Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Chemical Biology

Background:

• Stapled peptides are emerging as potent inhibitors of protein-protein interactions.
• Sondheimer dialkyne reagents enable strain-promoted double-click cycloadditions for peptide stapling.
• Functionalized stapled peptides offer improved biological properties but their development is limited.

Purpose of the Study:

• To synthesize novel substituted Sondheimer dialkyne variants.
• To apply these variants in creating functionalized stapled peptides targeting the p53-MDM2 interaction.
• To investigate the effect of substituents on reactivity and biological activity.

Main Methods:

• Synthesis of new Sondheimer dialkyne derivatives.
• Strain-promoted double-click cycloaddition reactions with diazido peptides.
• Preparation of p53-based stapled peptide inhibitors.
• Inhibition assays and density functional theory (DFT) calculations.

Main Results:

• Successful synthesis of novel substituted Sondheimer dialkyne reagents.
• Generation of potent stapled peptide inhibitors of the p53-MDM2 interaction.
• Identification of a meta-fluoro-substituted Sondheimer dialkyne derived stapled peptide as the most potent inhibitor.
• Elucidation of substituent effects on strain-promoted double-click reactivity via experimental and computational studies.

Conclusions:

• Substituted Sondheimer dialkynes are valuable tools for generating functionalized stapled peptides.
• The developed stapled peptides are potent inhibitors of the p53-MDM2 interaction, with therapeutic potential.
• Substituent modifications significantly influence both the reactivity and biological efficacy of Sondheimer dialkynes in peptide stapling.