Oxidative cleavage of the peptide backbone can be induced through metal catalysis, mimicking enzymatic processes in natural systems (Scheme 11A). Reactive oxygen species (ROS) is important biological species both for physiological and pathological conditions, where protein oxidation play pivotal roles. Through sophisticated design of a catalytic system with judicious choice of reaction components (catalysts, ligands, and oxidants), Oisaki, Kanai, and co-workers developed coppermediated backbone cleavage, selectively at serine residues (Scheme 11B). Single-electron oxidation of the primary alkylalcohol of serine through copper(II)-phenathroline complex and N-oxide reagent initiates the catalysis, and subsequent oxidation of the generated aldehyde group produces a hydrolytically unstable imide intermediate that eventually undergoes the bond cleavage. Though minor reactions at threonine (secondary alkylalcohol) would occur, the serineselective cleavage was achieved even for a small protein ubiquitin through this catalytic system. Another oxidative cleavage strategy is by a copper cluster that can generate ROS species with ascorbic acid to cause site-specific cleavage of lysozyme an enzyme (Scheme 11B). The three-dimensional structure of the copper cluster was attributed to the observed site-specific cleavage of the enzyme through binding interaction between the cluster and enzyme. As those reports showed a single example of a protein substrate for the catalytic cleavage, the future directions of the field are likely to expand the generality and scope of the methods to achieve enzyme-like catalysis. Serine-selective cleavage by a copper complex (top) and site-selective cleavage of lysozyme through reactive oxygen species (ROS) generation with a copper-and tungsten-based cluster (Cu-WD). The imide intermediate of the serine-selective cleavage can be hydrolyzed at both imide C=O groups (blue and pink), but only one of the two possible hydrolysis products is shown for the sake of simplicity. The image of ROS-mediated cleavage was reprinted with permission. Copyright 2023, American Chemical Society ().