Journal: Nat Chem Biol / Year: 2022 Title: A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein. Authors: Bhavesh Khatri / Ishika Pramanick / Sameer Kumar Malladi / Raju S Rajmani / Sahil Kumar / Pritha Ghosh / Nayanika Sengupta / R Rahisuddin / Narender Kumar / S Kumaran / Rajesh P Ringe / ...Authors: Bhavesh Khatri / Ishika Pramanick / Sameer Kumar Malladi / Raju S Rajmani / Sahil Kumar / Pritha Ghosh / Nayanika Sengupta / R Rahisuddin / Narender Kumar / S Kumaran / Rajesh P Ringe / Raghavan Varadarajan / Somnath Dutta / Jayanta Chatterjee / 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 ...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.
Name: Spike glycoprotein / type: protein_or_peptide / ID: 1 Details: NCBI Reference Sequence: YP_009724390.1 In our deposited construct, spike protein is composed of 1-1208 amino acid residues, which have the following mutations R682G, R683S, R685S, K986P, ...Details: NCBI Reference Sequence: YP_009724390.1 In our deposited construct, spike protein is composed of 1-1208 amino acid residues, which have the following mutations R682G, R683S, R685S, K986P, V987P. At the C terminus, there is Foldon oligomerization domain, HRV3C protease site, 6 His, Strep-tag II, linker, Strep-tag II, stop codon. Number of copies: 3 / Enantiomer: LEVO
Source (natural)
Organism: Severe acute respiratory syndrome coronavirus 2
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