%A Bhavesh  Khatri
%A Ishika  Pramanick
%A Sameer Kumar  Malladi 
%A Raju S  Rajmani
%A Sahil  Kumar
%A Pritha  Ghosh 
%A Nayanika  Sengupta
%A R  Rahisuddin
%A Narender  Kumar 
%A S  Kumaran 
%A Rajesh P  Ringe
%A Raghavan  Varadarajan
%A Somnath  Dutta
%A Jayanta  Chatterjee
%O The copyright of this article belongs to Nature
%J Nature Chemical Biology 
%T A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein
%X 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.
%D 2022
%I NATURE 
%L open2981