UCSF

Trichothecenes such as T2-toxin are toxic natural products produced by several species of fungi that grow on grain crops. This class of sesquiterpenes comprises over 200 family members that feature a tricyclic core with varying degrees of oxidation and further cyclization, and has received attention for their toxicity as well as their anticancer, antifungal, and immunomodulatory effects. Cellular and animal model studies support the hypothesis that their manifold biological effects arise at least in part due to inhibition of protein synthesis. Here we report a modular synthesis of the minimal trichothecene pharmacophore verrucarol, enabling straightforward structural modifications to investigate toxicity and molecular mechanisms of action. We found that while verrucarol inhibits human cytosolic protein synthesis in vitro, functionalization of the C4 and C15 alcohols is required for potent cellular toxicity in cancer cell lines and fibroblasts. We characterized the binding of verrucarol and diacetylverrucarol to the 50S subunit of the human cytosolic ribosome at 2.7 A resolution, revealing binding determinants that could not be resolved from the previous structures in yeast ribosomes. This work will enable new studies of trichothecenes required for food safety and for exploration of their use as therapeutics.