Discovery of a new structural class of competitive hDHODH inhibitors with in vitro and in vivo anti-inflammatory, immunosuppressive effects
| Autor: | Ruolan Li, Li Yeying, Xuexia Zhang, Xinhua Lu, Cui Xiaolan, Haizhou Zheng, Zhao Feng, Xu Yan, Jingtong Zhu, Jie Lin, Zhihui Zheng, Xiao Ren, Shen Wenbin |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Oxidoreductases Acting on CH-CH Group Donors medicine.medical_treatment T-Lymphocytes Anti-Inflammatory Agents Dihydroorotate Dehydrogenase Drug Evaluation Preclinical Arthritis Inflammation Pharmacology Xylenes 03 medical and health sciences Mice In vivo Interferon medicine Animals Humans Enzyme Inhibitors Cell Proliferation Chemistry Immunosuppression medicine.disease Arthritis Experimental In vitro High-Throughput Screening Assays Rats 030104 developmental biology Drug Design Dihydroorotate dehydrogenase Cytokines medicine.symptom Ex vivo Immunosuppressive Agents medicine.drug |
| Zdroj: | European journal of pharmacology. 791 |
| ISSN: | 1879-0712 |
| Popis: | Human dihydroorotate dehydrogenase (hDHODH) is an inner mitochondrial membrane enzyme that involves in the fourth step of the biosynthesis of pyrimidine base. Inhibitors of hDHODH have been proven efficacy for the treatments of inflammation, rheumatoid arthritis, multiple sclerosis and cancer. In the present study, ascochlorin (ASC) and its derivatives, natural compounds from fungal metabolites, were discovered as hDHODH inhibitors by high-throughput screening. Enzyme kinetics studies showed that ASC competitively binds to hDHODH at the site of coenzyme Q substrate. In ex vivo study, ASC significantly inhibited the ConA-stimulated T lymphocytes proliferation and interleukin-2, interferon-γ production. Furthermore, ASC showed significant in vivo anti-inflammatory and immunosuppressive effects on the mice ears swelling, allogenic skin grafts and rat collagen-induced arthritis animal disease models. ASC significantly reduced ears edema level of mice, increased the survival time of allogenic skin implanted on the mice and attenuated arthritis severity of rat model. In conclusion, ASC was identified as a new structural class of hDHODH inhibitors with efficient anti-inflammatory, immunosuppressive activity, and may be a promising candidate for the development of new therapy in the treatment of autoimmune diseases. |
| Databáze: | OpenAIRE |
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