Issue 40, 2021

Peptoid-based reprogrammable template for cell-permeable inhibitors of protein–protein interactions

Abstract

The development of inhibitors of intracellular protein–protein interactions (PPIs) is of great significance for drug discovery, but the generation of a cell-permeable molecule with high affinity to protein is challenging. Oligo(N-substituted glycines) (oligo-NSGs), referred to as peptoids, are attractive as potential intracellular PPI inhibitors owing to their high membrane permeability. However, their intrinsically flexible backbones make the rational design of inhibitors difficult. Here, we propose a peptoid-based rational approach to develop cell-permeable PPI inhibitors using oligo(N-substituted alanines) (oligo-NSAs). The rigid structures of oligo-NSAs enable independent optimization of each N-substituent to improve binding affinity and membrane permeability, while preserving the backbone shape. A molecule with optimized N-substituents inhibited a target PPI in cells, which demonstrated the utility of oligo-NSA as a reprogrammable template to develop intracellular PPI inhibitors.

Graphical abstract: Peptoid-based reprogrammable template for cell-permeable inhibitors of protein–protein interactions

Supplementary files

Article information

Article type
Edge Article
Submitted
18 Mar 2021
Accepted
02 Aug 2021
First published
03 Aug 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2021,12, 13292-13300

Peptoid-based reprogrammable template for cell-permeable inhibitors of protein–protein interactions

Y. Fukuda, M. Yokomine, D. Kuroda, K. Tsumoto, J. Morimoto and S. Sando, Chem. Sci., 2021, 12, 13292 DOI: 10.1039/D1SC01560E

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