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The ability to manipulate the chemical composition of proteins and peptides has been central to the development of improved polypeptide-based therapeutics and has enabled researchers to address fundamental biological questions that would otherwise be out of reach. Protein ligation, in which two or more polypeptides are covalently linked, is a powerful strategy for generating semisynthetic products and for controlling polypeptide topology. However, specialized tools are required to efficiently forge a peptide bond in a chemoselective manner with fast kinetics and high yield. Fortunately, nature has addressed this challenge by evolving enzymatic mechanisms that can join polypeptides using a diverse set of chemical reactions. Here, we summarize how such nature-inspired protein ligation strategies have been repurposed as chemical biology tools that afford enhanced control over polypeptide composition. Manipulating the chemical composition of proteins and peptides has been central to the development of polypeptide-based therapeutics and to help address fundamental biological questions. This Review describes how nature-inspired protein ligation strategies have been repurposed as chemical biology tools.
Pihl et al. (2023) studied this question.