title: A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein
creator: Khatri, Bhavesh 
creator: Pramanick, Ishika 
creator: Malladi , Sameer Kumar 
creator: Rajmani, Raju S 
creator: Kumar, Sahil 
creator: Ghosh , Pritha 
creator: Sengupta, Nayanika 
creator: Rahisuddin, R 
creator: Kumar , Narender 
creator: Kumaran , S 
creator: Ringe, Rajesh P 
creator: Varadarajan, Raghavan 
creator: Dutta, Somnath 
creator: 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
type: PeerReviewed
relation: https://www.nature.com/articles/s41589-022-01060-0
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 .       
relation: http://crdd.osdd.net/open/2981/