Variable-Length Ester-Based Staples for α-Helical Peptides by Using A Double Thiol-ene Reaction.

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Organic Synthesis

Background:

• Alpha-helical peptides are important for targeting intracellular proteins but often lack cell permeability.
• Developing methods to enhance peptide stability and cell penetration is crucial for drug discovery.

Purpose of the Study:

• To report a novel peptide stapling method utilizing a double thiol-ene reaction.
• To synthesize stapled peptides with enhanced cell permeability and improved alpha-helicity.
• To demonstrate the utility of this method for targeting intracellular proteins.

Main Methods:

• A double thiol-ene reaction between cysteine residues and a divinyl diester was employed for peptide stapling.
• The method allowed for facile synthesis of stapled peptides with varying bridge lengths.
• Stapled Axin mimetics and SIGK peptide analogues were synthesized and characterized.

Main Results:

• The novel peptide stapling method successfully produced stapled peptides with enhanced cell permeability.
• Stapled Axin mimetics showed improved alpha-helicity compared to unstapled versions.
• Cell-penetrating stapled SIGK peptide analogues exhibited moderate increases in alpha-helicity and were cell permeable.

Conclusions:

• The reported chemoselective peptide stapling method is a versatile tool for modifying synthetic alpha-helical peptides.
• This technique facilitates the development of stapled peptides for targeting intracellular protein-protein interactions.
• The method offers a facile approach to enhance the therapeutic potential of alpha-helical peptides.