Designing anti-inflammatory drugs from parasitic worms: a synthetic small molecule analogue of the Acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis.
Designing anti-inflammatory drugs from parasitic worms: a synthetic small molecule analogue of the Acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis.
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DOI：
10.1021/jm401251p
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发表时间：
2013-12-27
影响因子：
7.3
通讯作者：
Harnett W
中科院分区：
文献类型：
--
作者：
Al-Riyami L;Pineda MA;Rzepecka J;Huggan JK;Khalaf AI;Suckling CJ;Scott FJ;Rodgers DT;Harnett MM;Harnett W
尽管越来越多的证据表明寄生虫可以保护人类免于发展过敏性和自身免疫性疾病，并且持续鉴定出定义的蠕虫衍生的免疫调节分子，但迄今为止尚未从这些生物体开发出新的抗炎药物。我们已经以一种新的方式通过合成基于磷酸胆碱的药物样小分子文库来处理这一问题，磷酸胆碱是抗炎Acanthocheilonema viteae产品ES-62的活性部分，其作为免疫原性蛋白不适合用作药物。在初步体外筛选对相关巨噬细胞细胞因子应答的抑制作用后，选择含砜的磷酸胆碱类似物（11 a）用于在炎症、胶原诱导的关节炎（CIA）的体内模型中进行测试。测试显示，11 a在保护DBA/1小鼠免于发展CIA方面与ES-62一样有效，并且反映了其下调TLR/IL-1 R转导子MyD 88的作用机制。因此，11 a是抗炎药物开发的新原型。
In spite of increasing evidence that parasitic worms may protect humans from developing allergic and autoimmune diseases and the continuing identification of defined helminth-derived immunomodulatory molecules, to date no new anti-inflammatory drugs have been developed from these organisms. We have approached this matter in a novel manner by synthesizing a library of drug-like small molecules based upon phosphorylcholine, the active moiety of the anti-inflammatory Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is unsuitable for use as a drug. Following preliminary in vitro screening for inhibitory effects on relevant macrophage cytokine responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in an in vivo model of inflammation, collagen-induced arthritis (CIA). Testing revealed that 11a was as effective as ES-62 in protecting DBA/1 mice from developing CIA and mirrored its mechanism of action in downregulating the TLR/IL-1R transducer, MyD88. 11a is thus a novel prototype for anti-inflammatory drug development.
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影响因子：
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作者：
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