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primary topic: A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein

A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein
type: AcademicArticle
type: Article
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 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.
date: 2022-06-02
status: peerReviewed
status: published
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository
subject: QR Microbiology

NATURE
type: Organization

Nature Chemical Biology
type: Collection

Pritha Ghosh
type: Person
given name: Pritha
family name: Ghosh

Sameer Kumar Malladi
type: Person
given name: Sameer Kumar
family name: Malladi

Ishika Pramanick
type: Person
given name: Ishika
family name: Pramanick

Raghavan Varadarajan
type: Person
given name: Raghavan
family name: Varadarajan

Raju S Rajmani
type: Person
given name: Raju S
family name: Rajmani

S Kumaran
type: Person
given name: S
family name: Kumaran

Bhavesh Khatri
type: Person
given name: Bhavesh
family name: Khatri

Somnath Dutta
type: Person
given name: Somnath
family name: Dutta

Nayanika Sengupta
type: Person
given name: Nayanika
family name: Sengupta

Jayanta Chatterjee
type: Person
given name: Jayanta
family name: Chatterjee

Rajesh P Ringe
type: Person
given name: Rajesh P
family name: Ringe

Sahil Kumar
type: Person
given name: Sahil
family name: Kumar

Narender Kumar
type: Person
given name: Narender
family name: Kumar

R Rahisuddin
type: Person
given name: R
family name: Rahisuddin

HTML Summary of #2981 A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein
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primary topic: A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein

QR Microbiology
type: Concept