Chemical Synthesis and Biological Application of Carbohydrates and Glycoconjugates

摘要 碳水化合物无处不在，在许多重要的生物过程中起着至关重要的作用。的发展。 碳水化合物和糖偶联物的合成需要高效和选择性的化学方法 以了解碳水化合物的具体作用和治疗发展。最流行的 碳水化合物中的官能团是羟基。碳水化合物有两个根本性的挑战 与羟基有关的合成：1)存在时一个羟基的位置选择性官能化 许多其他看似相同的羟基，以及2)立体选择性糖基化。这其中的一个长期目标 计划的目的是开发方法来应对这些挑战，并提高效率和选择性 碳水化合物合成。在接下来的五年里，我们将开发能够选择性地实现功能的方法 羟基，如酰化、烷基化和硫酸盐化，在各种最小保护或不保护中 以一种可预测和普遍的方式提供糖苷。我们还将开发一种方法，可以选择性地移除 保护碳水化合物中的基团。选择性地安装在碳水化合物中的导向基团将 也使我们能够立体选择性地获得各种类型的糖苷键。这些转换可以 显著提高碳水化合物合成的效率和选择性。 该计划的另一个长期目标是制备具有新生物的碳水化合物和糖聚体 功能。糖蛋白上的某些糖链可以被溶酶体靶向受体识别，溶酶体靶向受体 然后将糖蛋白运输到溶酶体进行降解。为了利用这一自然过程， 最近报道了针对嵌合体的溶酶体对疾病相关细胞外的降解作用。 蛋白质。这些降解物是通过将细胞表面ltrs的碳水化合物配体与 能够与胞外蛋白靶标结合的配体。受体-配体的相互作用然后触发 通过受体介导的内吞作用使细胞外蛋白内化，从而进一步诱导 溶酶体内内源性胞外蛋白靶标的降解。这一新战略是对 现有的靶向蛋白质降解方法，主要集中在细胞内蛋白质上。在接下来的五年里 几年内，我们将开发一系列基于碳水化合物的ltrs配体，用于降解 各种胞外疾病相关蛋白。 在我们以前的研究中，我们认识到过渡金属催化剂和手性的巨大潜力。 糖合成中的有机催化剂及其在细胞类型选择中的独特应用 有针对性的蛋白质降解。在未来五年，我们将继续开发新的方法来解决 碳水化合物和糖偶联物的合成，研究它们在靶向蛋白质降解中的应用， 开拓新的研究方向。

ABSTRACT Carbohydrates are ubiquitous and play a vital role in many important biological processes. The development of efficient and selective chemical methods for the synthesis of carbohydrates and glycoconjugates is necessary to understand the specific roles of carbohydrates and for therapeutic development. The most prevalent functionality in carbohydrates is the hydroxyl group. There are two fundamental challenges in carbohydrate synthesis associated with the hydroxyl group: 1) site-selective functionalization of one hydroxyl in the presence of many other seemingly identical hydroxyls, and 2) stereoselective glycosylation. One long-term goal of this program is to develop methods to address these challenges and improve the efficiency and selectivity for carbohydrate synthesis. In the next five years, we will develop methods that can site-selectively functionalize hydroxyl groups, such as acylation, alkylation, and sulfation, in various minimally protected or unprotected glycosides in a predictable and general manner. We will also develop methods that can site-selectively remove protecting groups in carbohydrates. The directing groups that are site-selectively installed in carbohydrates will also allow us to access various types of glycosidic linkages stereoselectively. These transformations can significantly improve the efficiency and selectivity for the synthesis of carbohydrates. The other long-term goal of this program is to prepare carbohydrates and glycocongates with novel biological functions. Certain glycans on glycoproteins can be recognized by lysosome targeting receptors (LTRs), which then transport the glycoproteins to the lysosome for degradation. To take advantage of this natural process, lysosome targeting chimeras were recently reported for the degradation of disease-associated extracellular proteins. These degraders are created by conjugating carbohydrate ligands of LTRs on the cell surface with ligands that can bind to the extracellular protein targets. The receptor-ligand interaction then triggers the internalization of the extracellular proteins through receptor-mediated endocytosis, which further induces the degradation of the endogenous extracellular protein targets in the lysosome. This new strategy complements existing targeted protein degradation methods, which largely focus on intracellular proteins. In the next five years, we will develop a series of carbohydrate-based ligands for LTRs that can be used for the degradation of various extracellular disease associated proteins. During our previous studies, we recognized the enormous potential of transition metal catalysts and chiral organocatalysts in carbohydrate synthesis and the unique utility of glycoconjugates in cell-type selective targeted protein degradation. In the next five years, we will continue developing novel methods for the synthesis of carbohydrates and glycoconjugates, studying their applications in targeted protein degradation, and pioneering new research directions.