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A Synthetic Loop Replacement Peptide That Blocks Canonical NF‐κB Signaling
Author(s) -
Bruno Paul A.,
MorrissAndrews Alex,
Henderson Andrew R.,
Brooks Charles L.,
Mapp Anna K.
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201607990
Subject(s) - non canonical , peptide , chemistry , nf κb , computational biology , signal transduction , cancer research , microbiology and biotechnology , stereochemistry , biology , biochemistry
Aberrant canonical NF‐κB signaling is implicated in diseases from autoimmune disorders to cancer. A major therapeutic challenge is the need for selective inhibition of the canonical pathway without impacting the many non‐canonical NF‐κB functions. Here we show that a selective peptide‐based inhibitor of canonical NF‐κB signaling, in which a hydrogen bond in the NBD peptide is synthetically replaced by a non‐labile bond, shows an about 10‐fold increased potency relative to the original inhibitor. Not only is this molecule, NBD2, a powerful tool for dissection of canonical NF‐κB signaling in disease models and healthy tissues, the success of the synthetic loop replacement suggests that the general strategy could be useful for discovering modulators of the many protein–protein interactions mediated by such structures.