Project 3: Filamentous Fungi, Biological Testing

需要新的抗癌药物先导药物，特别是用于治疗耐药癌症。真菌一直是 许多药物的来源，青霉素和他汀类药物是最突出的两个例子。我们 项目3假设真菌含有抗癌药物先导物质，我们正在通过一个团队与 真菌学(MyCosynthetix，Inc./Pearce)、天然产物化学(UNG/Oberlie)和化学方面的专业知识 生物学(哥伦比亚/斯托克韦尔)。 在对来自Mycoythetix Inc.图书馆的数千种真菌培养物的检查中，项目3实施了 生物和化学议定书，以确定我们工作的优先顺序。在这样做的过程中，我们已经鉴定了数百种真菌 具有抗癌活性的代谢物，其中约三分之一是文献中新发现的。目前，我们有 将其中三个先导化合物优先用于进一步的临床前开发，我们的团队正在优化生物合成 用于药理学研究、PK/代谢和半合成的材料(以革兰氏规模生产为目标) 优化。在这三个线索中，轮枝菌素是最先进的，并获得了额外的资金，以进一步 在间皮瘤模型中检查纳米颗粒配方。 项目3还开发了在现场绘制真菌代谢物地图的方法，以便我们可以可视化相互作用 在共培养中研究真菌，目的是刺激隐秘的生物合成。产生新产品的另一个目标 化学多样性是指非天然天然产物的生物合成和/或半合成。 氟原子进入特权真菌衍生的支架中。

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.