Glycosylated Nanoparticles to Inhibit Receptor Clusteri

糖基化纳米颗粒抑制受体簇

• 批准号: 6717612
• 负责人: Alexander Wei
• 金额: $ 25.35万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6717612
• 关键词: biological signal transduction; cell proliferation; cell surface receptors; confocal scanning microscopy; disaccharides; fibroblast growth factor; glycosylation; growth factor receptors; growth inhibitors; ligands; nanotechnology; particle; protein tyrosine kinase; sulfation; transmission electron microscopy

DESCRIPTION (provided by applicant): Receptor tyrosine kinases and other cell-surface receptors are known to activate signal transduction pathways by ligand-induced dimerization or clustering, resulting in a range of important health-related consequences such as cell proliferation, inflammatory response, and angiogenesis. Receptor clustering is often promoted by heparin-binding proteins complexed onto nearby proteoglycans. This proposal will develop a new class of receptor inhibitors based on a novel concept called anti-clustering, in which nanometer-sized complexes will bind to multiple receptors but retain them in arrested states. Sulfated oligosaccharide ligands will be grafted onto colloidal gold nanoparticles, which will serve as multivalent scaffolds for the selective recruitment and orientation of heparin-binding signaling proteins such as growth factors or chemokines. Synthetic strategies will be developed for functionalizing nanoparticles with orthogonally protected oligosaccharides, which will be deprotected and sulfated in variable order to generate libraries of glycosylated nanoparticles (GNs) with variable sulfation patterns. Specific Aims include: (1) a robust method for encapsulating nanoparticles in nondesorptive coatings and functionalizing them with orthogonally protected oligosaccharides at low surface densities; (2) orthogonal protecting-group strategies for synthesizing disaccharides with up to 32 different sulfation patterns; (3) generation and characterization of sulfated GN libraries; (4) screening of GNs for highaffinity binding to fibroblast growth factors (FGFs), and their subsequent evaluation as inhibitors (anticlustering agents) against FGF receptor-mediated signal transduction using a cell proliferation assay.

描述（由申请人提供）：已知受体酪氨酸激酶和其他细胞表面受体可通过配体诱导的二聚化或聚类激活信号转导途径，从而导致一系列重要的健康相关后果，例如细胞增殖、炎症反应和血管生成。受体聚集通常是由复合到附近蛋白聚糖上的肝素结合蛋白促进的。该提案将基于一种称为抗聚集的新概念开发一类新型受体抑制剂，其中纳米尺寸的复合物将与多个受体结合，但将它们保留在停滞状态。硫酸化寡糖配体将被移植到胶体金纳米颗粒上，该纳米颗粒将作为多价支架，用于选择性招募和定向肝素结合信号蛋白（例如生长因子或趋化因子）。将开发用正交保护的寡糖功能化纳米颗粒的合成策略，这些寡糖将以不同的顺序脱保护和硫酸化，以生成具有不同硫酸化模式的糖基化纳米颗粒（GN）库。具体目标包括：（1）一种将纳米颗粒封装在非解吸涂层中并在低表面密度下用正交保护的寡糖对其进行功能化的稳健方法； (2) 用于合成具有多达 32 种不同硫酸化模式的二糖的正交保护基策略； (3)硫酸化GN文库的生成和表征； (4) 筛选与成纤维细胞生长因子 (FGF) 高亲和力结合的 GN，并随后使用细胞增殖测定对其作为 FGF 受体介导的信号转导的抑制剂（抗聚集剂）进行评估。