Pepys Mark B, Hirschfield Gideon M, Tennent Glenys A, Gallimore J Ruth, Kahan Melvyn C, Bellotti Vittorio, Hawkins Philip N, Myers Rebecca M, Smith Martin D, Polara Alessandra, Cobb Alexander J A, Ley Steven V, Aquilina J Andrew, Robinson Carol V, Sharif Isam, Gray Gillian A, Sabin Caroline A, Jenvey Michelle C, Kolstoe Simon E, Thompson Darren, Wood Stephen P
Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine, Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK.
Nature. 2006 Apr 27;440(7088):1217-21. doi: 10.1038/nature04672.
Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.
补体介导的炎症会加剧心脏病发作和中风时缺血性坏死的组织损伤，而心脏病发作和中风是发达国家最常见的死亡原因。大面积梗死会增加急性发病时的发病率和死亡率，并且在急性事件的幸存者中，较大的无功能瘢痕会对长期预后产生不利影响。因此，对于新的心脏保护和神经保护治疗存在重要的未满足医疗需求。我们之前已经表明，人C反应蛋白（CRP）是一种经典的急性期蛋白，它与受损组织中暴露的配体结合，然后激活补体，分别增加冠状动脉或脑动脉结扎大鼠的心肌和脑梗死面积。大鼠CRP不会激活大鼠补体，而人CRP会激活大鼠和人补体。因此，给大鼠注射人CRP是内源性人CRP作用的一个极佳模型。在此我们报告1,6-双（磷酸胆碱）-己烷作为CRP特异性小分子抑制剂的设计、合成及功效。该回文化合物的五个分子被两个五聚体CRP分子结合，交联并封闭CRP的配体结合B面并阻断其功能。给急性心肌梗死大鼠注射1,6-双（磷酸胆碱）-己烷可消除注射人CRP所导致的梗死面积增加和心脏功能障碍。因此，对CRP进行治疗性抑制是急性心肌梗死心脏保护的一种有前景的新方法，并且也可能为中风提供神经保护。潜在的更广泛应用包括其他以CRP产生增加为特征的炎症、感染和组织损伤情况，其中CRP与受损细胞中暴露的配体结合可能导致补体介导的组织损伤加剧。
