Discovery of a new structural class of competitive hDHODH inhibitors with in vitro and in vivo anti-inflammatory, immunosuppressive effects.
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.
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China.
Wenbin
W
Shen
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China.
Xiao
X
Ren
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China.
Jingtong
J
Zhu
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China.
Yan
Y
Xu
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China.
Jie
J
Lin
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China.
Yeying
Y
Li
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China.
Feng
F
Zhao
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China.
Haizhou
H
Zheng
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China.
Ruolan
R
Li
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China.
Xiaolan
X
Cui
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China.
Xuexia
X
Zhang
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China. Electronic address: luxinhua89@hotmail.com.
Xinhua
X
Lu
New Drug Research & Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, No. 388 Heping East Road, Shijiazhuang 050015, Hebei, China. Electronic address: anzhengzhihui@hotmail.com.
Zhihui
Z
Zheng
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D057166:High-Throughput Screening Assays; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D051381:Rats; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D014992:Xylenes / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D014992:Xylenes; D044925:Oxidoreductases Acting on CH-CH Group Donors
Anti-inflammatory; Ascochlorin; Ascochlorin (PubChem CID: 11258227); Ascofuranone (PubChem CID: 6434242); Chlorocylindrocarpol (PubChem CID: 25243464); DHODH inhibitor; Ilicicolin C (PubChem CID: 24094116); Immunosuppression; Rheumatoid arthritis