Project 3: Filamentous Fungi, Biological Testing

项目3：丝状真菌，生物检测

• 批准号: 10621882
• 负责人: NICHOLAS H. OBERLIES
• 金额: $ 29.86万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621882
• 关键词: Address; Anabolism; Antineoplastic Agents; Biological; Biological Assay; Biological Testing; Biology; Cell Death; Cells; Chemicals; Chemistry; Clinic; Coculture Techniques; Collaborations; Databases; Development; Dose; Drug Kinetics; Drug resistance; Evaluation; Fermentation; Fluorine; Formulation; Funding; Generations; Goals; Imidazole; In Situ; Ketones; Laboratories; Lead; Libraries; Literature; Maps; Mesothelioma; Metabolism; Methods; Mission; Modeling; Molds; Natural Products; Natural Products Chemistry; Nature; North Carolina; Penicillins; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology Study; Preclinical Drug Development; Process; Production; Protocols documentation; Research; Research Personnel; Resources; Sampling; Scientist; Source; Stress; Structure; Structure-Activity Relationship; Techniques; Testing; The science of Mycology; Time; Translating; Translations; Universities; Visualization; Work; analog; anti-cancer; anticancer activity; cancer cell; cancer therapy; drug discovery; erastin; fungus; in vivo; innovation; interest; nanoparticle; novel; novel anticancer drug; preclinical development; programs; refractory cancer; scaffold; scale up; skills; success; synergism; tool

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.

需要新的抗癌药物先导物，特别是用于治疗耐药性癌症。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假设真菌携带抗癌药物线索，我们正在通过一个团队解决这个问题， 真菌学专业知识（Mycosynthetix，Inc./皮尔斯）、天然产物化学（UNCG/Oberlies）和化学 生物学（哥伦比亚/斯托克韦尔）。 在对Mycosythetix Inc.图书馆的数千种真菌培养物的检查中，项目3已经实施， 生物和化学协议来确定我们的工作重点在这样做的过程中，我们已经确定了数百种真菌 具有抗癌活性的代谢物，其中约三分之一是新的文献。目前已经 优先考虑这些线索中的三个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（目标克规模生产） 优化.在这三个线索中，verticillins是最先进的，获得了额外的资金，以进一步 检查间皮瘤模型中的纳米颗粒制剂。 项目3还开发了原位绘制真菌代谢物的方法，这样我们就可以可视化相互作用 真菌的共培养，目的是刺激隐蔽的生物合成。另一个目标是产生新的 化学多样性是非天然天然产物的生物合成和/或半合成， 将氟原子注入特权的真菌衍生支架中。