Molecular Prosthetics and Lego Chemistry

分子修复学和乐高化学

• 批准号: 10552238
• 负责人: Martin D Burke
• 金额: $ 71.61万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552238
• 关键词: Animals; Area; Argininosuccinate lyase deficiency; Biochemical Reaction; Biological; Biology; Blood; Chemicals; Chemistry; Complex; Cyclization; Development; Disease; Enzymes; Health; Human; Industrialization; Ion Channel; Laboratories; Link; Lipids; Medicine; Methods; Molecular; Natural Products; Organic Synthesis; Organism; Ornithine carbamoyltransferase deficiency; Persons; Physiology; Plasma; Polyunsaturated Fatty Acids; Predisposition; Preparation; Process; Prosthesis; Protein Deficiency; Reagent; Research; Structure; Terpenes; Tissues; Tyrosinemias; capsule; enzyme deficiency; flexibility; frontier; human disease; mimicry; molecular scale; mouse model; novel strategies; programs; restoration; self assembly; small molecule

Project Summary/Abstract This proposal aims to substantially advance two frontier research areas, Molecular Prosthetics and Automated Small Molecule Synthesis, and thereby have a major impact on human health. The first half targets the development of a new class of molecular prosthetics that replace missing biochemical reactions. Our lab has recently demonstrated in animals and in people that small molecules can replace the function of deficient proteins, thus operating as prostheses on the molecular scale. We further illuminated specific mechanisms that permit imperfect functional mimicry to be sufficient for substantial physiology restoration due to the inherent robustness of living systems. In this proposal we will launch a new research direction to find small molecules that replace deficient enzymes. There are more than 100 human diseases linked to loss of enzyme function, and we will specifically target three examples: Ornithine Transcarbamylase Deficiency, Argininosuccinate Lyase Deficiency, and Hereditary Tyrosinemia Type 1. These diseases have two features in common that we propose render them susceptible to this approach: 1) a high concentration of the substrate for the missing enzyme, or an upstream precursor, builds up in the blood and/or tissues, and 2) the corresponding substrate has unique chemical reactivity. We hypothesize that these two features will permit imperfect small molecule reagents to serve as effective functional surrogates for missing enzymes in human blood plasma and in mouse models. The second half targets new molecular lego kits for automated synthesis of two functionally-rich classes of natural products: lipids and polycyclic terpenoids. Both classes perform many biological and industrial functions, yet remain inherently challenging to synthesize. Building on our recent development of a fully automated lego-like platform for small molecule synthesis, we plan to create a lego kits for on-demand preparation of both classes of compounds. Parallel retrosynthetic analysis showed that preparation of ~130 known polyunsaturated fatty acids requires only 26 building blocks, which we will prepare. We will also develop two new Csp3-C bond forming methods to iteratively assemble building blocks, and a Nextgen synthesis machine to render this process fully automated. We will apply this platform to better understand molecular prosthetic ion channels. We also plan to combine modular lego-like construction of linear molecules with cyclization-promoting self-assembled resorcinarene capsules to create a highly efficient and flexible lego kit for polycyclic terpenoids. To this end, we will define new structure-cyclization relationships, characterize their underpinnings, and leverage them to achieve efficient syntheses of complex polycyclic terpenoid natural products. Collectively these studies will push the frontiers of chemical biology and organic synthesis and open new frontiers for medicine.

项目总结/摘要 该提案旨在大幅推进两个前沿研究领域，分子修复学和自动化 小分子合成，从而对人类健康产生重大影响。上半场的目标是 开发了一种新的分子修复术，取代了缺失的生化反应。我们的实验室 最近在动物和人体中证明，小分子可以取代缺陷蛋白质的功能， 从而在分子尺度上作为假体工作。我们进一步阐明了特定机制， 由于固有的鲁棒性，不完美的功能模仿足以进行实质性的生理恢复 生命系统。在这个提案中我们将启动一个新的研究方向，寻找小分子， 缺乏酶。有100多种人类疾病与酶功能丧失有关，我们将 具体针对三个实例：鸟氨酸转氨甲酰淀粉酶缺乏，精氨琥珀酸裂解酶缺乏， 遗传性酪氨酸血症1型这些疾病有两个共同的特点，我们建议把它们 对这种方法敏感的是：1）高浓度的缺失酶的底物，或上游酶， 前体，在血液和/或组织中积累，和2）相应的底物具有独特的化学性质， 反应性我们假设，这两个特征将允许不完美的小分子试剂充当 在人血浆和小鼠模型中缺失酶的有效功能替代物。第二 Half的目标是自动合成两类功能丰富的天然产物的新型分子乐高试剂盒： 脂质和多环萜类化合物。这两类都有许多生物和工业功能，但仍然存在。 合成是一个固有的挑战。基于我们最近开发的全自动乐高平台 对于小分子合成，我们计划创建一个乐高套件，用于按需制备两类 化合物.平行逆合成分析表明，制备约130种已知的多不饱和脂肪酸， 只需要26块积木，我们会准备好的。我们还将开发两个新的Csp 3-C键形成 迭代组装构建块的方法，以及一个Nextgen合成机器来完全呈现这一过程 自动的我们将应用这个平台，以更好地了解分子假体离子通道。我们还计划 线性分子模块化乐高状结构与环化促进自组装的联合收割机 间苯二酚芳烃胶囊，以创建用于多环萜类化合物的高效和灵活的乐高套件。为此我们 将定义新的结构-环化关系，描述其基础，并利用它们来实现 复杂多环萜类天然产物的高效合成。总的来说，这些研究将推动 化学生物学和有机合成的前沿，并为医学开辟了新的前沿。