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

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.