Rational Activity Improvement of Cyclic Peptides through Stabilization and Rigidification of Main Chain Using φ/ψ...

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Medium-sized cyclic peptides are promising therapeutics for targeting protein-protein interactions.
• Rigidifying peptide conformation can enhance therapeutic activity by reducing flexibility.

Purpose of the Study:

• To develop a computational method for rational peptide rigidification.
• To optimize the main chain structure of medium-sized cyclic peptides for drug discovery.

Main Methods:

• Classified 36 types of alpha-amino acids and computed their free energy maps and torsional entropy.
• Analyzed X-ray crystallographic data of peptide AP0343 against computed maps.
• Validated the method by derivatizing AP0343 to the KRAS inhibitor LUNA18.

Main Results:

• Demonstrated rational main chain rigidification is achievable.
• Confirmed the utility of the method in a drug discovery project.
• Successfully optimized a peptide structure for a clinical KRAS inhibitor.

Conclusions:

• The developed method effectively optimizes main chain structures of cyclic peptides.
• This approach advances the development of orally available medium-sized cyclic peptides.
• Enables rational design for enhancing peptide drug efficacy and stability.