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

Abstract

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.