Synthesis of Polypeptides by Ring-opening Polymerization: A Concise Review

: The most economical and efficient route to prepare polypeptides from synthetic chemistry is through the Ring-Opening Polymerization (ROP) of amino acids using N-carboxyanhydride (NCA) monomers. Peptide polymers, in contrast to proteins, consist of repeated amino acid units and are comparatively simpler macromolecules. Despite their simplicity, these polypeptides offer a unique combination of beneficial traits found in both synthetic polymers (such as solubility, processability, and rubber elasticity) and natural proteins (including secondary structure, functionality, and biocompatibility). Nevertheless, NCA polymerization faces significant challenges, including intricate monomer purification and the necessity for processing toxic solvents. In this context, this review presents the fundamental principles of this polymer chemistry, the synthesis of NCA monomers, and the different methodologies to access polypeptides by ROP. It also explores the most recent advances in this field of research, with a focus on how new methods enable the use of more reactive initiators and the development of original processes, including the use of aqueous solvents.