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

Yasuhiro Fukuda; Marin Yokomine; Daisuke Kuroda; Kouhei Tsumoto; Jumpei Morimoto; Shinsuke Sando

doi:10.1039/d1sc01560e

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

Chem Sci. 2021 Aug 3;12(40):13292-13300. doi: 10.1039/d1sc01560e. eCollection 2021 Oct 20.

Authors

Yasuhiro Fukuda¹, Marin Yokomine¹, Daisuke Kuroda^{1

2}, Kouhei Tsumoto^{1

2

3}, Jumpei Morimoto¹, Shinsuke Sando^{1

2}

Affiliations

¹ Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo 7-3-1 Hongo, Bunkyo-ku Tokyo 113-8656 Japan jmorimoto@chembio.t.u-tokyo.ac.jp ssando@chembio.t.u-tokyo.ac.jp.
² Department of Bioengineering, Graduate School of Engineering, The University of Tokyo 7-3-1 Hongo, Bunkyo-ku Tokyo 113-8656 Japan.
³ Institute of Medical Science, The University of Tokyo 4-6-1, Shirokanedai, Minato-ku Tokyo 108-8639 Japan.

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.