Recent advances in the molecular engineering of synthetic polypeptides: Design, synthesis, functionality, and biological applications

Abstract

Proteins are intricate biomolecules composed of amino acids that perform a wide array of essential biological functions. In recent years, considerable efforts have been made to replicate their structural and functional complexity through synthetic approaches. Among these, the ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydride (NCA) has emerged as the most effective method for synthesizing high-molecular-weight polypeptides on a larger scale. Advances in controlled polymerization techniques, alongside improvements in NCA monomer synthesis, have significantly enhanced the precision and efficiency of polypeptide production. These developments have spurred progress in peptide engineering, enabling the creation of multiblock, branched, and functionally diverse polypeptides, including those incorporating non-natural motifs. Such modifications mimic post-translational modifications found in natural proteins, underscoring the increasing relevance of synthetic polypeptides in designing next-generation functional materials. Synthetic polypeptides and their potential in biomaterial applications have emerged as a highly active research area, particularly following the advent of controlled ROP of NCA monomers. In this article, we present a comprehensive overview of recent progress in the field, primarily over the past decade, emphasizing key developments and emerging directions. Furthermore, it explores how peptide engineering facilitates the development of tailor-made polypeptides with tunable properties, culminating in a discussion on their potential in self-assembly and biomaterials applications.