Macrocyclization strategies for cyclic peptides and peptidomimetics

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Biotechnology

Background:

• Peptides are a promising therapeutic class targeting challenging protein-protein interactions.
• Peptides face limitations like conformational flexibility and proteolytic degradation.
• Macrocyclization offers a strategy to enhance peptide stability and drug-like properties.

Purpose of the Study:

• To review and summarize current macrocyclization chemistries for peptide drug development.
• To provide an overview of methods applicable to solution-phase and solid-phase synthesis.
• To highlight cyclization reactions compatible with modern peptide screening techniques.

Main Methods:

• Review of established and emerging macrocyclization techniques.
• Categorization of chemistries based on resulting functional groups.
• Focus on reactions suitable for solution and solid-phase synthesis.
• Consideration of compatibility with high-throughput screening.

Main Results:

• Lactam formation, azide-alkyne cycloadditions, and ring-closing metathesis are key strategies.
• Unconventional cyclization reactions offer alternative approaches.
• The review categorizes methods by functional group and synthetic applicability.
• Emphasis on methods suitable for contemporary peptide screening.

Conclusions:

• Macrocyclization is crucial for overcoming peptide limitations in drug development.
• A diverse range of synthetic chemistries are available for peptide macrocyclization.
• Selection of appropriate chemistry depends on desired functional groups and screening compatibility.