Enzyme‐Inspired Design of Redox‐Active Molecules for Promotion of Oxidative Protein Folding

Protein folding is essential for maturation of nascent polypeptides into native proteins. In living cells, molecular chaperones and enzymes efficiently and synergistically promote protein folding. Inspired by biological folding systems, researchers have developed synthetic chemical chaperones for promoting protein folding in vitro. Many secretory proteins have multiple disulfide (SS) bonds, and therefore, their folding reactions are intrinsically an oxidative process, namely, oxidative folding. This review highlights representative strategies in the design of redox-active compounds that promote oxidative protein folding. Small-molecule thiols and disulfides were developed for oxidative folding promotion, which have been improved by optimizing their molecular structures and reactivities. The chemical features of natural folding enzymes have also inspired researchers to develop folding promoters that reproduce the structural and chemical features of the enzymes. Biological contexts have been considered recently, giving birth to stress-responsive folding promoters. These efforts described herein would pave the way for the development of novel synthetic reagents that enhance industrial protein production processes and prevent protein misfolding diseases.