The Plant Defensin Ppdef1 Is a Novel Topical Treatment for Onychomycosis

Abstract

Onychomycosis, or fungal nail infection, causes not only pain and discomfort but can also have psychological and social consequences for the patient. Treatment of onychomycosis is complicated by the location of the infection under the nail plate, meaning that antifungal molecules must either penetrate the nail or be applied systemically. Currently, available treatments are limited by their poor nail penetration for topical products or their potential toxicity for systemic products. Plant defensins with potent antifungal activity have the potential to be safe and effective treatments for fungal infections in humans. The cystine-stabilized structure of plant defensins makes them stable to the extremes of pH and temperature as well as digestion by proteases. Here, we describe a novel plant defensin, Ppdef1, as a peptide for the treatment of fungal nail infections. Ppdef1 has potent, fungicidal activity against a range of human fungal pathogens, including Candida spp., Cryptococcus spp., dermatophytes, and non-dermatophytic moulds. In particular, Ppdef1 has excellent activity against dermatophytes that infect skin and nails, including the major etiological agent of onychomycosis Trichophyton rubrum. Ppdef1 also penetrates human nails rapidly and efficiently, making it an excellent candidate for a novel topical treatment of onychomycosis.

Fighting pathogenic yeasts with plant defensins and anti-fungal proteins from fungi

“…The other three plant defensins shown in Fig. 1 A, which are Ppdef1 from Picramnia pentandra , the rice OsAFP1, and the maize ZmD32, were identified in data mining in in silico approaches and produced recombinantly (Kerenga et al 2019 ; Ochiai et al 2018 ; van der Weerden et al 2023 ). In Fig.…”

“…1 Sequence and structure of plant defensins and fungal AFPs. A Alignment of the sequence of the plant defensins NaD1 (UniProt ID: Q8GTM0), OsAFP1 (Q6K209), ZmD32 (B6SJE6), PsD1 (P81929), DmAMP1 (P0C8Y4), RsAFP2 (P30230), and Ppdef1 (van der Weerden et al 2023 ). B Alignment of the sequence of the fungal AFPs PAF (B6HWK0), PeAfpA (A0A0A2K8K6), PAFB (D0EXD3), PAFC (B6HMF2), and NFAP2 (A0A1D0CRT2).…”

“…Additionally to RsAFP2, RsAFP1 and HsAFP1 were also shown to reduce the biofilm-forming capability of C. albicans (Vriens et al 2016 , 2015 ). Defensins able to inhibit the growth of both yeast species are DmAMP1 (Bleackley et al 2019 ; Thevissen et al 2004 ), NaD1 (Bleackley et al 2014 ; Hayes et al 2013 ), OsAFP1 (Ochiai et al 2018 ), and Ppdef1 (Parisi et al 2024 ; van der Weerden et al 2023 ).…”

“…Cysteine disulfide bonds are shown in yellow, basic amino acids in blue, and acid amino acids in red. The location of the N-terminus, C-terminus, and the γ-motifs is indicated 2019; Ochiai et al 2018;van der Weerden et al 2023). In Fig.…”

“…Some of them are potent anti-yeast agents against the model fungus Saccharomyces cerevisiae or even against life-threatening Candida species. Overall, plant defensins and AFPs show a multi-target mechanism of action different from those of the traditional anti-fungals, making fungal isolates less likely to overcome their inhibitory action and, therefore, limiting the appearance of acquired resistance (Thevissen et al 2007;van der Weerden et al 2023). This review will focus on plant defensins and AFPs active against Candida spp.…”