Biocompatible Chemistry for In Vivo Metabolite Modification

用于体内代谢物修饰的生物相容性化学

基本信息

批准号：
8354079
负责人：
Emily Patricia Balskus
金额：
$ 253.5万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (Provided by the applicant) Abstract: Chemical modifications of small molecule metabolites occur in every organism and play a fundamental role in essentially all biological processes, from the construction of the building blocks for genetic information storage and cellular enzymatic machinery to the continual processing of nutrients that sustains life. Although these reactions have been thoroughly investigated from an observational standpoint, there have been relatively few attempts to manipulate biological chemistry using tools and approaches from organic synthesis. This proposal details a strategy for developing biocompatible reactions, non-enzymatic chemical transformations that can be used to manipulate the structures of small molecules in the presence of living organisms. We have initiated preliminary investigations aimed at establishing a proof-of-concept for two approaches that connect biological and synthetic chemistry: the use of microbial metabolites as chemical reagents and the ability of small molecules to catalyze reactions that can support the growth of auxotrophic microorganisms. These experiments are designed to demonstrate that non-enzymatic reactions can proceed in the presence of microbes and have the ability to interact with microbial metabolism. The knowledge gained from these initial studies will then be applied to problems in the areas of synthetic chemistry, synthetic biology/metabolic engineering, and medicine. The challenges associated with this project are substantial; however, its potential scientific impact on multiple fields is significant. If successul, our ability to manipulate small molecules in vivo using chemical methods will open entirely new avenues for investigation at the interface of chemistry and biology with the potential to greatly impact human health. Public Health Relevance: The ability to chemically modify small molecules in living organisms has the potential for broad impact on multiple research areas related to public health, including synthetic biology and drug discovery. Biocompatible transformations, synthetic reactions capable of interfacing with the chemistry of life, will open up new methods for sustainably discovering and supplying important medications. In addition, the agents behind these transformations may themselves be used as therapeutics, and this novel mode of action would represent an entirely new way to think about designing small molecule drugs.

描述（申请人提供）摘要：小分子代谢产物的化学修饰发生在每个生物体中，并在所有生物过程中都起着基本作用，从建造构建基础的遗传信息存储和细胞酶机制到持续维持生命的营养物质的持续处理。尽管这些反应从观察的角度进行了彻底研究，但使用有机合成中的工具和方法来操纵生物化学的尝试相对较少。该建议详细介绍了一种开发生物相容性反应的策略，即非酶化化学转化，可用于在存在生物体的情况下操纵小分子的结构。我们已经开始了初步研究，旨在建立一种连接生物学和合成化学方法的方法的概念验证：将微生物代谢物用作化学试剂以及小分子在催化可支持辅助营养微生物生长的反应的能力。这些实验旨在证明非酶反应可以在存在微生物的情况下进行，并具有与微生物代谢相互作用的能力。然后，从这些初步研究中获得的知识将应用于合成化学，合成生物学/代谢工程和医学领域的问题。与该项目相关的挑战是重大的。但是，它对多个领域的潜在科学影响很大。如果成功，我们使用化学方法在体内操纵小分子的能力将为化学和生物学界面开放全新的途径，以极大地影响人类健康。公共卫生相关性：化学修改生物体中小分子的能力具有对与公共卫生有关的多个研究领域的广泛影响，包括合成生物学和药物发现。生物相容性转化，能够与生命化学接触的合成反应，将为可持续发现和提供重要药物提供新的方法。此外，这些转化背后的代理本身可以用作治疗学，而这种新颖的作用方式将代表一种考虑设计小分子药物的全新方法。