Applications of Click Chemistry in Glycobiology

点击化学在糖生物学中的应用

• 批准号: 8078003
• 负责人: Peng Wu
• 金额: $ 24.4万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078003
• 关键词: Aldehydes; Alkynes; Anabolism; Azides; Biochemical; Biomedical Research; Biopolymers; Biosensor; Carbon Nanotubes; Cell Communication; Cell surface; Cells; Chemicals; Chemistry; Detection; Development; Disease; Enzymes; Genetic; Genetic Transcription; Glycobiology; Goals; Grant; Hyperglycemia; In Situ; Inflammation; Insulin Resistance; Intercept; Knowledge; Libraries; Life; Malignant Neoplasms; Mentors; Modification; Molecular; Pathway interactions; Phase; Polysaccharides; Post-Translational Protein Processing; Process; Protein Glycosylation; Protein-Carbohydrate Interaction; Reaction; Research; Series; Site; System; Therapeutic Intervention; Transcriptional Regulation; Transferase; Translations; base; diabetes mellitus therapy; experience; functional group; glycosylation; inhibitor/antagonist; professor; protein transport; research study; small molecule; tool

Cell surface glycans are major determinants of cell-cell interactions. Changes In cell surface glycosylation mark the onset of cancer and inflammation. Inside the cell, they can regulate transcription, translation as well as protein trafficking. Progress toward delineating the molecular basis of glycan function, however, has been rather slow. This is partly due to the fact that the biosynthesis of glycans, unlike other biopolymers, is neither template-driven nor under direct transcriptional control. Therefore, conventional genetic and biochemical approaches for elucidating glycan function, and its relevance to disease, have yielded limited information. The long term goal of this project is to implement click chemistry-a set of powerful, reliable and selective reactions-as a general tool for fundamental studies of glycobiology. With the experience and knowledge gained from the K99 phase, I will expand my research in two new directions in the next granting period (ROO). Aim 1 is to discover/develop small molecule inhibitors of glycan biosynthetic and processing enzymes using enzyme-templated in situ click chemistry. For proof of principle, I chose 0-beta-N-acetylglucosamlnyl-transferase (OGT) as the first target. I plan to develop fragment libraries that will be screened for self-assembled inhibitors of OGT. Given the correlation of excessive 0-GlcNAc modification with prolonged hyperglycemia, which in turn triggers insulin resistance, the compounds developed may have applications in diabetes therapy. Aim 2 is to intercept glycan biosynthetic pathways with synthetic unnatural substrates bearing bioorthogonal functional groups, such as azides and alkynes. In parallel, I will also develop new selective reactions based on click chemistry for their subsequent detection in live cells.

细胞表面糖是细胞 - 细胞相互作用的主要决定因素。细胞表面糖基化的变化 标记癌症和炎症的发作。在细胞内，它们也可以调节转录，翻译 作为蛋白质运输。然而，朝着划定聚糖功能的分子基础的进展一直是 相当慢。这部分是由于以下事实：与其他生物聚合物不同，聚糖的生物合成也不是 模板驱动或在直接转录控制下。因此，常规遗传和生化 阐明聚糖功能及其与疾病相关的方法产生了有限的信息。 该项目的长期目标是实施点击化学 - 一组强大，可靠和选择性 反应 - 作为糖生物学基础研究的一般工具。 凭借从K99阶段获得的经验和知识，我将在两个新的方面扩展研究 下一个授予期（ROO）的指示。目的1是发现/发展聚糖的小分子抑制剂 使用原位点击化学的酶，生物合成和加工酶。为了证明原则，我 选择0-beta-n-乙基葡萄糖氨基烷尼尔 - 转移酶（OGT）作为第一个目标。我计划开发碎片库 将筛选OGT的自组装抑制剂。考虑到过度0-GLCNAC的相关性 长时间高血糖的修饰，进而触发胰岛素抵抗，化合物 开发的可能在糖尿病治疗中有应用。目标2是用 具有生物正交官能团的合成非天然底物，例如叠氮化物和炔烃。在 并行，我还将根据点击化学反应进行新的选择性反应，以便其随后的检测 活细胞。

项目成果

Chemoenzymatic synthesis of the sialyl Lewis X glycan and its derivatives.

唾液酸路易斯 X 聚糖及其衍生物的化学酶法合成。

• DOI: 10.1016/j.carres.2010.03.032
• 发表时间: 2010-06-16
• 期刊: CARBOHYDRATE RESEARCH
• 影响因子: 3.1
• 作者: del Amo, David Soriano;Wang, Wei;Besanceney, Christen;Zheng, Tianqing;He, Yizheng;Gerwe, Brian;Seidel, Ronald D., III;Wu, Peng
• 通讯作者: Wu, Peng

Chemical probing of glycans in cells and organisms.

• DOI: 10.1039/c2cs35416k
• 发表时间: 2013-05-21
• 期刊: Chemical Society reviews
• 影响因子: 46.2
• 作者: Rouhanifard SH;Nordstrøm LU;Zheng T;Wu P
• 通讯作者: Wu P

Sulfated ligands for the copper(I)-catalyzed azide-alkyne cycloaddition.

• DOI: 10.1002/asia.201100385
• 发表时间: 2011-10-04
• 期刊: CHEMISTRY-AN ASIAN JOURNAL
• 影响因子: 4.1
• 作者: Wang, Wei;Hong, Senglian;Andrew Tran;Jiang, Hao;Triano, Rebecca;Liu, Yi;Chen, Xing;Wu, Peng
• 通讯作者: Wu, Peng