HEPARIN-BINDING PEPTIDES FROM CELL ADHESION PROTEINS

来自细胞粘附蛋白的肝素结合肽

• 批准号: 6191515
• 负责人: DALLAS Leroy RABENSTEIN
• 金额: $ 29.31万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6191515
• 关键词: affinity chromatography; antithrombin III; binding proteins; calorimetry; cell adhesion molecules; chemical binding; circular dichroism; fibronectins; heparin; high performance liquid chromatography; human immunodeficiency virus 1; intermolecular interaction; laminin; melanoma; metastasis; nuclear magnetic resonance spectroscopy; oligosaccharides; peptide analog; protein sequence; protein structure function; synthetic peptide; thrombospondins; tissue /cell culture; virus replication; vitronectin

Cell adhesion plays a critical role in the development of many diseases, including arthritis, metastatic cancer and diseases caused by the invasion of cells by viruses and bacteria. Cell adhesion is mediated by interactions between receptors on the cell surface and ligands of the extracellular matrix or other surfaces. Receptor molecules include the glycosaminoglycan part of proteoglycans such as heparan sulfate proteoglycan and ligands include cell adhesion proteins such as fibronectin. The motivation for the proposed research is that interruption of the cell adhesion process with synthetic peptides and/or oligosaccharides has potential as a therapeutic intervention (anti-adhesion therapy) in the development of diseases in which cell adhesion plays a critical role. For example, heparin binding fragments of cell adhesion proteins can inhibit the experimental metastasis of several metastatic tumors and heparin can inhibit the replication of human immunodeficiency virus type- 1 (HIV-1). The long term objectives are to characterize, in detail at the molecular level, the interactions involved in the binding of peptides by heparin, starting with peptides which have the amino acid sequences of heparin-binding domains of cell adhesion proteins and other proteins. The knowledge to be gained is of clinical interest because it will provide a fundamental basis from which to design new synthetic peptides with even greater selectivity and specificity for use in anti-adhesion therapy and for neutralization of the anticoagulant activity of heparin. The specific aims of the research are to identify peptide and heparin motifs with a propensity for binding, to determine if binding involves site specific or delocalized electrostatic interactions, to determine the strength of the binding in terms of binding constants, and to characterize structural features of the heparin-peptide complexes. These objectives will be achieved using information obtained from high field nuclear magnetic resonance (NMR) spectroscopy experiments.

细胞粘附在许多疾病的发展中起着关键作用，包括关节炎、转移性癌症和由病毒和细菌入侵细胞引起的疾病。细胞粘附是由细胞表面受体与细胞外基质或其他表面的配体之间的相互作用介导的。受体分子包括蛋白聚糖的糖胺聚糖部分，如硫酸肝素蛋白聚糖，配体包括细胞粘附蛋白，如纤维连接蛋白。提出这项研究的动机是，用合成肽和/或低聚糖来中断细胞粘附过程，在细胞粘附起关键作用的疾病的发展中，有可能作为一种治疗干预（抗粘附治疗）。例如，细胞粘附蛋白的肝素结合片段可以抑制几种转移性肿瘤的实验转移，肝素可以抑制人类免疫缺陷病毒-1型（HIV-1）的复制。长期目标是在分子水平上详细描述肝素结合肽所涉及的相互作用，从具有细胞粘附蛋白和其他蛋白质的肝素结合域氨基酸序列的肽开始。所获得的知识具有临床意义，因为它将为设计具有更高选择性和特异性的新合成肽提供基础，用于抗粘连治疗和中和肝素的抗凝血活性。该研究的具体目的是鉴定具有结合倾向的肽和肝素基序，确定结合是否涉及位点特异性或离域静电相互作用，根据结合常数确定结合的强度，并表征肝素-肽复合物的结构特征。这些目标将利用高场核磁共振（NMR）光谱实验获得的信息来实现。