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: 10164799
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164799
• 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; 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/antagonist; 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.

项目概要 乙酰肝素酶被认为是癌症侵袭性表型的主要调节因子， 癌症患者预后不良的重要因素，也是治疗的主要目标。 虽然基于碳水化合物的乙酰肝素酶已经被开发出来，但没有被转化为 在临床上使用。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调节： 底物硫酸化序列，并且仅具有特定硫酸化模式的底物被切割 通过乙酰肝素酶。尽管人类乙酰肝素酶的晶体结构最近已被解析， 它仍然不允许确定具有确定的 N- 和 O- 的结合表位的结构 乙酰肝素酶每个亚位点的硫酸化模式。为了应对这些挑战，目标 1 需要 用于 HS 库并行组合合成的新模块化化学方法 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了解和 乙酰肝素酶如何选择有利的切割位点。在目标 2 中，我们建议开发乙酰肝素酶- 抑制硫酸化寡糖的高效性和临床适用性。在目标 3 中，最 Aim 2 中开发的强效抑制剂将测试与其他 HS 结合的交叉生物活性 蛋白质，负责介导抗凝和血管生成活性，抗体- 诱发血小板减少和肿瘤细胞转移。最终目标是了解如果 乙酰肝素酶的体外抑制作用将转化为体内，我们将评估其有效性 抑制淋巴瘤肿瘤生长和实验性转移的最有效的抑制剂。 总之，该项目将提供对硫酸盐识别基序的深入了解和有利的 用于开发乙酰肝素酶抑制剂的切割位点。本项目的重大影响是 如果成功的话，可能会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。