Stapled Peptide Design

Peptide stapling is a strategy for constraining short peptides typically in an alpha-helical conformation. Stapling is carried out by covalently linking the side-chains of two amino acids, thereby forming a peptide macrocycle. Peptide “stapling” via interside-chain hydrocarbon linkages has emerged as one of the most promising approaches for the generation of potent and stable type Ⅰ peptidomimetics of α-helical protein binding motifs. Once inside the cell, stapled peptides are stable, and able to initiate or inhibit protein-protein interactions that are useful for the treatment of cancer, insulin secretion, inflammation and many other disease states.

Advantages of stapled peptides in drug design

The introduction of a hydrocarbon staple confers high levels of α-helical content and results in:
• SBetter target affinity (5 to 5,000-fold increase)
• STargeting of either extracellular or intracellular proteins
• SViable pharmacokinetics and in vivo stability
• SDisruption of protein-protein interactions
• SCell penetration through endocytic vesicle trafficking
• SIncreased proteolytic resistance and serum half-life
• SNon-immunogenicity