Large Macrocyclic Libraries via Thioether Cyclization

Area of Science:

• Medicinal Chemistry
• Peptide Synthesis
• Drug Discovery

Background:

• Macrocyclic peptides offer high specificity and binding affinity for drug discovery.
• Intracellular targets are often undruggable by small molecules.
• Traditional macrocycle synthesis is labor-intensive and limits scalability.

Purpose of the Study:

• To develop a streamlined protocol for synthesizing large macrocyclic peptide libraries.
• To enable high-throughput generation of macrocycles for screening.
• To facilitate the discovery of drug candidates for challenging targets.

Main Methods:

• Utilized automated solid-phase peptide synthesis (SPPS).
• Employed purification-free cyclization of linear dithiol peptides in high-throughput array formats.
• Incorporated bis-electrophilic linkers for thioether cyclization and LC-MS for quality control.

Main Results:

• Successfully generated diverse macrocyclic peptide libraries.
• Demonstrated a robust and scalable workflow.
• Enabled efficient synthesis without labor-intensive purification steps.

Conclusions:

• The developed method significantly accelerates the synthesis of macrocyclic libraries.
• This facilitates the discovery of novel drug candidates targeting difficult biomolecular interactions.
• The protocol is suitable for large-scale screening campaigns.