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（申请人提供）：天然产物及其衍生物是药物发现的丰富来源;据估计，市场上超过60%的药物来自天然来源。然而，在过去的三十年里，旨在利用天然产物进行药物发现的研究严重下降，部分原因是我们在新天然产物发现和类似物生产方面的能力有限。天然产物纯化、定量、生产和多样化的创新技术是天然产物研究领域的一个范式转变，促进基于天然产物的药物发现和开发的迫切需要。由于标记天然产物可以解决这些具有挑战性的天然产物研究方面，本提案旨在开发一种新的策略，克服已知的方法标记天然产物的生物正交功能的局限性。为此，我们将探索不寻常的合成生物学， 系统提供了生物正交功能，并开发了用于天然产物，特别是难以化学合成或衍生的复杂天然产物的原位标记的通用平台。这一策略的成功将直接产生正交功能化的天然产物类似物，可以进行简单的化学修饰用于药物筛选。更重要的是，用独特的化学处理标记天然产物将使通过生物正交化学研究天然产物的可视化，富集，定量和作用模式成为可能，从而对我们解决天然产物生物合成，生物学和药理学中具有挑战性的问题的能力产生深远的影响。此外，一种新的天然产物为基础的，定量的，高通量的筛选方法的基础上，这种标签策略，在这里提出了一个有用的工具，为发展天然产物的生物合成酶，可以有效地发挥作用，在特定的途径，以产生天然产物类似物在高滴度。这种筛选方法将被用来理解和工程化的几个重要的家庭的天然产物的生物合成新的抗生素和抗癌药物的发现。拟议的跨学科项目在天然产物生物合成，蛋白质工程和生物正交化学方面进行了多项创新，如果成功，将大大扩展天然产物研究工具包，并在酶学，生物合成和医学方面产生广泛影响。因此，它是唯一适合于新的创新者奖方面的意义，新颖性，以及研究者的创新和创造力的记录。该项目与研究小组的其他工作重叠最少，同时与各种研究项目提供良好的协同作用，并完全符合我们的主要研究主题之一：利用酶的力量进行天然产物的生物合成，最终应用于促进人类健康。