Cell Permeability

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.

Published in JACS, researchers in the Dehua Pei laboratory, 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 IΚB kinase α/β (IKKα/β)-binding domain of NF-ΚB essential modulator, NEMO, resulting in the discovery of several cell-permeable bicyclic peptides, which inhibited the NEMO-IKK&beata; interaction with low μM IC50 values.

Further optimization of one of the hits led to a relatively potent and cell-permeable NEMO inhibitor, IC50 = 1.0 μM, which selectively inhibited canonical NF-ΚB signaling in mammalian cells and the proliferation of cisplatin-resistant ovarian cancer cells.

This inhibitor provides a useful tool for investigating the biological functions of NEMO/NF-&KappaB and a potential lead for further development of a novel class of anti-inflammatory and anticancer drugs.

Cell-Permeable Bicyclic Peptidyl Inhibitors against NEMO-IκB Kinase Interaction Directly from a Combinatorial Library
Curran A. Rhodes, Patrick G. Dougherty, Jahan K. Cooper, Ziqing Qian, Steffen Lindert, Qi-En Wang, and Dehua Pei
J Am Chem Soc. 2018 Sep 26;140(38):12102-12110