Peptide Macrocyclization Inspired by Non-Ribosomal Imine Natural Products

Area of Science:

• Chemical Synthesis
• Organic Chemistry
• Biochemistry

Background:

• Peptide macrocyclization is crucial for developing therapeutics and understanding biological processes.
• Existing methods often require protecting groups and harsh conditions, limiting scope and efficiency.

Purpose of the Study:

• To develop a versatile and efficient thermodynamic approach for peptide macrocyclization.
• To access structurally diverse macrocycles, including natural product analogues and peptides with non-native motifs.

Main Methods:

• Exploiting the reactivity of transient macrocyclic peptide imines toward nucleophiles.
• Performing reactions in aqueous media under mild conditions, without side chain protecting groups.
• Utilizing variable-temperature NMR and circular dichroism for structural analysis.

Main Results:

• Successful synthesis of structurally diverse macrocyclic peptides, including analogues of natural products.
• Demonstrated tolerance of all proteinogenic functional groups and compatibility with aqueous media.
• Preparation of macrocycles with non-native motifs, isotopic labels, and bioorthogonal handles.

Conclusions:

• The developed thermodynamic approach offers a powerful and general strategy for peptide macrocyclization.
• Preorganization of linear peptide substrates is not essential for successful macrocyclization.
• The method facilitates the synthesis of complex cyclic peptides under environmentally friendly conditions.