Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus.
Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus.
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DOI：
10.1177/0961203315591031
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发表时间：
2015-11
期刊：
影响因子：
2.6
通讯作者：
Harnett MM
中科院分区：
文献类型：
--
作者：
Rodgers DT;Pineda MA;Suckling CJ;Harnett W;Harnett MM
ES-62是一种由寄生虫Acanthocheilonema viteae分泌的含磷酸胆碱（PC）的免疫调节剂，可预防系统性红斑狼疮（SLE）MRL/Lpr小鼠模型中的肾炎。然而，ES-62不适合作为治疗药物开发，因此我们设计了基于其活性PC部分的药物样小分子类似物（SMA）。为了提供基于ES-62的SMA在SLE中表现出治疗潜力的概念证据，我们研究了两种SMA在肾损伤发作后给予MRL/Lpr小鼠时保护免于肾炎的能力。在蛋白尿发作后给药时，评价SMA 11 a和12 b抑制MRL/Lpr小鼠抗核抗体（ANA）生成和随后肾脏病理学的能力。SMA 11 a和12 b抑制ANA和蛋白尿的发展。保护反映了肾细胞MyD 88表达的下调，这与IL-6的产生减少有关，IL-6是一种细胞因子，有望成为这种疾病的治疗靶点。SMA 11 a和12 b提供了基于寄生虫的安全免疫调节机制的合成化合物可以表现出作为用于SLE的新型药物的治疗潜力的原理证明，SLE是一种目前治疗仍然不足的疾病。
ES-62, a phosphorylcholine (PC)-containing immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, protects against nephritis in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE). However, ES-62 is not suitable for development as a therapy and thus we have designed drug-like small molecule analogues (SMAs) based around its active PC-moiety. To provide proof of concept that ES-62-based SMAs exhibit therapeutic potential in SLE, we have investigated the capacity of two SMAs to protect against nephritis when administered to MRL/Lpr mice after onset of kidney damage. SMAs 11a and 12b were evaluated for their ability to suppress antinuclear antibody (ANA) generation and consequent kidney pathology in MRL/Lpr mice when administered after the onset of proteinuria. SMAs 11a and 12b suppressed development of ANA and proteinuria. Protection reflected downregulation of MyD88 expression by kidney cells and this was associated with reduced production of IL-6, a cytokine that exhibits promise as a therapeutic target for this condition. SMAs 11a and 12b provide proof of principle that synthetic compounds based on the safe immunomodulatory mechanisms of parasitic worms can exhibit therapeutic potential as a novel class of drugs for SLE, a disease for which current therapies remain inadequate.