In Situ Natural Product Labeling and Applications

原位天然产品标签和应用

基本信息

批准号：
9976696
负责人：
Wenjun Zhang
金额：
$ 47.7万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2022-08-31
项目状态：
已结题

项目摘要

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60%以上的药物来自天然来源。然而，在过去三十年中，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。迫切需要天然产物纯化、定量、超量生产和多样化的创新技术，以实现天然产物研究领域的范式转变，并促进基于天然产物的药物发现和开发。由于标记天然产品可以解决天然产品研究中的这些具有挑战性的方面，因此该提案旨在开发一种新颖的策略，克服已知的具有生物正交功能的天然产品标记方法的局限性。为此，我们将探索生物合成生物学的不寻常之处系统提供生物正交功能并开发用于天然产物原位标记的通用平台，特别是难以化学合成或衍生化的复杂天然产物。该策略的成功将直接产生正交功能化的天然产物类似物，可以对其进行简单的化学修饰以进行药物筛选。更重要的是，用独特的化学句柄标记天然产物将能够通过生物正交化学对天然产物进行可视化、富集、定量和作用模式研究，从而对我们解决天然产物生物合成中具有挑战性的问题的能力产生深远的影响。生物学、药理学。此外，本文提出了一种基于这种标记策略的新型基于天然产物的定量、高通量筛选方法，作为进化天然产物生物合成酶的有用工具，该酶可以在特定途径中有效发挥作用，以高滴度生产天然产物类似物。该筛选方法将用于了解和设计几个重要天然产物家族的生物合成，以用于新抗生素和抗癌药物的发现。拟议的跨学科项目连接了天然产物生物合成、蛋白质工程和生物正交化学领域的多项创新，如果成功，将极大地扩展天然产物研究工具包，并对酶学、生物合成和医学产生广泛影响。因此，就其重要性、新颖性以及研究者的创新性和创造力记录而言，它非常适合新创新者奖。该项目与研究小组的其他工作几乎没有重叠，同时与各种研究项目提供良好的协同作用，并完美契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，最终应用于人类进步健康。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Engineered biosynthesis of alkyne-tagged polyketides.

DOI：
10.1016/bs.mie.2021.11.013
发表时间：
2022
期刊：
Methods in enzymology
影响因子：
0
作者：
通讯作者：

Biosynthesis of Isonitrile- and Alkyne-Containing Natural Products.

DOI：
10.1146/annurev-chembioeng-092120-025140
发表时间：
2022-06-10
期刊：
ANNUAL REVIEW OF CHEMICAL AND BIOMOLECULAR ENGINEERING
影响因子：
8.4
作者：
Flores, Antonio Del Rio;Barber, Colin C.;Narayanamoorthy, Maanasa;Gu, Di;Shen, Yuanbo;Zhang, Wenjun
通讯作者：
Zhang, Wenjun

Probing the Acyl Carrier Protein-Enzyme Interactions within Terminal Alkyne Biosynthetic Machinery.

探索末端炔生物合成机器中酰基载体蛋白-酶的相互作用。