Molecular Prosthetics and Lego Chemistry

项目摘要/摘要 这项提议旨在大幅推进分子假体和自动化这两个前沿研究领域 小分子合成，从而对人类健康产生重大影响。上半年的目标是 开发一类新的分子假体，以取代缺失的生化反应。我们的实验室有 最近在动物和人类身上证明了小分子可以取代缺乏蛋白质的功能， 从而在分子尺度上作为假体运行。我们进一步说明了允许 由于固有的健壮性，不完美的功能模仿足以进行实质性的生理恢复 生命系统的一部分。在这项提议中，我们将启动一个新的研究方向，以寻找取代 酶缺乏。有100多种人类疾病与酶功能丧失有关，我们将 具体针对三个例子：鸟氨酸转氨基甲酸酶缺乏症，精氨酸丁二酸裂解酶缺乏症， 和遗传性酪氨酸血症1型。这些疾病有两个共同特征，我们认为 容易受到这种方法的影响：1)缺失酶的底物浓度高，或上游 前体，在血液和/或组织中积聚，以及2)相应的底物具有独特的化学物质 反应性。我们假设，这两个特征将允许不完美的小分子试剂作为 人血浆和小鼠模型中缺失酶的有效功能替代物。第二 Half瞄准了新的乐高分子工具包，用于自动合成两类功能丰富的天然产品： 脂类和多环萜类。这两个类别都执行许多生物和工业功能，但仍然存在 与生俱来的合成挑战。以我们最近开发的类似乐高的全自动平台为基础 在小分子合成方面，我们计划创建一套乐高试剂盒，用于按需制备这两类 化合物。平行逆合成分析表明，制备~130个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Csp3-C键形成 迭代地组装构建块的方法，以及完全呈现该过程的NextGen合成机 自动化的。我们将利用这个平台来更好地了解分子假体离子通道。我们还计划 将线性分子的模块化类乐高结构与环化促进自组装相结合 间苯二酚胶囊为多环萜类化合物创造了一种高效和灵活的乐高试剂盒。为此，我们 将定义新的结构-环化关系，描述它们的基础，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，并开辟医学的新前沿。

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.