RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis.
RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis.
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DOI：
10.3892/ijmm.2012.1129
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发表时间：
2012-12
影响因子：
5.4
通讯作者：
Nakajima T
中科院分区：
文献类型：
--
作者：
Yagishita N;Aratani S;Leach C;Amano T;Yamano Y;Nakatani K;Nishioka K;Nakajima T
类风湿性关节炎（RA）显著影响生活质量。我们最近克隆了一种与内质网相关降解（ERAD）途径有关的环型E3泛素连接酶synoviolin。滑膜因子在类风湿滑膜细胞中高度表达，可能参与RA的发病机制。抑制滑膜活动是治疗类风湿性关节炎的一种潜在有效的治疗方法。我们对小分子进行了高通量筛选，以寻找滑膜自泛素化活性的抑制剂。我们发现了两类小分子，分别命名为LS-101和LS-102，它们抑制滑膜小提琴的活性。LS-102选择性地抑制滑膜酶活性，而LS-101抑制广泛的ring型E3连接酶。此外，这些抑制剂抑制类风湿滑膜细胞的增殖，并显着降低RA小鼠模型的疾病严重程度。我们的研究结果表明，抑制滑膜鞘是治疗类风湿性关节炎的一种潜在的有效方法。
Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway. Synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of RA. Inhibition of synoviolin activity is a potentially useful therapeutic approach for the treatment of RA. We conducted a high-throughput screen of small molecules to find inhibitors of synoviolin autoubiquitination activity. We identified two classes of small molecules, named LS-101 and LS-102, which inhibited synoviolin activity. LS-102 selectively inhibited synoviolin enzymatic activity, while LS-101 inhibited a broad array of RING-type E3 ligases. Moreover, these inhibitors suppressed the proliferation of rheumatoid synovial cells, and significantly reduced the severity of disease in a mouse model of RA. Our results suggest that inhibition of synoviolin is a potentially useful approach in the treatment of RA.
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影响因子：
3.7
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Hasegawa D;Fujii R;Yagishita N;Matsumoto N;Aratani S;Izumi T;Azakami K;Nakazawa M;Fujita H;Sato T;Araya N;Koike J;Tadokoro M;Suzuki N;Nagata K;Senoo H;Friedman SL;Nishioka K;Yamano Y;Itoh F;Nakajima T
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通讯作者：
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通讯作者：
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