Selective inhibition of the membrane attack complex of complement by low molecular weight components of the aurin tricarboxylic acid synthetic complex
Selective inhibition of the membrane attack complex of complement by low molecular weight components of the aurin tricarboxylic acid synthetic complex
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DOI：
10.1016/j.neurobiolaging.2011.12.005
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发表时间：
2012-10-01
影响因子：
4.2
通讯作者：
McGeer, Patrick L.
中科院分区：
文献类型：
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作者：
Lee, Moonhee;Guo, Jian-Ping;McGeer, Patrick L.
补体在先天免疫系统和适应性免疫系统中都起着至关重要的作用。它识别靶点，调理它，产生过敏毒素，并通过膜攻击复合物（MAC）直接杀死细胞。在活细胞表面上组装C5 b-9（n）的最终功能可以通过旁观者裂解杀死宿主细胞。在这里，我们首次确定化合物，可以抑制旁观者溶解，而不干扰其他基本功能的补体。我们发现，金精三羧酸（ATA），金精四羧酸（AQA），金精六羧酸（AHA），阻止C9 C5 b-8的加成，使MAC不能形成。这些分子抑制人、大鼠和小鼠红细胞的溶血，半数最大抑制浓度（IC 50）在纳摩尔范围内。当口服给阿尔茨海默病型B6 SJL-Tg小鼠时，它们抑制血清中MAC的形成并改善记忆力。尸检显示，他们没有任何器官受损的证据。金精三羧酸、金精四羧酸和金精六羧酸可以是阿尔茨海默病和其中发生来自MAC的自损伤的其他退行性疾病的有效治疗剂。(c)2012 Elsevier Inc. All rights reserved.
Complement plays a vital role in both the innate and adaptive immune systems. It recognizes a target, opsonizes it, generates anaphylatoxins, and directly kills cells through the membrane attack complex (MAC). This final function, which assembles C5b-9(n) on viable cell surfaces, can kill host cells through bystander lysis. Here we identify for the first time compounds that can inhibit bystander lysis while not interfering with the other essential functions of complement. We show that aurin tricarboxylic acid (ATA), aurin quadracarboxylic acid (AQA), and aurin hexacarboxylic acid (AHA), block the addition of C9 to C5b-8 so that the MAC cannot form. These molecules inhibit hemolysis of human, rat, and mouse red cells with a half maximal inhibitory concentration (IC50) in the nanomolar range. When given orally to Alzheimer disease type B6SJL-Tg mice, they inhibit MAC formation in serum and improve memory retention. On autopsy, they show no evidence of harm to any organ. Aurin tricarboxylic acid, aurin quadracarboxylic acid, and aurin hexacarboxylic acid may be effective therapeutic agents in Alzheimer disease and other degenerative disorders where self damage from the MAC occurs. (c) 2012 Elsevier Inc. All rights reserved.