Recent Chemical Biology Insights Towards Reversible Stapled Peptides
Ying Chen, Chuan Dai, Jinyan Han, Yun Xing, Feng Yin, Zigang Li
Abstract
Peptides are increasingly recognized for their advantages over small molecules in the modulation of protein-protein interactions (PPIs), particularly in terms of potency and selectivity. "Staples" can be coupled to the amino acid residues of linear peptides to limit their conformation, improving the stability, membrane permeability, and resistance to proteolysis of peptides. However, the addition of staples can sometimes lead to the complete inactivation of the original peptide or result in extensive interactions that complicate biophysical analysis. Reversible stapled peptides provide an excellent solution to these issues. Besides, probes based on reversible stapled peptides are also indispensable tools for thoroughly investigating PPIs. Consequently, the development of diverse reversible stapling techniques for stapled peptides is crucial for broadening the applications of peptide molecules in drug discovery, drug delivery, and as tools in chemical biology research. This review aims to summarize representative chemical design strategies for reversible stapled peptides, focusing on reversible chemical stapling methods involving sulfhydryl, amino, and methylthio groups, as well as reversible modulation of the conformational states of stapled peptides. Additionally, we demonstrate some intriguing biological applications of stapled peptides and, finally, suggest future research directions in the field that will serve as references for related researchers.