Small Cell-Penetrating Glyco-Decoys Sidetrack Selectin Ligand Biosynthesis

小细胞穿透糖诱饵侧链选择配体生物合成

• 批准号: 8521620
• 负责人: KHUSHI L MATTA
• 金额: $ 14.9万
• 依托单位: TUMOREND, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2015-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521620
• 关键词: Acetates; Acetylation; Adhesions; Adhesives; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Area; Arthritis; Autoimmune Process; Binding; Blood Platelets; Blood Vessels; CD44 gene; Carbohydrates; Cardiovascular system; Cell Adhesion; Cell Adhesion Molecules; Cell surface; Cells; Chemistry; Colon Carcinoma; Data; Disease; E-Selectin; Endothelial Cells; Enzymes; Epitopes; Event; Family; Feasibility Studies; Fucosyltransferase; Glycolipids; Glycoproteins; Glycosides; HL-60 Cells; HL60; Hyaluronic Acid; Immigration; Inflammation; Inflammatory; Inorganic Sulfates; Investigation; Knowledge; L-Selectin; Lead; Legal patent; Leukocytes; Licensing; Ligand Binding; Ligands; Malignant Epithelial Cell; Malignant Neoplasms; Membrane; Metabolic; Monosaccharides; Mucins; Neoplasm Metastasis; Normal Cell; P-Selectin; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Play; Polysaccharides; Process; Property; Role; Selectins; Sickle Cell; Side; Small Business Innovation Research Grant; Specificity; Structure; Surface; System; Testing; Therapeutic; Time; Unspecified or Sulfate Ion Sulfates; Vertebral column; Work; analog; base; cancer cell; combat; design; esterase; inhibitor/antagonist; interest; meetings; member; migration; novel; novel strategies; perilla alcohol; programs; receptor; sialyl-Lex; small molecule; tool

DESCRIPTION: We have preliminary data for a small molecule glyco-decoy that specifically side-tracks the biosynthesis of the ligand for E-selection, and is a candidate for a novel anti-inflammatory. The three members E, L and P of the selection family are inflammatory adhesion molecules expressed constitutively on the surface of blood leukocytes and on activated endothelial cells and platelets. Discoveries of glycans sialyl LeX and sialyl Lea as mucin glycoprotein ligands for the selection family of cell adhesion proteins has stirred immense interest in pursuit of small molecules for treatment of inflammatory, vascular and cancer diseases. The underlying premise is that controlling the rate of leukocyte adhesion by antagonizing selectin-ligand interactions can lead to new therapies to combat these diseases. GlycoMimetics, Inc., has licensed a selectin ligand derivative to Pfizer in 2011 for $340M with the first indication sickle cell inflammation, as an example of the newly perceived commercial value in this area. We took a different approach, focusing on specificities of sets of enzymes that construct the native ligands. Among PSGL1, E selection and L selection, the latter is known to bind sulfated mucin-glycans. Our findings led to the discovery of sulfo-LeX, sulfo-Lea and various core 2 (Galss3 [Galss4GlcNAcss6]GalNAc¿) glycans as the ligands for these cell adhesion proteins. In another approach, we focused on synthesis of modified analogs of monosaccharides such as 4-fluoro-GlcNAc acetates and 4-fluoro-GalNAc acetates as cell-penetrating metabolic inhibitors of the selection ligand assembly enzymes. We also synthesized small molecules as glyco-decoys to disrupt biosynthesis of natural ligands of these selections. A small synthetic glyco-decoy competes with the natural acceptor-substrate and thus diverts the synthesis of the glycan chains from endogenous glycoproteins and glycolipids to soluble ligands, which act as inhibitors of selection binding to cell-bound ligand. Secondarily, ligand absence on cell-bound molecules in the presence of the glyco-decoy precludes adhesion events that begin the inflammatory process. The underlying theme of this strategy is that biosynthetic knowledge about specificity of key enzymes as "hits" is a compelling requirement for developing small molecules for therapeutic discoveries based on inhibiting selection adhesion systems. We have examined specificity of enzyme assembly of N-glycan ligands for E selections. Preliminarily, we have discovered a novel compound that disrupts the biosynthesis of glycans for E selections (patent submitted). In Phase I, the prime objective is to synthesize analogs and related compounds and test as inhibitors of E selection ligand biosynthesis in HL60 cells. CD44 is endowed with a ligand for E selection, and also has a specific receptor for hyaluronic acid, promoting migration in normal cells. CD44 is highly expressed in various cancer cells. A small molecule inhibiting biosynthesis of E selection-specific N-glycans such as in CD44 brings new potential tools for mitigation of inflammatory disorders and adhesion events in cancer. This Phase I proposal meets the central tenet of the SBIR program for promising commercial products.

产品说明：我们有一种小分子糖诱饵的初步数据，它特异性地侧跟踪E-选择配体的生物合成，是一种新型抗炎药的候选药物。选择家族的三个成员E、L和P是组成性表达在血液白细胞表面和活化的内皮细胞和血小板上的炎性粘附分子。作为细胞粘附蛋白选择家族的粘蛋白糖蛋白配体的聚糖sialyl LeX和sialyl莱亚的发现已经激起了对用于治疗炎症、血管和癌症疾病的小分子的追求的巨大兴趣。基本前提是通过拮抗选择素-配体相互作用来控制白细胞粘附的速率可以导致对抗这些疾病的新疗法。GlycoMimetics，Inc.，2011年，辉瑞公司以3.4亿美元的价格将一种选择素配体衍生物授权给辉瑞公司，其第一个适应症是镰状细胞炎症，这是该领域新发现的商业价值的一个例子。我们采取了不同的方法，专注于构建天然配体的酶的特异性。在PSGL 1、E选择和L选择中，已知后者结合硫酸化粘蛋白-聚糖。我们的研究结果导致发现磺基-LeX，磺基-Lea和各种核心2（Galss 3 [Galss 4GlcNAcss 6]GalNAc <$）聚糖作为这些细胞粘附蛋白的配体。在另一种方法中，我们专注于合成单糖的修饰类似物，如4-氟-GlcNAc乙酸酯和4-氟-GalNAc乙酸酯，作为选择配体组装酶的细胞穿透代谢抑制剂。我们还合成了小分子作为糖诱饵，以破坏这些选择的天然配体的生物合成。一个小的合成糖诱饵与天然受体底物竞争，从而将聚糖链的合成从内源性糖蛋白和糖脂转移到可溶性配体，其作为选择结合细胞结合配体的抑制剂。其次，在糖诱饵存在的情况下，细胞结合分子上的配体缺失排除了开始炎症过程的粘附事件。这一战略的基本主题是，生物合成的知识特异性的关键酶作为“命中”是一个令人信服的要求开发小分子的治疗发现的基础上抑制选择粘附系统。我们已经检查了N-聚糖配体的酶组装对于E选择的特异性。初步，我们发现了一种新型化合物，可以破坏E选择聚糖的生物合成（已提交专利）。在第一阶段，主要目标是合成类似物和相关化合物，并在HL 60细胞中作为E选择配体生物合成的抑制剂进行测试。CD 44被赋予E选择的配体，并且还具有透明质酸的特异性受体，促进正常细胞中的迁移。CD 44在多种癌细胞中高度表达。一种抑制E选择特异性N-聚糖（如CD 44）生物合成的小分子为缓解癌症中的炎症性疾病和粘附事件带来了新的潜在工具。这一第一阶段的建议符合SBIR计划的中心原则，为有前途的商业产品。