title: A Synthetic Loop Replacement Peptide That Blocks Canonical NF-κB Signaling.
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.
authors: Department of Chemistry, University of Michigan, Ann Arbor, USA.|Life Sciences Institute, Program in Chemical Biology, University of Michigan, Ann Arbor, USA.
authors: Paul A
authors: PA
authors: Bruno
authors: Department of Chemistry, University of Michigan, Ann Arbor, USA.
authors: Alex
authors: A
authors: Morriss-Andrews
authors: Department of Chemistry, University of Michigan, Ann Arbor, USA.|Life Sciences Institute, Program in Chemical Biology, University of Michigan, Ann Arbor, USA.
authors: Andrew R
authors: AR
authors: Henderson
authors: Department of Chemistry, University of Michigan, Ann Arbor, USA.
authors: Charles L
authors: CL
authors: Brooks
authors: Department of Chemistry, University of Michigan, Ann Arbor, USA.|Life Sciences Institute, Program in Chemical Biology, University of Michigan, Ann Arbor, USA.
authors: Anna K
authors: AK
authors: Mapp
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D016328:NF-kappa B; D010455:Peptides
keywords: inhibitors; medical chemistry; peptide loops; peptidomimetics; protein-protein interactions