Lewis acidic metal complexes can serve as a catalyst to cleave amide bonds in proteins at specific amino acid sequences (Scheme 13A, 13B). Proteases such as trypsin or pepsin are enzymes to catalyze proteolysis (i.e., hydrolysis of the peptide backbones) and are widely used for proteomic studies. Although the proteolysis processes with such natural enzymes can proceed efficiently in mild conditions, their exclusive cleavage recognition patterns (e.g., Lys and Arg for trypsin) are not always compatible with a peptide or protein of interest, and development of non-natural, artificial proteolytic systems with alternative sequence recognition patterns has been actively studied. Metal catalysts that displays Lewis acidic nature can be used as alternatives to natural proteases, for example. The metal center of such Lewis acid catalysts would facilitate the hydrolysis of the amide backbone by interaction with the carbonyl oxygen of the amide backbone making the carbonyl group more susceptible to the nucleophilic addition. An example includes a report by Kanai and co-workers showing scandium (III) triflate catalyst-mediated serine/threonine selective cleavage. Kostic and co-workers reported a different type of amide backbone cleavage with histidine and methionine selectivity using palladium-based catalysts. In addition, N-terminal residue-selective cleavage through the chelation of the α-amino group can be achieved with cobalt(III) complex as well (Scheme 13B, 13C). In order to facilitate selective and efficient cleavage process by a metal complex, Suh and co-workers developed a system making use of reversible imine formation between aldehyde tethered to the metal-ligand and amine on proteins, which enabled specific cleavage at Gln(91)-Ser (92) and Ala( )-Thr( ) of myoglobin protein (Scheme 13B, 13C). Such a reversible bond-forming process can be also applicable to site-specific installation of functionality as well. Instead of the reversible covalent-bond formation, supramolecular catalysis has been leveraged to induce the proximity-driven effects for peptide cleavage as well. Those catalytic proteolysis examples demonstrated that choice of metals and ligand design can produce enzyme-like catalytic systems, and there have been many other reports of different metal systems as described in recent review articles. Serine residues in proteins can be catalytically modified in carboxylic acid-based non-aqueous media (Scheme 13C). Although serine undergoes a variety of enzymatic modifications in living systems, 203 chemical modification of serine remains to be one of the challenging tasks owing to the modest nucleophilicity of the side chain and the abundance of the OH groups in aqueous media. Encourage by the catalytic tryptophan labeling in nonaqueous medium (i.e., hexafluoroisopropanol or HFIP) as described above, Ohata and co-workers described that carboxylic acids could serve as a potentially protein-compatible reaction medium for serine-targeting modification, 202 which was motivated by the widespread use of many carboxylic acid-based compounds as biocompatible buffer components in biochemistry and protein science (e.g., acetate, glycine, and citrate buffers). The chemical modification of hydroxyl groups of serine residue proceeds with an acid catalyst (e.g., trifluoroacetic acid and dysprosium(III) triflate) in carboxylic acid media where the excess carboxylic acid serves as an electrophile and reacts with the hydroxyl group (i.e., Fischer esterification-type reaction). The method was shown to be able to label protein substrates as well, including an intact antibody (trastuzumab), concanavalin A, and chymotrypsin. As chemoselective serine labeling strategies have been simply lacking, this acylation chemistry may be of indicative of the power of the nonaqueous, catalytic approach for protein modification.