A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein.
Nat Chem Biol
; 18(10): 1046-1055, 2022 10.
Article
in En
| MEDLINE
| ID: mdl-35654847
ABSTRACT
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 22 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.
Full text:
1
Database:
MEDLINE
Main subject:
Angiotensin-Converting Enzyme 2
/
COVID-19
Limits:
Humans
Language:
En
Journal:
Nat Chem Biol
Journal subject:
BIOLOGIA
/
QUIMICA
Year:
2022
Type:
Article
Affiliation country:
India