期刊
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
卷 30, 期 6, 页码 1281-1286出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijmm.2012.1129
关键词
rheumatoid arthritis; synoviolin; E3 ubiquitin ligase; endoplasmic reticulum associated degradation; inhibitor
资金
- Naito Foundation
- Natural Science Scholarship Daiichi-Sankyo Foundation of Life Science
- Bureau of Social Welfare and Public Health
- Ministry of Health Labour and Welfare Japan Society for the Promotion of Science
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [24791006, 23659502, 23659176] Funding Source: KAKEN
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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