Hydrophobicity and helicity regulate the antifungal activity of 14-helical β-peptides

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Candida albicans is a major fungal pathogen causing candidiasis and candidemia.
• Antimicrobial peptides (AMPs) show antifungal potential but lack pharmaceutical efficacy due to low activity and selectivity.
• Alpha-peptide AMPs offer design insights for stable structures, like 14-helical beta-peptides.

Purpose of the Study:

• To investigate how hydrophobicity and helicity influence the antifungal activity and selectivity of 14-helical beta-peptides against Candida albicans.
• To determine the correlation between these structural features and hemolysis against human red blood cells.
• To identify design criteria for potent and selective antifungal agents.

Main Methods:

• Synthesized and characterized 14-helical beta-peptides with varying hydrophobicity and helical structure-forming propensity.
• Assayed antifungal activity against Candida albicans.
• Assessed hemolytic activity against human red blood cells.

Main Results:

• Both antifungal activity and hemolysis correlated with hydrophobicity.
• Intermediate hydrophobicity yielded high antifungal activity and selectivity for Candida albicans.
• Enhanced helical structure stability broadened the selective antifungal activity window across hydrophobicity levels.
• Cooperative effects between hydrophobicity and helicity were observed in regulating activity and specificity.

Conclusions:

• Hydrophobicity and helicity are critical determinants of 14-helical beta-peptide antifungal activity and selectivity.
• Optimizing these features can lead to potent and selective antifungal agents.
• Findings provide a framework for designing novel antimicrobial peptides against Candida albicans.