Conformationally constrained cyclic grafted peptidomimetics targeting protein-protein interactions

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Sunflower trypsin inhibitor-1 (SFTI-1) is a scaffold for designing therapeutic peptides.
• Grafted peptides often adopt multiple conformations due to proline residues, limiting their therapeutic potential.
• Stabilizing peptide conformation is key for developing effective drug candidates.

Purpose of the Study:

• To stabilize a grafted SFTI-1 peptide into a major conformation using a dibenzofuran (DBF) moiety.
• To investigate the structural and binding properties of the SFTI-DBF peptide.
• To explore the sequence-dependent nature of conformational constraints in SFTI-1 grafting.

Main Methods:

• Incorporation of a dibenzofuran moiety into the peptide backbone, replacing a Pro-Pro sequence.
• Nuclear Magnetic Resonance (NMR) spectroscopy to determine peptide conformation in solution.
• Surface Plasmon Resonance (SPR) analysis to assess binding affinity to CD58 protein.
• Molecular docking studies to model protein-peptide complex formation.

Main Results:

• The SFTI-DBF peptide adopted a single, major conformation in solution, characterized as a twisted beta-strand.
• SFTI-DBF demonstrated binding to the CD58 protein.
• A protein-SFTI-DBF complex model was successfully generated.
• A similar grafting strategy on a different peptide failed to yield a stable conformation and resulted in loss of biological activity.

Conclusions:

• Grafting organic moieties like DBF can stabilize SFTI-1 peptides into specific conformations for therapeutic applications.
• The success of conformational stabilization and retention of biological activity is sequence-dependent.
• This study highlights the potential of SFTI-1 as a scaffold for designing stable, functional therapeutic peptides.