating the promise of this class of peptides that inhibit protein-protein interaction through target dimerization.
Identifiants
pubmed: 35654847
doi: 10.1038/s41589-022-01060-0
pii: 10.1038/s41589-022-01060-0
pmc: PMC9512702
doi:
Substances chimiques
Peptides
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
Peptidyl-Dipeptidase A
EC 3.4.15.1
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1046-1055Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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