TY  - JOUR
N1  - The copyright of this article belongs to Nature
ID  - open2981
UR  - https://www.nature.com/articles/s41589-022-01060-0
A1  - Khatri, Bhavesh 
A1  - Pramanick, Ishika 
A1  - Malladi , Sameer Kumar 
A1  - Rajmani, Raju S 
A1  - Kumar, Sahil 
A1  - Ghosh , Pritha 
A1  - Sengupta, Nayanika 
A1  - Rahisuddin, R 
A1  - Kumar , Narender 
A1  - Kumaran , S 
A1  - Ringe, Rajesh P 
A1  - Varadarajan, Raghavan 
A1  - Dutta, Somnath 
A1  - Chatterjee, Jayanta 
Y1  - 2022/06/02/
N2  - 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.
PB  - NATURE 
JF  - Nature Chemical Biology 
TI  - A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein
ER  -