Discovery of a new structural class of competitive hDHODH inhibitors with in vitro and in vivo anti-inflammatory, immunosuppressive effects

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• 作者：Wenbin Shen ; Xiao Ren ; Jingtong Zhu ; Yan Xu ; Jie Lin ; Yeying Li ; Feng Zhao ; Haizhou Zheng ; Ruolan Li ; Xiaolan Cui ; Xuexia Zhang ; Xinhua Lu ; ^{luxinhua89@hotmail.com" class="auth_mail" title="E-mail the corresponding author} ; Zhihui Zheng ; ^{anzhengzhihui@hotmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Ascochlorin (PubChem CID ; 11258227) ; Ascofuranone (PubChem CID ; 6434242) ; Ilicicolin C (PubChem CID ; 24094116) ; Chlorocylindrocarpol (PubChem CID ; 25243464)
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：791
• 期：Complete
• 页码：205-212
• 全文大小：1799 K

文摘

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.