Cell-Permeable Bicyclic Peptidyl Inhibitors against NEMO-I?B Kinase Interaction Directly from a Combinatorial Library.

ABSTRACT: Macrocyclic peptides are capable of binding to flat protein surfaces such as the interfaces of protein-protein interactions with antibody-like affinity and specificity, but generally lack cell permeability in order to access intracellular targets. In this work, we designed and synthesized a large combinatorial library of cell-permeable bicyclic peptides, in which the first ring consisted of randomized peptide sequences for potential binding to a target of interest, while the second ring featured a family of different cell-penetrating motifs, for both cell penetration and target binding. The library was screened against the I?B kinase ?/? (IKK?/?)-binding domain of NF-?B essential modulator (NEMO), resulting in the discovery of several cell-permeable bicyclic peptides, which inhibited the NEMO-IKK? interaction with low ?M IC50 values. Further optimization of one of the hits led to a relatively potent and cell-permeable NEMO inhibitor (IC50 = 1.0 ?M), which selectively inhibited canonical NF-?B signaling in mammalian cells and the proliferation of cisplatin-resistant ovarian cancer cells. The inhibitor provides a useful tool for investigating the biological functions of NEMO/NF-?B and a potential lead for further development of a novel class of anti-inflammatory and anticancer drugs.

SUBMITTER: Rhodes CA 

PROVIDER: S-EPMC6231237 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature