Project 3: Filamentous Fungi, Biological Testing

项目3：丝状真菌，生物检测

• 批准号: 10410426
• 负责人: NICHOLAS H. OBERLIES
• 金额: $ 26.79万
• 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/10410426
• 关键词: Address; Anabolism; Antineoplastic Agents; Biological; Biological Assay; Biological Testing; Biology; Cell Death; Cells; Chemicals; Chemistry; Clinic; Coculture Techniques; Databases; Development; Dose; Drug Kinetics; Drug resistance; Evaluation; Fermentation; Fluorine; Formulation; Funding; Generations; Goals; Imidazole; In Situ; Institutes; 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; Work; analog; anti-cancer; anticancer activity; base; 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; 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，特别是治疗耐药癌症的先导物。真菌已经被