Tailoring Structures of Sulfated Oligosaccharides for Modulating Heparanase Activity

用于调节乙酰肝素酶活性的硫酸低聚糖的剪裁结构

• 批准号: 10402831
• 负责人: Hien M Nguyen
• 金额: $ 34.66万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402831
• 关键词: Active Sites; Address; Adverse effects; Antibodies; Anticoagulants; Antineoplastic Agents; Antithrombins; Beta-glucuronidase; Binding; Binding Proteins; Biological Assay; Cancer Patient; Carbohydrates; Carbon Dioxide; Charge; Chemicals; Clinic; Clinical; Clinical Research; Collaborations; Combinatorial Synthesis; Crystallization; Development; Disease; Docking; Drug Kinetics; Enzymes; Epitopes; Extracellular Matrix; Glycosides; Goals; Growth Factor; Heparanase inhibitors; Heparin; Heparitin Sulfate; Human; Hydrogen Bonding; Hydrolysis; In Vitro; Individual; Inflammation; Kinetics; Lead; Libraries; Lymphoma; Malignant Neoplasms; Mediating; Metabolic; Monosaccharides; Neoplasm Metastasis; North America; Oligosaccharides; Organic Chemistry; Outcome; P-Selectin; PF4 Gene; Pattern; Pharmacotherapy; Phenotype; Prognosis; Property; Proteins; Site; Specificity; Structure; Substrate Interaction; Substrate Specificity; Sulfate; Testing; Thrombocytopenia; Translating; Trisaccharides; Tumor Biology; angiogenesis; base; cancer therapy; clinical application; computer studies; design; effectiveness evaluation; heparanase; improved; in vivo; inhibitor; insight; lymphoid structures; pyranose; sugar; targeted treatment; tumor; tumor behavior; tumor growth

PROJECT SUMMARY Heparanase is recognized as a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy. Although carbohydrate-based heparanase have been developed, but none were translated into use in the clinic. Additionally, interaction of heparanase with heparan sulfate (HS) is regulated by substrate sulfation sequences, and only substrates with specific sulfation patterns are cleaved by heparanase. Although the crystal structure of human heparanase has been recently resolved, it still does not allow determination of the structure of binding epitopes with defined N-and O- sulfation patterns at each subsite of heparanase. To address these challenges, Aim 1 entails a new modular chemical approach for the parallel combinatorial synthesis of a library of HS trisaccharide substrates, representing all possible N-acetyl as well as O- and N-sulfation motifs. Our strategy provides a systematic understanding of substrate specificity for heparanase and how heparanase selects favorable cleavage site. In Aim 2, we propose to develop heparanase- inhibiting sulfated oligosaccharides of high efficacy and clinical applicability. In Aim 3, the most potent inhibitors developed in Aim 2 will be tested for cross-bioactivity to other HS-binding proteins, which are responsible for mediating anticoagulant and angiogenic activity, antibody- induced thrombocytopenia, and tumor cell metastasis. With the ultimate goal of understanding if the in vitro inhibition of heparanase would translate in vivo, we will evaluate the effectiveness of the most potent inhibitor(s) in inhibiting lymphoma tumor growth and experimental metastasis. Together, this project will provide insight into sulfate-recognition motifs and favorable cleavage site for use to develop inhibitors of heparanase. The significant impact of this project is that, if successful, it could lead to the discovery of a heparanase-inhibiting small carbohydrate molecule for treatment of lymphomas, which are the fifth leading cancer in the North America, produce tumors predominantly in lymphoid structures.

项目摘要 肝素酶被公认为是癌症侵略性表型的主要调节剂， 癌症患者预后不良的重要因素和治疗的主要靶标。 尽管已经开发了基于碳水化合物的乙par菜酶，但没有人翻译成 在诊所使用。此外，肝素酶与乙par醇（HS）的相互作用受到调节 底物硫酸盐序列，并且仅裂解具有特定硫酸化模式的底物 由肝素酶。尽管最近解决了人肝素酶的晶体结构，但 它仍然不允许确定用定义的N和O-确定结合表位的结构 每个乙酰肝素酶的硫酸化模式。为了应对这些挑战，目标1需要 新的模块化化学方法，用于HS库的平行组合合成 三糖底物，代表所有可能的N-乙酰基以及O-和N-硫化基序。 我们的策略为肝素酶的底物特异性提供了系统的理解和 肝素酶如何选择有利的裂解位点。在AIM 2中，我们建议开发乙酰肝素酶 - 抑制高功效和临床适用性的硫化寡糖。在AIM 3中，最多 AIM 2中开发的有效抑制剂将经过对其他HS结合的跨生物活性测试 蛋白质负责介导抗凝剂和血管生成活性，抗体 - 诱导的血小板减少症和肿瘤细胞转移。以理解是否的最终目标 体外抑制肝素酶会在体内翻译，我们将评估 抑制淋巴瘤肿瘤生长和实验转移的最有效抑制剂。 该项目将共同洞悉硫酸盐识别图案和有利 用于开发乙酰肝素酶抑制剂的切割部位。该项目的重大影响是 如果成功的话，这可能导致发现抗肝素酶的小碳水化合物 治疗淋巴瘤的分子，淋巴瘤是北美第五个主要癌症的分子 主要在淋巴结构中产生肿瘤。