Electrophilic helical peptides that bond covalently, irreversibly, and selectively in a protein-protein interaction site

Dantas De Araujo, Aline, Lim, Junxian, Good, Andrew C., Skerlj, Renato T. and Fairlie, David P. (2017) Electrophilic helical peptides that bond covalently, irreversibly, and selectively in a protein-protein interaction site. ACS Medicinal Chemistry Letters, 8 1: 22-26. doi:10.1021/acsmedchemlett.6b00395

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Author Dantas De Araujo, Aline
Lim, Junxian
Good, Andrew C.
Skerlj, Renato T.
Fairlie, David P.
Title Electrophilic helical peptides that bond covalently, irreversibly, and selectively in a protein-protein interaction site
Journal name ACS Medicinal Chemistry Letters   Check publisher's open access policy
ISSN 1948-5875
Publication date 2017-01-01
Year available 2016
Sub-type Article (original research)
DOI 10.1021/acsmedchemlett.6b00395
Open Access Status File (Author Post-print)
Volume 8
Issue 1
Start page 22
End page 26
Total pages 5
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted abstract
Protein–protein interactions mediate most physiological and disease processes. Helix-constrained peptides potently mimic or inhibit these interactions by making multiple contacts over large surface areas. However, despite high affinities, they typically have short lifetimes bound to the protein. Here we insert both a helix-inducing constraint and an adjacent electrophile into the native peptide ligand BIM to target the oncogenic protein Bcl2A1. The modified BIM peptide bonds covalently and irreversibly to one cysteine within the helix-binding groove of Bcl2A1, but not to two other exposed cysteines on its surface, and shows no covalent bonding to other Bcl2 proteins. It also penetrates cell membranes and bonds covalently to Bcl2A1 inside cells. This innovative approach to increasing receptor residence time of helical peptides demonstrates the potential to selectively silence a PPI inside cells, with selectivity over other nucleophilic sites on proteins.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Created: Mon, 05 Dec 2016, 23:39:44 EST by Susan Allen on behalf of Institute for Molecular Bioscience