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 .
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Additional Information: | The copyright of this article belongs to Nature |
| Subjects: | Q Science > QR Microbiology |
| Depositing User: | Dr. K.P.S.Sengar |
| Date Deposited: | 22 Jul 2022 04:58 |
| Last Modified: | 22 Jul 2022 04:58 |
| URI: | http://crdd.osdd.net/open/id/eprint/2981 |
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