tetano
Editor, Senior Moderator
Nat Chem Biol
. 2022 Jun 2.
doi: 10.1038/s41589-022-01060-0. Online ahead of print.
A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein
Bhavesh Khatri[SUP] 1 [/SUP], Ishika Pramanick[SUP] #[/SUP][SUP] 1 [/SUP], Sameer Kumar Malladi[SUP] #[/SUP][SUP] 1 [/SUP], Raju S Rajmani[SUP] 1 [/SUP], Sahil Kumar[SUP] 2 [/SUP], Pritha Ghosh[SUP] 1 [/SUP], Nayanika Sengupta[SUP] 1 [/SUP], R Rahisuddin[SUP] 3 [/SUP], Narender Kumar[SUP] 3 [/SUP], S Kumaran[SUP] 3 [/SUP], Rajesh P Ringe[SUP] 2 [/SUP], Raghavan Varadarajan[SUP] 1 [/SUP], Somnath Dutta[SUP] 4 [/SUP], Jayanta Chatterjee[SUP] 5 [/SUP]
Affiliations
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.
. 2022 Jun 2.
doi: 10.1038/s41589-022-01060-0. Online ahead of print.
A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein
Bhavesh Khatri[SUP] 1 [/SUP], Ishika Pramanick[SUP] #[/SUP][SUP] 1 [/SUP], Sameer Kumar Malladi[SUP] #[/SUP][SUP] 1 [/SUP], Raju S Rajmani[SUP] 1 [/SUP], Sahil Kumar[SUP] 2 [/SUP], Pritha Ghosh[SUP] 1 [/SUP], Nayanika Sengupta[SUP] 1 [/SUP], R Rahisuddin[SUP] 3 [/SUP], Narender Kumar[SUP] 3 [/SUP], S Kumaran[SUP] 3 [/SUP], Rajesh P Ringe[SUP] 2 [/SUP], Raghavan Varadarajan[SUP] 1 [/SUP], Somnath Dutta[SUP] 4 [/SUP], Jayanta Chatterjee[SUP] 5 [/SUP]
Affiliations
- PMID: 35654847
- DOI: 10.1038/s41589-022-01060-0
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.