Modular Synthesis of N-Glycans and Homogeneous Glycoproteins

N-聚糖和均质糖蛋白的模块化合成

• 批准号: 1954031
• 负责人: Chi-Huey Wong
• 金额: $ 53.99万
• 依托单位: The Scripps Research Institute
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1954031&HistoricalAwards=false
• 关键词: Modular; Synthesis; Glycans; Homogeneous; Glycoproteins

With this award, the Chemical Synthesis Program of the NSF Division of Chemistry is supporting the research of Professor Chi-Huey Wong at The Scripps Research Institute. Professor Wong and his research team are developing new ways to link sugar molecules to form oligosaccharides (relatively small carbohydrates) using chemical and enzymatic tools. These new methods for the construction of oligosaccharides are then being used to assemble glycoproteins (proteins that have sugars attached to them) and to understand how the oligosaccharide fragments affect protein function. Glycoproteins perform many important biological functions that are central to the immune, digestive, and reproductive systems, for example. Since most proteins in higher organisms are modified with oligosaccharides of varying sequence, length and branching, at multiple loci, there is considerable microheterogeneity for any given glycoprotein. This makes it difficult to establish clear structure/function relationships for glycoproteins. The development of methods for the defined synthesis of oligosaccharides and their use for the assembly of homogeneous glycoproteins is critically important for such studies. The work being done in the Wong group is also providing graduate and undergraduate students, as well as postdoctoral researchers, with interdisciplinary training in chemistry, chemical biology, molecular biology, and biochemistry.Understanding the effect of glycosylation on protein folding, structure and function is vitally important in biology and medicine and requires access to a large number of complex structurally-defined asparagine-linked N-glycans. Professor Wong and his research group are addressing this challenge by designing modular chemoenzymatic methods for assembling oligosaccharides. More specifically, they are developing methods to prepare multi-antennary N-linked glycans with fluorinated sialic acid and fucosylated functionalities, as well as optimizing enzymes to achieve transfers of tri-and tetrantennary oligosaccharides. The significant array of N-glycans being prepared in these studies is then available to generate homogeneous glycoproteins, such as monoclonal antibodies, for the study of their activities. All modules, enzymes, and reagents being discovered are also being made available to the community to provide a useful hybrid synthetic/enzymatic toolbox to facilitate the critical need for better understanding of protein glycosylation and to advance research in glycoscience.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

有了这个奖项，NSF化学部的化学合成计划正在支持斯克里普斯研究所的Chi-Huey Wong教授的研究。黄教授和他的研究团队正在开发新的方法，利用化学和酶的工具连接糖分子形成寡糖（相对较小的碳水化合物）。这些构建寡糖的新方法随后被用于组装糖蛋白（与糖连接的蛋白质），并了解寡糖片段如何影响蛋白质功能。糖蛋白执行许多重要的生物学功能，例如对免疫、消化和生殖系统至关重要。由于高等生物中的大多数蛋白质在多个位点上被不同序列、长度和分支的寡糖修饰，因此任何给定的糖蛋白都存在相当大的微观异质性。 这使得难以建立糖蛋白的明确结构/功能关系。开发确定的寡糖合成方法及其用于均质糖蛋白组装的方法对于此类研究至关重要。Wong团队的工作也为研究生、本科生和博士后研究人员提供了化学、化学生物学、分子生物学和生物化学等跨学科的培训。了解糖基化对蛋白质折叠、结构和功能的影响在生物学和医学中至关重要，需要获得大量复杂的结构确定的天冬酰胺连接的N-聚糖。Wong教授和他的研究小组正在通过设计组装寡糖的模块化化学酶方法来应对这一挑战。更具体地说，他们正在开发制备具有氟化唾液酸和岩藻糖基化官能团的多触角N-连接聚糖的方法，以及优化酶以实现三和四末端寡糖的转移。然后，在这些研究中制备的N-聚糖的重要阵列可用于产生同质糖蛋白，例如单克隆抗体，用于研究其活性。所有被发现的模块、酶和试剂也将提供给社区，以提供有用的混合合成/酶工具箱，促进对更好地理解蛋白质糖基化的迫切需要，并推进糖科学的研究。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。

项目成果

Homogeneous antibody and CAR-T cells with improved effector functions targeting SSEA-4 glycan on pancreatic cancer

• DOI: 10.1073/pnas.2114774118
• 发表时间: 2021-12-14
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Lin, Chih-Wei;Wang, Yu-Jen;Wong, Chi-Huey
• 通讯作者: Wong, Chi-Huey