Functional Engineering of Bioactive Peptides: Chemical Modifications and Synthetic Biology Approaches

Bioactive peptides (BPs) are widely distributed and exhibit remarkable physiological activities. However, their natural forms are frequently characterized by short half-lives, low membrane permeability, poor stability, and inadequate oral bioavailability, which severely limit their applications in the food, pharmaceutical, and biomaterial fields. Therefore, modification and engineering of natural BPs are essential to surmount these inherent limitations. Synthetic biology-based modification strategies, including amino acid substitution, sequence truncation and hybridization, side-chain functionalization, and main-chain/side-chain integration, are comprehensively summarized in this review. Chemical modification strategies, such as terminal modification, cyclization, backbone modification, polymer conjugation, lipidation, and glycosylation, are also discussed, with particular attention to their advantages, potential drawbacks, and practical limitations. Based on 122 studies identified through systematic literature searches across major scientific databases, this review also discusses the current challenges and future trends in BP modification, providing theoretical guidance and innovative insights for the further development and enhanced utilization of BPs.