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

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein
 
Creator Khatri, Bhavesh
Pramanick, Ishika
Malladi , Sameer Kumar
Rajmani, Raju S
Kumar, Sahil
Ghosh , Pritha
Sengupta, Nayanika
Rahisuddin, R
Kumar , Narender
Kumaran , S
Ringe, Rajesh P
Varadarajan, Raghavan
Dutta, Somnath
Chatterjee, Jayanta
 
Subject QR Microbiology
 
Description 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.
 
Publisher NATURE
 
Date 2022-06-02
 
Type Article
PeerReviewed
 
Relation https://www.nature.com/articles/s41589-022-01060-0
http://crdd.osdd.net/open/2981/
 
Identifier 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 .