In Situ Natural Product Labeling and Applications

原位天然产品标签和应用

• 批准号: 8955368
• 负责人: Wenjun Zhang
• 金额: $ 235.5万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8955368
• 关键词: Accounting; Address; Anabolism; Antibiotics; Antineoplastic Agents; Award; Biological Factors; Biology; Chemicals; Chemistry; Complex; Creativeness; Development; Drug usage; Engineering; Enzymatic Biochemistry; Enzymes; Family; Future; Health; Human; Imagery; In Situ; Label; Marketing; Medicine; Methods; Modern Medicine; Modification; Natural Product Drug; Organism; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Preclinical Drug Evaluation; Product Labeling; Production; Property; Protein Engineering; Research; Research Personnel; Research Project Grants; Research Proposals; Source; Therapeutic; analog; base; combinatorial; drug development; drug discovery; high throughput screening; improved; innovation; innovative technologies; novel; novel strategies; public health relevance; scaffold; screening; success; synthetic biology; tool

 DESCRIPTION (provided by applicant): Natural products and their derivatives have been rich sources for drug discovery; it has been estimated that more than 60% of the drugs that are in the market derive from natural sources. However, during the last three decades, research aimed at exploiting natural products for drug discovery has seriously declined, in part due to our limite capability in new natural product discovery and analogue production. Innovative technology for natural product purification, quantification, overproduction, and diversification is urgently neede to make a paradigm shift in the field of natural product research and to promote natural product-based drug discovery and development. As tagging natural products can address these challenging aspects of natural product research, this proposal seeks to develop a novel strategy that overcomes the limitations of known methods for tagging natural products with a bioorthogonal functionality. To this end, we will explore the unusual synthetic biology that living systems offer for bioorthogonal functionalities and develop general platforms for the in situ labeling of natural products, particularly complex natural products that are difficult to be synthesized or derivatized chemically. The success of this strategy will directly produce orthogonally functionalized natural product analogues that can be subjected to facile chemical modification for drug screening. More importantly, tagging natural products with a unique chemical handle will enable the visualization, enrichment, quantification, and mode of action study of natural products through bioorthogonal chemistry, and thus have a profound impact on our ability to address challenging questions in natural product biosynthesis, biology, and pharmacology. In addition, a novel natural product-based, quantitative, high-throughput screening method based on this tagging strategy is proposed here as a useful tool for evolving natural product biosynthetic enzymes that can efficiently function in specific pathways to produce natural product analogues in high titers. This screening method will be leveraged to understand and engineer the biosynthesis of several important families of natural products for new antibiotic and anticancer drug discovery. The proposed interdisciplinary project bridges multiple innovations in natural product biosynthesis, protein engineering, and bioorthogonal chemistry, and if successful, will vastly expand the natural product research toolkit and have broad impact in enzymology, biosynthesis, and medicine. It is therefore uniquely suited to the New Innovator Award with respect to its significance, novelty, and the investigator's record of innovativeness and creativity. This project has minimal overlap with other efforts in the research group, while providing good synergy with various research projects and fitting perfectly in one of our main research themes: to harness the power of enzymes towards the biosynthesis of natural products with ultimate applications in advancing human health.

 描述（由适用提供）：天然产品及其衍生物是药物发现的丰富来源；据估计，市场中有超过60％的药物来自自然来源。但是，在过去的三十年中，旨在利用天然产品进行药物发现的研究严重下降，部分原因是我们在新的天然产品发现和模拟生产中的极限能力。迫切需要自然产品纯化，定量，过量生产和多样化的创新技术，需要在自然产品研究领域进行范式转移，并促进基于天然产品的药物发现和开发。由于标记天然产品可以解决自然产品研究的这些挑战方面，因此该提案旨在制定一种新型策略，该策略克服了已知方法对具有生物正交功能的自然产品标记的局限性。为此，我们将探索生活的异常合成生物学 系统提供生物正交功能，并为天然产品的原位标记开发一般平台，尤其是复杂的天然产品，这些产品难以合成或化学化。该策略的成功将直接产生正交功能化的天然产物类似物，这些类似物可以进行药物筛查的轻便化学修饰。更重要的是，用独特的化学手柄标记天然产品将使天然产物通过生物核化学对天然产物的可视化，富集，定量和作用方式进行标记，从而对我们在天然产物生物合成，生物学和药理学中解决挑战性问题的能力产生深远的影响。此外，此处提出了一种基于这种标记策略的新型天然产品，定量的高通量筛选方法，作为一种有用的工具，用于进化天然产物生物合成酶，该酶可以在高滴度中产生天然产物类似物的特定途径中有效发挥作用。这种筛选方法将被利用以了解和设计新的抗生素和抗癌药物的几种重要天然产物家族的生物合成。拟议的跨学科项目桥接了自然产物生物合成，蛋白质工程和生物方向共管化学方面的多项创新，如果成功，将大大扩展自然产品研究工具包，并对酶学，生物合成和药物产生广泛的影响。因此，它非常适合新的创新者奖，它的意义，新颖性以及研究人员的创新性和创造力记录。该项目与研究小组的其他努力重叠最小，同时为各种研究项目提供了良好的协同作用，并完美地拟合了我们的主要研究主题之一：利用酶的能力朝着天然产品的生物合成，并在增进人类健康方面具有最终的应用。