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Angew Chem Int Ed Engl. 2016 Nov 21;55(48):14997-15001. doi: 10.1002/anie.201607990. Epub 2016 Oct 28.

A Synthetic Loop Replacement Peptide That Blocks Canonical NF-κB Signaling.

Author information

1
Department of Chemistry, University of Michigan, Ann Arbor, USA.
2
Life Sciences Institute, Program in Chemical Biology, University of Michigan, Ann Arbor, USA.

Abstract

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.

KEYWORDS:

inhibitors; medical chemistry; peptide loops; peptidomimetics; protein-protein interactions

PMID:
27791341
PMCID:
PMC5587901
DOI:
10.1002/anie.201607990
[Indexed for MEDLINE]
Free PMC Article

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