Synthesis, Structure, and Activity of the Antifungal Plant Defensin PvD₁

Available treatments for invasive fungal infections have limitations, including toxicity and the emergence of resistant strains. Therefore, there is an urgent need for alternative solutions. Because of their unique mode of action and high selectivity, plant defensins (PDs) are worthy therapeutic candidates. Chemical synthesis remains a preferred method for the production of many peptide-based therapeutics. Given the relatively long sequence of PDs, as well as their complicated posttranslational modifications, the synthetic route can be considered challenging. Here, we describe a total synthesis of PvD₁, the defensin from the common bean Phaseolus vulgaris. Analytical, structural, and functional characterization revealed that both natural and synthetic peptides fold into a canonical CSαβ motif stabilized by conserved disulfide bonds. Moreover, synthetic PvD₁ retained the biological activity against four different Candida species and showed no toxicity in vivo. Adding the high resistance of synthetic PvD₁ to proteolytic degradation, we claim that conditions are now met to consider PDs druggable biologicals.