Recent advances in protein synthesis: from chemical synthesis to backbone editing

Proteins are the primary executors of life processes. Precise analysis and manipulation of their structure and function are fundamental to life science research. Although traditional recombinant expression systems are widely used, they face challenges in preparing proteins with uniform post-translational modifications, specific labels, or non-canonical structural units. Since the advent of liquid- and solid-phase peptide synthesis, coupled with ligation methods like native chemical ligation and enzymatic ligation, has enabled the chemical total synthesis of medium-to-large proteins. Meanwhile, genetic code expansion has broadened the chemical space of proteins by incorporating noncanonical amino acids. In recent years, with the development of peptide backbone reconstitution and split-intein systems, researchers can now perform in situ editing of protein backbones both in vitro and in cellular environments. Following the theme “from chemical synthesis to backbone editing,” this review summarizes recent methodological progress in solid-phase peptide synthesis, ligation reactions, genetic code expansion, and protein editing. It aims to provide a reference for the precise construction and functional study of proteins.