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(申请人提供)：已知受体酪氨酸激酶和其他细胞表面受体通过配体诱导的二聚化或聚集来激活信号转导通路，导致一系列重要的健康相关后果，如细胞增殖、炎症反应和血管生成。受体聚集通常是由肝素结合蛋白络合在附近的蛋白多糖上促进的。这项提议将基于一种名为反聚集的新概念开发一类新的受体抑制剂，在这种概念中，纳米级的复合体将与多个受体结合，但将它们保持在受阻状态。硫化低聚糖配体将被接枝到胶体金纳米颗粒上，作为选择性招募和定向肝素结合信号蛋白的多价支架，如生长因子或趋化因子。将开发合成策略，使具有正交保护的寡糖的纳米颗粒功能化，这些纳米颗粒将被去保护并以不同的顺序硫酸盐化，以产生具有不同硫化模式的糖基化纳米颗粒(GN)的文库。具体目标包括：(1)一种稳健的方法将纳米颗粒包裹在非脱附涂层中，并在低表面密度下用正交保护的寡糖对其进行功能化；(2)用于合成多达32种不同硫化模式的双糖的正交保护基团策略；(3)硫化GN文库的生成和表征；(4)筛选与成纤维细胞生长因子(FGFs)高度结合的GN，以及随后利用细胞增殖实验评价它们作为抑制成纤维细胞生长因子受体介导的信号转导的抑制剂(抗聚集剂)的作用。