How are 1,2,3-triazoles accommodated in helical secondary structures?

Area of Science:

• Peptide chemistry and structural biology
• Medicinal chemistry and drug discovery
• Biophysical characterization of biomolecules

Background:

• 1,4-Disubstituted-1,2,3-triazole (Tz) is frequently employed as a trans-amide bond mimic in peptide research.
• However, the detrimental effects of Tz on native peptide activity and its impact on peptide secondary structures remain underexplored.
• Understanding these structural consequences is crucial for designing stable and functional peptide-based therapeutics.

Purpose of the Study:

• To systematically investigate the structural and functional consequences of incorporating 1,4-disubstituted-1,2,3-triazole (Tz) into model peptaibols.
• To elucidate how Tz substitution affects the secondary structure stability of peptides, specifically α-helices and 310 helices.
• To assess the impact of Tz insertion on the antimicrobial activity of peptaibols.

Main Methods:

• A comprehensive 'Tz scan' was conducted by systematically replacing peptide bonds with Tz in two model peptaibols: alamethicin F50/5 (α-helix) and bergofungin D (310 helix).
• Antimicrobial activity assays were performed to evaluate the functional impact of Tz incorporation.
• Structural analyses were carried out using circular dichroism (CD) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and X-ray diffraction to determine the effects on secondary structure.

Main Results:

• The insertion of Tz into the peptide sequences, regardless of its position, completely abolished the antimicrobial activity of both model peptaibols.
• Structural investigations revealed significant alterations in helical secondary structures upon Tz incorporation.
• Five crystal structures of Tz-containing peptaibols showed varying degrees of helical perturbation, ranging from minor changes to partial structural disorder.

Conclusions:

• 1,4-Disubstituted-1,2,3-triazole (Tz) incorporation significantly impairs the helical secondary structures of peptides.
• Tz substitution leads to a loss of native peptide function, specifically antimicrobial activity.
• The study highlights the structural instability introduced by Tz, cautioning against its use as a simple amide bond mimic in peptide design without thorough structural evaluation.