Antifungal activity of rationally designed γ-core peptide derivatives of ascomycetous antifungal proteins

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In recent years, the incidence of infections caused by human pathogenic fungi has significantly increased, primarily because of the rapid spread of resistance to antifungal agents commonly used in clinical settings. Consequently, the World Health Organization has urged the use of antifungal therapies based on fundamentally novel molecules in clinical practice. In this regard, synthetic peptides (γAFPs) designed on the basis of the evolutionarily conserved γ-core motifs of antifungal proteins (GXC-X3-9-C) originating from Eurotiomycetes represent promising candidates. In this study, we investigated 19 γAFPs with diverse fungal origins and varying physicochemical properties. The in vitro antifungal efficacy of these agents was determined by the overall positive net charge and hydrophilicity and strongly influenced by the net charge-to-hydropathy ratio. Specifically, γAFPs with a moderately positive net charge tend to be more hydrophilic, which could enhance their antifungal efficacy. Regarding the most effective γAFPs, we demonstrated that their antifungal activity is exerted through plasma membrane disruption, and these treatments can engage in synergistic in vitro interactions with conventional antifungal drugs (terbinafine and fluconazole) that interfere with plasma membrane biosynthesis. Using the Galleria mellonella larval infection model, we verified that these potent γAFPs can prevent Candida albicans infection or prolong larval survival in Aspergillus fumigatus infection, and the observed in vitro synergistic interactions also appeared under this in vivo condition. These findings underscore the potential applicability of certain γAFPs as standalone or adjuvant therapeutic agents in the treatment of systemic and superficial fungal infections. Keywords antifungal peptide, γ-core

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