Natural Product HCV Drugs from Rare Plant-Microbe Interactions

来自稀有植物-微生物相互作用的天然产物 HCV 药物

• 批准号: 9230277
• 负责人: Mark T Hamann
• 金额: $ 29.81万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9230277
• 关键词: Natural; Product; HCV; Drugs; Rare

The key objective of this project involves the exploration of US rare and endangered plants and their unique host-microbiome community. These communities will be studied for their biosynthesis and production of new classes of natural products (NPs) HCV drug leads with unique MOAs. The project involves a well established collaborative relationship with the laboratories of Prof Mark Hamann and at the University of Mississippi and Tony Whitaker with RFS Pharma and Raymond Schinazi at Emory University/Atlanta VA. The collective expertise provides a unique opportunity to explore new sources for treatments for HCV which are resistant to current forms of treatment. The specific aims of this program include: 1. A collection and phylogenetic analysis of 100 endangered plant associated bacteria and fungi strains each year. Phylogenetically diverse and unique US endangered plant species (20) will be evaluated for bacteria and fungi which inhibit HCV. This will provide 500 unique bacteria and fungi over the course of the five year project period. 2. Innovative epigenetic tools will be applied to stimulate production of secondary metabolites from silent genes. These will include regulatory tools available commercially as well as those derived from the host endangered plant itself. Each new strain will be subjected to 10 or more epigenetic tools. Highly sensitive HPLC with UV-TOF-ELS detection and small volume NMR will be utilized to evaluate NP production from genes silent under standard culture conditions. 3. A unique HCV real time PCR assay is featured in this grant application as a primary screen to identify extracts obtained from Aim 2 with HCV selectivity for fractionation in aim 4. 4. Active leads from Aim 3 will be purified using HPLC with MS, UV and ELSD detection. Repeated bioassays using real time PCR will be completed until HCV selective metabolites are generated. Natural product structures will be assigned using integrated NMR, HPLC-MS, UV, IR and X-ray crystallographic analysis.

该项目的关键目标涉及探索美国稀有和濒危植物及其独特的宿主菌群社区。这些社区的生物合成和新类别的天然产品（NPS）HCV药物铅具有独特的MOAS的生物合成和生产。该项目涉及与马克·哈曼（Mark Hamann）教授以及密西西比大学和托尼·惠特克（Tony Whitaker）的实验室建立了良好的合作关系，与埃默里大学/亚特兰大弗吉尼亚州的RFS Pharma和Raymond Schinazi一起建立了合作关系。 集体专业知识为探索HCV治疗的新来源提供了一个独特的机会，HCV具有抗性治疗形式。 该计划的具体目的包括：1。每年对100种濒危植物相关细菌和真菌菌株的收集和系统发育分析。 将对抑制HCV的细菌和真菌进行系统发育多样和独特的美国濒危植物物种（20）。 在五年项目期间，这将提供500种独特的细菌和真菌。 2。将应用创新的表观遗传工具来刺激无声基因的二级代谢产物的产生。 这些将包括商业上可用的监管工具，以及从寄托濒临灭绝的植物本身衍生的工具。 每种新菌株将受到10个或更多的表观遗传工具。 具有UV-TOF-ELS检测的高度敏感的HPLC和小体积NMR将用于评估标准培养条件下沉默的基因的NP产生。 3。在本赠款应用程序中介绍了独特的HCV实时PCR分析作为主要屏幕，以识别AIM 2从AIM 4中获得的AIM 2获得的提取物，以分级为AIM4。4。AIM3中的主动铅将使用MS，UV和ELSD检测的HPLC使用HPLC纯化。 使用实时PCR的重复生物测定将完成，直到生成HCV选择性代谢物为止。 天然产品结构将使用集成的NMR，HPLC-MS，UV，IR和X射线晶体学分析分配。