Design of Proteolytic-Resistant Antifungal Peptides by Utilizing Minimum d‑Amino Acid Ratios

Antifungal peptides are an appealing alternative to standard
antifungal
medicines due to their unique mechanism of action and low-level resistance.
However, their susceptibility to protease degradation keeps hindering
their future development. Herein, a library was established to design
peptides with protease resistance and high antifungal activity. The
peptides were incorporated with minimal D-amino acids to further improve
the protease stability. The most active peptide, IR3, demonstrated
good antifungal activity and low toxicity, and its molecular integrity
was maintained after protease hydrolysis for 8 h at 2 mg/mL. Furthermore,
IR3 could permeate the fungal cell wall, disrupt the cell membrane,
produce reactive oxygen species, and induce apoptosis in fungal cells. In vivo experiments confirmed that IR3 could effectively
treat fungal keratitis. Collectively, these findings suggest that
IR3 is a promising antifungal agent and may be beneficial in the design
and development of protease-resistant antifungal peptides.