creators_name: Khatri, Bhavesh 
creators_name: Pramanick, Ishika 
creators_name: Malladi , Sameer Kumar 
creators_name: Rajmani, Raju S 
creators_name: Kumar, Sahil 
creators_name: Ghosh , Pritha 
creators_name: Sengupta, Nayanika 
creators_name: Rahisuddin, R 
creators_name: Kumar , Narender 
creators_name: Kumaran , S 
creators_name: Ringe, Rajesh P 
creators_name: Varadarajan, Raghavan 
creators_name: Dutta, Somnath 
creators_name: Chatterjee, Jayanta 
type: article
datestamp: 2022-07-22 04:58:45
lastmod: 2022-07-22 04:58:45
metadata_visibility: show
title: A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein
ispublished: pub
subjects: QR
note: The copyright of this article belongs to Nature
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
date_type: published
publication: Nature Chemical Biology 
publisher: NATURE 
refereed: TRUE
official_url: https://www.nature.com/articles/s41589-022-01060-0
citation:   Khatri, Bhavesh  and Pramanick, Ishika  and Malladi , Sameer Kumar  and Rajmani, Raju S  and Kumar, Sahil  and Ghosh , Pritha  and Sengupta, Nayanika  and Rahisuddin, R  and Kumar , Narender  and Kumaran , S  and Ringe, Rajesh P  and Varadarajan, Raghavan  and Dutta, Somnath  and Chatterjee, Jayanta   (2022) A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein.  Nature Chemical Biology .