Synoviolin inhibitors for treatment of fibrosis

用于治疗纤维化的滑膜素抑制剂

• 批准号: 23659502
• 负责人: YAGISHITA Naoko
• 金额: $ 2.33万
• 依托单位: St. Marianna University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23659502/
• 关键词: 関節リウマチ; 滑膜細菌; シノビオリン; 小胞体関連分解; 線維化; 阻害剤; 滑膜細胞

Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned synoviolin, an E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation pathway. Synoviolin is highly expressed in rheumatoid synovial cells and is involved in the pathogenesis of RA. Inhibition of synoviolin activity is a potentially useful therapeutic approach for the treatment of RA. We recently 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 and liver fibrosis. Our results suggest that inhibition of synoviolin is a potentially useful approach in the treatment of fibrosis.

类风湿关节炎(RA)严重影响患者的生活质量。我们最近克隆了一种E3泛素连接酶，它与内质网相关的降解途径有关。滑膜蛋白在类风湿滑膜细胞中高表达，参与了类风湿关节炎的发病过程。抑制滑膜蛋白活性是治疗类风湿关节炎的一种有潜力的治疗方法。我们最近发现了两类小分子，命名为LS-101和LS-102，它们可以抑制滑膜小球的活性。LS-102选择性地抑制滑膜素酶活性，而LS-101则抑制广泛的环型E3连接酶。此外，这些抑制剂抑制类风湿滑膜细胞的增殖，并显著降低了类风湿关节炎和肝纤维化小鼠模型的疾病严重程度。我们的结果表明，抑制突触素在治疗纤维化方面是一种潜在的有用方法。

项目成果

シノビオリンから見た関節リウマチの病態研究

滑膜素视角下类风湿性关节炎的病理学研究

• 发表时间: 2011
• 作者: 八木下尚子;他1名
• 通讯作者: 他1名

RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis.

• DOI: 10.3892/ijmm.2012.1129
• 发表时间: 2012-12
• 期刊: International journal of molecular medicine
• 影响因子: 5.4
• 作者: Yagishita N;Aratani S;Leach C;Amano T;Yamano Y;Nakatani K;Nishioka K;Nakajima T
• 通讯作者: Nakajima T

ER stress signaling as a chronic inflammation

作为慢性炎症的内质网应激信号

• 发表时间: 2011
• 作者: Yagishita N;Aratani S;Yamano Y;Nishioka K;Nakajima T
• 通讯作者: Nakajima T

E3 ユビキチンリガ-ゼシノビオリンの線維化への関与

E3泛素连接器-zecinoviolin参与纤维化

• 发表时间: 2011
• 作者: 八木下尚子;荒谷聡子;佐藤知雄;藤井亮爾;山野嘉久;西岡久寿樹;中島利博
• 通讯作者: 中島利博

Importance of E3 ubiquitin ligase Synoviolin in fibrogenesis

E3 泛素连接酶滑膜蛋白在纤维发生中的重要性

• 发表时间: 2011
• 作者: Yagishita N;Hasegawa D;Aratani S;Yamano Y;Nakajima T
• 通讯作者: Nakajima T