Derivatisable Cyanobactin Analogues: A Semisynthetic Approach

Area of Science:

• Biochemistry
• Organic Chemistry
• Medicinal Chemistry

Background:

• Natural cyclic peptides exhibit potent biological activities, making them attractive therapeutic leads.
• Challenges include limited availability, undefined targets, and difficulties in chemical diversification for property optimization.

Purpose of the Study:

• To utilize cyanobactin family enzymes for heterocyclization and macrocyclization of chemically synthesized peptide substrates.
• To enable larger-scale synthesis and controlled derivatization of cyclic peptides for drug discovery.

Main Methods:

• Chemically synthesized peptide substrates with orthogonal reactive groups (azide, dehydroalanine) were employed.
• Enzymatic cyclization using cyanobactin enzymes was performed on these unnatural substrates.
• Chemical diversification, including fluorescent labeling, was achieved using the introduced reactive groups.

Main Results:

• Enzymes demonstrated compatibility and efficiency with unnatural substrates containing azide or dehydroalanine.
• Scalable synthesis of cyclic peptides with orthogonal handles was achieved.
• Fluorescent labeling enabled potential target identification strategies.

Conclusions:

• The combination of chemical synthesis and enzymatic transformation offers a powerful strategy for cyclic peptide drug discovery.
• This approach can overcome limitations associated with natural cyclic peptides, renewing interest in their therapeutic potential.
• Unnatural cyclic peptide analogues can be readily generated and investigated as novel therapeutics.