Merck Serono Geneva Research Centre Geneva, Switzerland.
Front Immunol. 2012 Oct 16;3:293. doi: 10.3389/fimmu.2012.00293. eCollection 2012.
Heparin, a glycosaminoglycan (GAG), has both anti-inflammatory and anti-coagulant properties. The clinical use of heparin against inflammation, however, has been limited by concerns about increased bleeding. While the anti-coagulant activity of heparin is well understood, its anti-inflammatory properties are less so. Heparin is known to bind to certain cytokines, including chemokines, small proteins which mediate inflammation through their control of leukocyte migration and activation. Molecules which can interrupt the chemokine-GAG interaction without inhibiting coagulation could therefore, represent a new class of anti-inflammatory agents. In the present study, two approaches were undertaken, both focusing on the heparin-chemokine relationship. In the first, a structure based strategy was used: after an initial screening of potential small molecule binders using protein NMR on a target chemokine, binding molecules were optimized through structure-based design. In the second approach, commercially available short oligosaccharides were polysulfated. In vitro, these molecules prevented chemokine-GAG binding and chemokine receptor activation without disrupting coagulation. However, in vivo, these compounds caused variable results in a murine peritoneal recruitment assay, with a general increase of cell recruitment. In more disease specific models, such as antigen-induced arthritis and delayed-type hypersensitivity, an overall decrease in inflammation was noted, suggesting that the primary anti-inflammatory effect may also involve factors beyond the chemokine system.
肝素是一种糖胺聚糖（GAG），具有抗炎和抗凝血特性。然而，肝素在炎症方面的临床应用受到了增加出血风险的担忧的限制。尽管肝素的抗凝血活性得到了很好的理解，但它的抗炎特性却知之甚少。肝素已知可与某些细胞因子（包括趋化因子）结合，趋化因子是通过控制白细胞迁移和激活来介导炎症的小蛋白。因此，能够在不抑制凝血的情况下中断趋化因子-GAG 相互作用的分子可能代表一类新的抗炎剂。在本研究中，采用了两种方法，均侧重于肝素-趋化因子关系。在第一种方法中，采用了基于结构的策略：在使用目标趋化因子的蛋白质 NMR 对潜在小分子结合物进行初步筛选后，通过基于结构的设计对结合分子进行了优化。在第二种方法中，对商业上可获得的短寡糖进行了多硫酸化。在体外，这些分子可防止趋化因子-GAG 结合和趋化因子受体激活，而不破坏凝血。然而，在体内，这些化合物在小鼠腹膜募集测定中引起了不同的结果，导致细胞募集普遍增加。在更具疾病特异性的模型中，如抗原诱导的关节炎和迟发型超敏反应，观察到炎症总体减轻，这表明主要的抗炎作用可能还涉及趋化因子系统以外的因素。
