期刊
NATURE CHEMICAL BIOLOGY
卷 18, 期 10, 页码 1046-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-022-01060-0
关键词
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资金
- Science and Engineering Research Board (SERB), Government of India [IPA/2020/000094]
- Ministry of Human Resource Development (MHRD), Government of India [STARS-1/171]
- SERB [IPA/2020/000168]
- Bill and Melinda Gates Foundation [INV-005948]
- Office of the Principal Scientific Advisor, Government of India [SP/OPSA-20-0004]
- Government of India: DST- FIST
- Government of India: MHRD-FAST
- DBT-IISc Partnership Program
- UGC Center for Advanced Study
- JC Bose Fellowship from DST
- Ramalingaswami fellowship from DBT
- DBT-BUILDER Program [BT/INF/22/SP22844/2017]
- DST-FIST [SR/FST/LSII-039/2015]
- Bill and Melinda Gates Foundation [INV-005948] Funding Source: Bill and Melinda Gates Foundation
This study demonstrates the design and development of a therapeutically effective peptide against SARS-CoV-2 by targeting dimerization, providing a promising approach for inhibiting viral infection.
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.
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