Pezadeftide Mode of Action
Hexima is proud to present new data describing the unique mechanism of action of pezadeftide as a potent antifungal peptide. The abstract is below along with a link to the poster.
Pezadeftide is a potent antifungal peptide with rapid fungicidal activity via a unique mechanism of action
Van der Weerden N.L.¹ ², McKenna, J.² , Parisi K.² , Hayes, B.M.² , Bleackley M.R.² , and Aldridge, M.L.¹ , Welburn, P.J ¹ ,
Anderson M.A.¹ ²
¹ Hexima Limited, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
² La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
Background: Fungal infections of skin, hair and nails are extremely common and can be caused by a broad range of fungal pathogens including dermatophytes, yeasts, and non-dermatophytic molds. Pezadeftide is a plant defensin peptide with potent fungicidal activity against a range of fungal pathogens that cause skin and nail infections, including Trichophyton spp., Candida spp, and a range of non-dermatophytic molds. Pezadeftide is currently in development as a new topical treatment for onychomycosis.
Methods: The activity of pezadeftide against a range of fungal pathogens was tested using the microbroth dilution method to determine the Minimal Inhibitory Concentration (MIC) and Minimal Fungicidal Concentration (MFC). Fluorescent dyes were employed to assess the effect of pezadeftide on various cellular components. To identify potential targets for pezadeftide, a yeast deletion library was screened for fitness in the presence of low concentrations of pezadeftide.
Results: Pezadeftide has potent antifungal activity across a broad range of fungal pathogens that cause dermatophytic infections. Pezadeftide inhibits growth at low micromolar concentrations and is fungicidal at similar concentrations, suggesting that its primary mode-of-action is fungicidal. Pezadeftide rapidly enters fungal cells and causes a rapid mitochondrial response that results in hyperpolarization of the mitochondrial membrane. Fusion of the vacuoles and production of reactive oxygen species are observed prior to disruption of the plasma membrane and cell death.
Conclusions: Pezadeftide is a potent, broad-spectrum antifungal with a fungicidal mode-of-action. It rapidly kills fungal cells via interaction with the mitochondria, hyperpolarisation of the mitochondrial membrane and production of reactive oxygen species.