Tag-like cyclic peptides: Modular affinity elements for protein integration and bioengineering applications

Cyclic peptides have emerged as highly versatile compounds in drug development and bioengineering, offering unique structural stability, binding specificity, and reduced susceptibility to proteolysis compared to their linear counterparts. These properties make cyclic peptides valuable in a range of therapeutic applications, from antimicrobial and anticancer agents to affinity tags in protein engineering. This review provides a comprehensive overview of cyclic peptide types, synthesis methods, and the latest advances in cyclic peptide-based therapeutics. Particular emphasis has been placed on "tag-like" cyclic peptides, which can function as affinity tags for enhancing the bioactivity and targeting capabilities of larger proteins. We explore various cyclization techniques, including disulfide bridging, metal-mediated linkers, and organic reagents, that facilitate the production of both monocyclic and bicyclic peptides with optimized pharmacokinetic and stability profiles. Recent advancements in display technologies, such as phage and mRNA display, further underscore the therapeutic potential of cyclic peptides, enabling rapid identification of candidates with high affinity and selectivity for a range of targets. This review discusses the potential of cyclic peptides as affinity tags that can be engineered onto proteins of interest, bridging the gap between small molecules and larger biologics, and explores future directions for their use in enhancing protein purification, detection, and interaction studies in protein engineering projects.