Targeting intracellular protein-protein interactions with macrocyclic peptides
Year: 2020
Type: other
Abstract: We are exploring macrocyclic peptides (including mono- and bicyclic peptides) as a general modality for targeting intracellular protein-protein interactions (PPIs), by leveraging a novel class of highly active cyclic cell-penetrating peptides (CPPs). In the first approach, potent PPI inhibitors such as linear peptides, stapled peptides, cyclic peptides, and proteins, which are generally impermeable to the cell membrane, are rendered cell-permeable and biologically active by conjugating them to a cyclic CPP. In an alternative approach, macrocyclic peptide libraries containing cyclic CPPs are synthesized in the one bead-two compound format and screened for binding to PPI targets of interest, resulting in cell-permeable and biologically active hits directly from library screening. Potent, selective, proteolytically stable, and cell-permeable macrocyclic peptidyl inhibitors have been generated against several intracellular PPIs including calcineurin-NFAT, MDM2-p53, u03b2-catenin-TCF, Keap1-Nrf2, and NEMO-IKK interactions.
Author: Dehua Pei
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4243204323