Peptide synthesis: a review of classical and emerging methods

Peptides are essential bioactive compounds with broad applications in nutraceuticals, pharmaceuticals, cosmetics, and materials. As their applications continue to grow, the development of efficient and sustainable synthesis methods has emerged as a major focus of research. This review provides a comprehensive summary of the primary methods for peptide synthesis, including biosynthesis, classical solution-phase peptide synthesis (CSPS), solid-phase peptide synthesis (SPPS), liquid-phase peptide synthesis (LPPS), and emerging technologies such as transition metal catalysis, photocatalysis, and electrochemistry. Special emphasis is placed on the recent advancements in CSPS, SPPS, LPPS, and emerging technologies, with a particular focus on the integration of green chemistry principles into SPPS and emerging techniques. These methods not only involve the construction of peptide molecules but also the conversion of linear peptides into cyclic peptides. Through an in-depth review of the relevant literature, this paper outlines the fundamental principles, advantages, and limitations of each method, while exploring their potential to enhance synthesis efficiency, reduce production costs, and minimize environmental impact. This study aims to explore innovative pathways in peptide synthesis, drive its applications in biomedicine and materials chemistry, and advocate for the deep integration of green and sustainable principles into research and practice.