Stretching Peptides to Generate Small Molecule β-Strand Mimics

Area of Science:

• Chemical Biology
• Medicinal Chemistry
• Structural Biology

Background:

• Protein-protein interactions (PPIs) are crucial in disease mechanisms but difficult to target due to shallow binding surfaces.
• Existing methods for targeting PPIs are limited, especially for accessing extended backbone structures.

Purpose of the Study:

• To develop a novel method for creating rigid, extended-backbone peptide macrocycles.
• To enable the targeting of challenging protein-protein interaction (PPI) interfaces.

Main Methods:

• Incorporation of a rigid, linear diyne brace between side chains at the i to i+2 positions of peptides.
• Utilized Nuclear Magnetic Resonance (NMR) and density functional theory (DFT) for structural and conformational analysis.
• Developed a high-throughput synthesis approach for the diyne-braced peptides.

Main Results:

• Generated a family of low-molecular-weight, extended-backbone peptide macrocycles with stable, rigid conformations in solution.
• Demonstrated that the peptide conformation can be tuned to explore extended conformational space.
• Achieved excellent conversions (>95%) for diyne brace formation and showed the utility of the technique with inhibitors of bacterial type 1 signal peptidase.

Conclusions:

• The diyne brace strategy provides a versatile platform for designing conformationally constrained peptides.
• This approach facilitates the exploration of extended peptide conformational space for targeting PPIs.
• The developed peptide macrocycles hold potential for therapeutic and probe development against diseases driven by PPIs.