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:

• Better target affinity (5 to 5,000-fold increase)
• Targeting of either extracellular or intracellular proteins
• Viable pharmacokinetics and in vivo stability
• Disruption of protein-protein interactions
• Cell penetration through endocytic vesicle trafficking
• Increased proteolytic resistance and serum half-life
• Non-immunogenicity

Available Stapled Peptide Design Services

Creative Peptides provides multiple methods for synthesizing stapled peptides.

• Grubbs catalysts are routinely used in olefin metathesis to incorporate hydrocarbon staples into peptides.

• The high efficiency and mild conditions of “click” reaction (Copper-catalyzed Huisgen 1,3-dipolar cycloaddition reaction) combined with the ease of synthesis of the necessary unnatural amino acids, allows for facile synthesis of triazole-stapled peptides.

• UV-induced reaction between tetrazoles and alkenes has been used by Madden et al. to staple peptides for inhibition of the p53-MDM2/MDMX interaction.

Creative Peptides has extensively developed stapled peptide structures and is the company of choice to manufacture your stapled peptide requirements, providing a confidential and efficient service at competitive prices. Every step of peptide synthesis is subject to Creative Peptides’ stringent quality control. Typical delivery specifications include:

• HPLC chromatogram
• Mass spec analysis
• Synthesis report
• Certificate of Analyses

References

1. Zhang, H., Curreli, F., Waheed, A. A., Mercredi, P. Y., Mehta, M., Bhargava, P & Summers, M. F. (2013). Dual-acting stapled peptides target both HIV-1 entry and assembly. Retrovirology, 10(1), 136.
2. Tan, Y. S., Lane, D. P., & Verma, C. S. (2016). Stapled peptide design: principles and roles of computation. Drug Discovery Today, 21(10), 1642-1653.
3. Lau, Y. H., De Andrade, P., Wu, Y., & Spring, D. R. (2015). Peptide stapling techniques based on different macrocyclisation chemistries. Chemical Society Reviews, 44(1), 91-102.