Biocompatible Chemistry for In Vivo Metabolite Modification

描述（由申请人提供） 摘要：小分子代谢物的化学修饰发生在每一种生物体中，并且在基本上所有生物过程中发挥基本作用，从构建遗传信息存储和细胞酶机制的构件到持续处理维持生命的营养物质。虽然这些反应已经从观察的角度进行了彻底的研究，但使用有机合成的工具和方法来操纵生物化学的尝试相对较少。该提案详细介绍了开发生物相容性反应的策略，非酶化学转化可用于在活生物体存在下操纵小分子的结构。我们已经启动了初步调查，旨在建立一个概念验证的两种方法，连接生物和合成化学：使用微生物代谢产物作为化学试剂和小分子催化反应，可以支持营养缺陷型微生物的生长的能力。这些实验旨在证明非酶促反应可以在微生物存在下进行，并具有与微生物代谢相互作用的能力。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巨大的;然而，它对多个领域的潜在科学影响是巨大的。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的界面研究开辟全新的途径，并有可能极大地影响人类健康。 公共卫生相关性：化学修饰活生物体中的小分子的能力有可能对与公共卫生相关的多个研究领域产生广泛影响，包括合成生物学和药物发现。生物相容性转化，能够与生命化学相互作用的合成反应，将为可持续地发现和供应重要药物开辟新的方法。此外，这些转变背后的药物本身也可以用作治疗药物，这种新的作用模式将代表一种全新的方式来思考设计小分子药物。

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.