Advances in Hydrocarbon Stapled Peptides via Ring‐Closing Metathesis: Synthetic Strategies, Structural Diversity, and Therapeutic Applications

作者：Linji Li, Rong Li, Yanan Jiang, Jingru Chao, Si Chen, Hongli Liao, Xiang Li · 发表于：ChemBioChem · 年份：2025 · DOI：10.1002/cbic.202500527 · 被引用次数：4 · 研究领域：Chemical Synthesis and Analysis、Antimicrobial Peptides and Activities、Biochemical and Structural Characterization

Peptide stapling has emerged as a powerful strategy to stabilize α-helical structures in peptides, thereby enhancing their proteolytic resistance, membrane permeability, and biological activity. Among the various stapling methodologies, hydrocarbon stapling via ruthenium-catalyzed ring-closing metathesis remains the most widely adopted due to its robust chemical efficiency and synthetic compatibility with solid-phase peptide synthesis. This review summarizes key advancements in hydrocarbon stapling technologies, including mono- and multiple-stapling, solution- and solid-phase approaches, and newer developments such as stitched and aza-stapled peptides. The integration of rigidified anchoring residues (e.g., cyclobutane or carbocyclic α, α-disubstituted amino acids) and orthogonal metathesis strategies has significantly expanded the structural diversity and functional potential of stapled peptides. Furthermore, novel bioorthogonal modifications and imaging capabilities, such as Raman-active diyne bridges, have opened new directions in therapeutic and diagnostic applications. Together, these innovations underscore the growing utility of stapled peptides in modulating protein-protein interactions and advancing peptide drug discovery.