PinA and XYP1 Peptides Strongly Bind Candida albicans Membranes, Inhibiting Fungal Growth

Multidrug-resistant strains of Candida albicans (C. albicans) pose a significant clinical challenge, leading to high mortality, particularly in intensive care units where biofilm formation complicates treatment. Current antifungal treatments are often ineffective against these resistant pathogens. Antifungal peptides (AFPs) offer a promising alternative due to their high efficacy, low toxicity, and reduced risk of resistance development. This study explores novel AFPs specifically targeting the fungal membrane, a crucial mechanism for antifungal action, to address this unmet medical need.

Researchers integrated computational modeling with experimental validation to identify novel AFPs. Four candidate peptides—HIV-F9170 (GWEALKYLWNLLQYW), PinA (WRWWKWWK), PinB (WPTKWWK), and XYP1 (KIKWFKAMKSIAKFIAKDQLKKHL)—were evaluated. AlphaFold2 was used for structure prediction, followed by molecular dynamics (MD) simulations to assess their binding and interaction stability with a model C. albicans membrane. Subsequently, in vitro antifungal assays were performed to confirm their efficacy in inhibiting fungal growth, and cytotoxicity was assessed against HEK-293 cells.

Molecular dynamics (MD) simulations revealed distinct binding profiles for the candidate peptides.

PinA and XYP1 demonstrated strong binding and stable interactions with the model C. albicans membrane, suggesting a robust mechanism of action. In contrast, HIV-F9170 and PinB did not show comparable binding affinity or stability in the simulations. Correspondingly, in vitro antifungal assays confirmed that only PinA and XYP1 effectively inhibited C. albicans fungal growth. Crucially, these two active peptides exhibited no cytotoxicity toward HEK-293 cells, indicating a favorable safety profile. These findings provide a mechanistic basis for the observed antifungal activity, linking specific membrane interaction to biological efficacy.