Synthesis of the Antifungal and Antiviral Cyclic Lipodepsipeptides Verlamelins A and B

Fungal infections and the growing threat of antifungal resistance present significant challenges to both public health and food safety worldwide. Cross-resistance is a particular concern when agricultural fungicides, such as widely used triazoles, share chemical structures with human antifungal agents, potentially reducing their therapeutic efficacy. In response, cyclic depsipeptides, verlamelin A and its demethylated derivative verlamelin B, have emerged as promising alternatives. These compounds exhibit potent antifungal activity against several key phytopathogenic fungi, such as Magnaporthe grisea, Bipolaris maydis, and Botrytis cinerea, with efficacy comparable to established antifungal agents like ketoconazole and amphotericin B, and exhibit antiviral effects against herpes simplex virus type 1 (HSV-1). Herein, we report the first total synthesis of verlamelins A and B via solid-phase peptide synthesis (SPPS) followed by late-stage solution-phase macrolactamization.