Native Peptide Cyclization, Sequential Chemoselective Amidation in Water.

Area of Science:

• Chemical Synthesis
• Medicinal Chemistry
• Biochemistry

Background:

• Peptide and protein structural modification via chemical synthesis is challenging due to difficulties in selective side chain and terminus modification.
• Direct alpha-peptide ligation without premodification, especially with all proteinogenic amino acids, remains a significant hurdle in peptide synthesis.

Purpose of the Study:

• To introduce Native Peptide Cyclization (NPC), a novel chemoselective method for intramolecular peptidyl ligation.
• To enable direct cyclization of unprotected linear peptides without prior modification.
• To simplify peptide ligation for efficient cyclic peptide preparation and therapeutic applications.

Main Methods:

• Native Peptide Cyclization (NPC) utilizes controlled, sequential C- and N-terminal activation through pH modulation.
• The method operates in an aqueous environment, simplifying the ligation process.
• NPC allows for the direct cyclization of unprotected linear peptides.

Main Results:

• NPC achieves chemoselective intramolecular peptidyl ligation without requiring peptide premodification.
• The method successfully cyclizes unprotected linear peptides, including those with all proteinogenic amino acids at the ligation site.
• NPC simplifies the labor-intensive nature of traditional peptide synthesis.

Conclusions:

• Native Peptide Cyclization (NPC) offers a simplified and efficient approach to cyclic peptide preparation.
• This water-based method reduces the complexity and labor associated with peptide ligation.
• NPC enables cost-effective production of macrocycle-based therapeutics.