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: 9816301
• 负责人: Hien M Nguyen
• 金额: $ 36.01万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816301
• 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; Cleaved cell; Clinic; Clinical; Clinical Research; Collaborations; Combinatorial Synthesis; Crystallization; Development; Disease; Docking; Drug Kinetics; Effectiveness; Enzymes; Epitopes; Extracellular Matrix; Glycosides; Goals; Growth Factor; Heparanase inhibitors; Heparin; Heparitin Sulfate; Human; Hydrogen Bonding; Hydrolysis; In Vitro; Individual; Inflammation; Kinetics; Lead; Libraries; Lymphoid; Lymphoma; Malignant Neoplasms; Mediating; Metabolic; Monosaccharides; Neoplasm Metastasis; North America; Oligosaccharides; Organic Chemistry; Outcome; P-Selectin; Pattern; Pharmacotherapy; Phenotype; Platelet Factor 4; Property; Proteins; Site; Specificity; Structure; Substrate Interaction; Substrate Specificity; Testing; Thrombocytopenia; Translating; Trisaccharides; Tumor Biology; Unspecified or Sulfate Ion Sulfates; angiogenesis; base; cancer therapy; clinical application; computer studies; design; heparanase; improved; in vivo; inhibitor/antagonist; insight; outcome forecast; protein B; pyranose; sugar; sulfation; 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 乙酰肝素酶被认为是癌症侵袭性表型的主要调节因子， 这是癌症患者预后不良的重要原因，也是治疗的主要目标。 虽然已经开发了基于碳水化合物的乙酰肝素酶，但没有一种被翻译成 在诊所使用。此外，乙酰肝素酶与硫酸乙酰肝素（HS）的相互作用受以下因素的调节： 底物硫酸化序列，并且只有具有特定硫酸化模式的底物被切割 乙酰肝素酶虽然最近已经解析了人乙酰肝素酶的晶体结构， 它仍然不能确定具有确定的N-和O-的结合表位的结构， 硫酸化模式在每个亚位点的乙酰肝素酶。为了应对这些挑战，目标1需要 一种新的用于HS文库的并行组合合成的模块化化学方法 三糖底物，代表所有可能的N-乙酰基以及O-和N-硫酸化基序。 我们的策略提供了对乙酰肝素酶底物特异性的系统理解， 乙酰肝素酶如何选择有利的切割位点。在目标2中，我们提出开发乙酰肝素酶- 抑制硫酸化低聚糖的高效性和临床适用性。在目标3中， 目标2中开发的有效抑制剂将测试与其他HS结合的交叉生物活性。 蛋白质，负责介导抗凝血和血管生成活性，抗体- 诱导的血小板减少症和肿瘤细胞转移。最终目标是理解， 体外对乙酰肝素酶的抑制作用将在体内转化，我们将评估 在抑制淋巴瘤肿瘤生长和实验转移中最有效的抑制剂。 总之，该项目将提供深入了解硫酸盐识别基序和有利的 用于开发类肝素酶抑制剂的切割位点。该项目的重大影响是 如果成功的话，它可能会导致发现一种抑制乙酰肝素酶的小碳水化合物， 用于治疗淋巴瘤的分子，淋巴瘤是北美第五大癌症， 主要在淋巴结构中产生肿瘤。