Tweaking inhibitor boosts potency

Abstract

Replacing a hydrogen bond with a covalent bond boosts the potency of a peptide inhibitor of a key cellular signaling pathway implicated in cancer and other diseases. The signaling protein central to this pathway is NF-κB. One way to block NF-κB signaling is by disrupting protein-protein interactions in a complex that regulates NF-κB activation. An inhibitor of this complex called the NEMO binding domain (NBD) peptide was reported more than a decade ago. But that inhibitor wasn’t very stable and so it became a therapeutic dead end. Anna K. Mapp and coworkers at the University of Michigan have come up with a modification that stabilizes the inhibitor and boosts its potency significantly in cell assays (Angew. Chem. Int. Ed. 2016, DOI: 10.1002/anie.201607990). A hydrogen bond is critical for stabilizing the original inhibitor when it binds to NEMO, a protein in the NF-κB-regulating complex. The amino acids that form the hydrogen