APPROACHES TO CHARACTERIZATION OF ANTIINFECTIVE AGENTS

抗感染剂的表征方法

• 批准号: 2886084
• 负责人: Mark T Hamann
• 金额: $ 6.74万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2886084
• 关键词: HIV infections; Porifera; Tunicata; X ray crystallography; algae; antifungal agents; antiinfective agents; antimalarial agents; antiprotozoal agents; antiviral agents; chemical structure function; communicable diseases; coral; cytotoxicity; drug discovery /isolation; drug screening /evaluation; enzyme inhibitors; high performance liquid chromatography; mass spectrometry; microorganism disease chemotherapy; nuclear magnetic resonance spectroscopy; opportunistic infections; saltwater environment

The primary focus of this project is the isolation and characterization of new chemotypes for the treatment of infectious diseases. This includes research involving the development of instrumentation for the rapid and thorough analysis of bioactive organic compounds in complex biological mixtures. Our goal is to integrate the most powerful tools available for the purification and structure determination of organic materials into a single system while being able to recover nearly 95 percent of the purified sample for biological evaluation. The most promising metabolites will be studied for structure-activity relationships (SAR) using semi-synthesis, microbial transformations and molecular modeling. Natural product research during the last few decades has yielded thousands of novel organic compounds from the marine environment. The bioassays guiding these isolations typically have been antimicrobial, antitumor, antiviral or antiinflammatory. Little has been done to explore the oceans for compounds with activity against HIV, AIDS OI, TB and other infectious diseases. Additionally, because of the limits associated with the conventional self-contained underwater breathing apparatus (SCUBA), the majority of the compounds characterized from the marine environment are the results of shallow water collections (-30m). Dr. Michael Boyd, of the Laboratory of Drug Discovery Research and Development at the National Cancer Institute indicates that mass screening has proved to be the most effective means of discovering entirely new chemotypes not even suspected to have relevant biochemical properties. The objective of this proposed research program is to collect and screen marine samples for possible treatments of HIV and AIDS OI from depths and locations in the ocean which have remained unexplored. The active component(s) of those extracts showing promising activity will be isolated using preparative and semi-preparative high pressure liquid chromatography (HPLC) interfaced with NMR and FTMS. The chemical structures of the biologically active secondary metabolites will be determined with the use of LC-NMR-FTMS and 2D NMR. Methods for providing sufficient quantities for in vivo testing via synthesis, semi-synthesis or reisolation will be addressed for promising compounds. SAR studies will be conducted utilizing chemical and microbial transformations of biologically active secondary metabolites combined with molecular modeling studies.

该项目的主要重点是用于治疗传染病的新化学型的分离和表征。 这包括涉及开发仪器的研究，用于快速、彻底地分析复杂生物混合物中的生物活性有机化合物。 我们的目标是将可用于有机材料纯化和结构测定的最强大工具集成到单个系统中，同时能够回收近 95% 的纯化样品用于生物评估。 将利用半合成、微生物转化和分子建模来研究最有前途的代谢物的构效关系（SAR）。过去几十年的天然产物研究已经从海洋环境中产生了数千种新型有机化合物。指导这些分离的生物测定通常是抗菌、抗肿瘤、抗病毒或抗炎的。 在海洋中探索具有抗艾滋病毒、艾滋病性骨关节炎、结核病和其他传染病活性的化合物的努力还很少。此外，由于传统自给式水下呼吸器 (SCUBA) 的限制，海洋环境中表征的大多数化合物都是浅水收集 (-30m) 的结果。美国国家癌症研究所药物发现研究与开发实验室的迈克尔·博伊德博士表示，大规模筛选已被证明是发现全新化学型的最有效方法，甚至不被怀疑具有相关的生化特性。 该拟议研究计划的目标是从尚未探索的海洋深度和地点收集和筛选海洋样本，以寻找可能治疗艾滋病毒和艾滋病成骨不全症的方法。这些具有良好活性的提取物的活性成分将使用与 NMR 和 FTMS 接口的制备型和半制备型高压液相色谱 (HPLC) 进行分离。 生物活性次生代谢物的化学结构将通过 LC-NMR-FTMS 和 2D NMR 确定。通过合成、半合成或再分离为体内测试提供足够数量的方法将针对有前景的化合物进行研究。 SAR 研究将利用生物活性次生代谢物的化学和微生物转化以及分子建模研究来进行。