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Landscaping macrocyclic peptides: stapling hDM2-binding peptides for helicity, protein affinity, proteolytic
Aline D de Araujo1, Junxian Lim1, Kai-Chen Wu1
1Division of Chemistry and Structural Biology, ARC Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, The University of Queensland Brisbane QLD 4072 Australia d.fairlie@uq.edu.au.
This study explores how different cyclic peptide structures affect their ability to target proteins. Rigid cyclic peptides show improved helicity, binding, and stability, but cell uptake depends on hydrophobicity and aromaticity.
Area of Science:
- Medicinal Chemistry
- Peptide Therapeutics
- Structural Biology
Background:
- Cyclic peptides are promising for modulating protein-protein interactions.
- Effective delivery of cyclic peptides to intracellular targets remains a challenge.
- Stabilizing peptide structure is key for therapeutic potential.
Purpose of the Study:
- To systematically compare helix-inducing cyclization constraints on peptide properties.
- To evaluate the impact of macrocycle structure on helicity, binding, stability, and cell uptake.
- To optimize cyclic peptide design for therapeutic applications.
Main Methods:
- Systematic variation of cyclization constraints (e.g., hydrocarbon, lactam, thioether).
- Modification of linker position (i to i+4 or i to i+7 bridges).
- Assessment of alpha-helicity, protein-binding affinity, protease resistance, and cell uptake.
Main Results:
- Rigidifying the macrocycle enhanced alpha-helicity, target affinity, and proteolytic stability.
- The extent of improvement varied depending on the specific constraint used.
- Cell uptake was primarily influenced by the hydrophobicity and aromaticity of the macrocycle.
Conclusions:
- Cyclization constraints significantly impact the biophysical and cellular properties of cyclic peptides.
- Structural rigidity is crucial for enhancing therapeutic potential, but cell permeability requires specific physicochemical properties.
- Tailoring macrocycle characteristics is essential for developing effective cyclic peptide drugs.
