Macrocyclisation of small peptides enabled by oxetane incorporation

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Biochemistry

Background:

• Cyclic peptides are vital drug candidates but face synthetic challenges.
• Efficient synthesis of cyclic peptides is crucial for drug discovery and development.

Purpose of the Study:

• To investigate the impact of replacing backbone amide C=O bonds with oxetane rings on peptide macrocyclization.
• To explore oxetane incorporation as a strategy to improve synthetic yields and rates of cyclic peptide formation.

Main Methods:

• Standard solution- and solid-phase peptide synthesis techniques were employed.
• Head-to-tail macrocyclizations were performed with oxetane-modified precursors.
• NMR spectroscopy and molecular dynamics simulations were used to analyze conformational changes.
• Inhibition assays were conducted to assess the bioactivity of oxetane-modified peptide inhibitors.

Main Results:

• Oxetane ring incorporation significantly improved macrocyclization yields, reaction rates, and product distribution.
• The oxetane modification was found to be superior to N-methylation for enhancing cyclization efficiency.
• Experimental evidence confirmed that oxetane modification induces a turn in linear peptide backbones.
• Conformational analysis revealed reduced flexibility and a new intramolecular H-bond near the oxetane.
• An oxetane-modified peptide inhibitor of Aminopeptidase N retained bioactivity.

Conclusions:

• Replacing amide C=O bonds with oxetane rings is a powerful strategy for enhancing cyclic peptide synthesis.
• Oxetane modification offers a promising route to overcome synthetic hurdles in developing cyclic peptide-based therapeutics.
• This approach facilitates the synthesis of challenging macrocyclic peptides and maintains their biological activity.