Project 3: Filamentous Fungi, Biological Testing

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There is a need for new anticancer drug leads, particularly for treating drug- resistant cancers. Fungi have been the source of many drug leads, with penicillin and the statins as two of the most prominent examples. We hypothesized by Project 3 that fungi harbor anticancer drug leads, and we are addressing this via a team with expertise in mycology (Mycosynthetix, Inc./Pearce), natural products chemistry (UNCG/Oberlies), and chemical biology (Columbia/Stockwell). In the examination of thousands of fungal cultures from the Mycosythetix Inc.library, Project 3 has implemented biological and chemical protocols to prioritize our efforts. In doing so, we have identified hundreds of fungal metabolites with anticancer activity, approximately a third of which are new to the literature. Currently, we have prioritized three of these leads for further preclinical development, and our team is optimizing the biosynthesis of materials (targeting gram scale production) for pharmacology studies, PK/metabolism, and semi-synthetic optimization. Of the three leads, the verticillins are the most advanced, with additional funding procured to further examine a nanoparticle formulation in models of mesothelioma. Project 3 has also developed methods to map fungal metabolites in situ, so that we can visualize the interaction of fungi in co-culture, with the aim of stimulating cryptic biosynthesis. An additional goal for generating new chemical diversity is the biosynthesis and/or semi-synthesis of non-natural natural products, via the incorporation of fluorine atoms into the privileged fungal-derived scaffolds.