2022 年 2 巻 3 号 p. rev-1-rev-17
Oxidative folding is an essential process for polypeptide chains containing cysteine (Cys) residues to form a bioactive three-dimensional structure. During this process, the folded state with the correct disulfide (SS) combination, which is found in the native state, cannot be obtained at 100% yield because various byproducts, such as misfolded states with mispaired SS bonds, oligomers, and aggregates are simultaneously produced. The formation of misfolded states in vivo has been suggested to cause critical human diseases such as neurodegenerative disorders. Therefore, the development of methods to promote the correct structural maturation of polypeptides, including Cys residues, both in vivo and in vitro, is a challenging task in protein synthesis, medicine, and drug discovery. To rapidly form correctly folded proteins at high yields, two potential strategies are available. First, called the outside strategy, is to control oxidative folding from the outside of proteins using artificial small molecules as catalyst and a reagent that mimics the function of protein disulfide isomerase, which catalyzes SS-related reactions during oxidative folding in cells. Second, called the inside strategy, is to insert mimics of SS linkage(s) into the inside of polypeptides to form a rigid covalent bond chemoselectively, thereby avoiding the formation of a misfolded state having mispaired SS bonds. In this review, recent developments and trends based on the unique redox properties of selenols and diselenides, which are selenium analogs of thiols and disulfides, respectively, are outlined, and their future prospects are discussed.