Chemical Synthesis and Biological Application of Carbohydrates and Glycoconjugates

碳水化合物和糖复合物的化学合成和生物应用

• 批准号: 10552167
• 负责人: Weiping Tang
• 金额: $ 37.85万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552167
• 关键词: Acylation; Address; Alkylation; Binding; Biological; Biological Process; Carbohydrates; Cell surface; Chemicals; Chimera organism; Complement; Development; Disease; Extracellular Protein; Glycoconjugates; Glycoproteins; Glycosides; Goals; Hydroxyl Radical; Instruction; Ligands; Lysosomes; Methods; Play; Polysaccharides; Preparation; Process; Proteins; Reporting; Research; Role; Series; Site; Sulfate; Transition Elements; catalyst; cell type; chemical synthesis; extracellular; glycosylation; human disease; hydroxyl group; improved; novel; programs; protein degradation; public health relevance; receptor; receptor mediated endocytosis; therapeutic development

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.

抽象的 碳水化合物无处不在，在许多重要的生物过程中发挥着至关重要的作用。的发展 需要有效且选择性的化学方法来合成碳水化合物和糖复合物 了解碳水化合物的具体作用和治疗开发。最普遍的 碳水化合物中的官能团是羟基。碳水化合物有两个基本挑战 与羟基相关的合成：1）在存在下对一个羟基进行位点选择性官能化 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 碳水化合物的合成。在接下来的五年中，我们将开发可以选择性功能化的方法 各种最低限度保护或未保护的羟基，例如酰化、烷基化和硫酸化 以可预测和一般的方式分析糖苷。我们还将开发可以位点选择性去除的方法 碳水化合物中的保护基团。位点选择性安装在碳水化合物中的导向基团将 还允许我们立体选择性地访问各种类型的糖苷键。这些转变可以 显着提高碳水化合物的合成效率和选择性。 该计划的另一个长期目标是用新型生物材料制备碳水化合物和糖基化合物。 功能。糖蛋白上的某些聚糖可以被溶酶体靶向受体 (LTR) 识别， 然后将糖蛋白转运至溶酶体进行降解。为了利用这个自然过程， 最近报道溶酶体靶向嵌合体可降解与疾病相关的细胞外细胞 蛋白质。这些降解剂是通过将细胞表面的 LTR 碳水化合物配体与 可以与细胞外蛋白质靶标结合的配体。然后受体-配体相互作用触发 通过受体介导的内吞作用将细胞外蛋白内化，进一步诱导 溶酶体中内源性细胞外蛋白靶标的降解。这一新战略补充了 现有的靶向蛋白质降解方法主要集中于细胞内蛋白质。在接下来的五年里 年内，我们将开发一系列基于碳水化合物的LTR配体，可用于降解 各种细胞外疾病相关蛋白。 在我们之前的研究中，我们认识到过渡金属催化剂和手性催化剂的巨大潜力 碳水化合物合成中的有机催化剂以及糖复合物在细胞类型选择性中的独特用途 靶向蛋白质降解。未来五年，我们将继续开发新方法 碳水化合物和糖复合物的合成，研究它们在靶向蛋白质降解中的应用， 并开拓新的研究方向。