DHODH:FMN binds DHODH inhibitors

Stable Identifier
R-HSA-9708759
Type
Reaction [binding]
Species
Homo sapiens
Compartment
ReviewStatus
5/5
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Dihydroorotate dehydrogenase (DHODH) is the fourth, and rate-limiting enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. DHODH's expression is selectively upregulated in proliferating and activated lymphocytes, making it a target susceptible to pharmacological inhibition in activated immune cells. Inhibition of DHODH causes a reduction in the available pyrimidine pool, which leads to metabolic stress and apoptosis in highly activated cells. DHODH inhibitors are used clinically to treat autoimmune diseases such as rheumatoid arthritis (Davis et al. 1996, Breedveld & Dayer 2000) and multiple sclerosis (Palmer 2010).

Novel potent inhibitors of human DHODH (S312, S416, vidofludimus and brequinar), as well as the existing drugs leflunomide and teriflunomide, all possess dual action of antiviral and immuno-regulation against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. These drugs may have clinical potentials to cure SARS-CoV-2 or other RNA viruses (Xiong et al. 2020, Coelho & Oliveira 2020, Hu et al. 2020, Maghzi et al. 2020). Brequinar has entered Phase 1/2 clinical evaluation in COVID-19 patients (NCT04425252).
Literature References
PubMed ID Title Journal Year
21157651 Teriflunomide, an inhibitor of dihydroorotate dehydrogenase for the potential oral treatment of multiple sclerosis

Palmer, AM

Curr Opin Investig Drugs 2010
32735689 Dihydroorotate dehydrogenase inhibitors in SARS-CoV-2 infection

Oliveira, PJ, Coelho, AR

Eur J Clin Invest 2020
32754890 Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Xiong, R, Zhang, L, Xu, K, Sun, Y, Zhu, L, Li, H, Jiang, X, Zhao, Z, Shan, J, Chen, Y, Shen, Z, Zou, G, Lan, K, Shang, W, Xiao, G, Tong, Y, Wu, Y, Ding, M, Liu, Y, Xu, L, Wang, Y, Lavillete, D, Wang, R, Zhao, Y, Li, S

Protein Cell 2020
8573583 The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase

Pitts, WJ, Magolda, RL, Cain, GA, Copeland, RA, Davis, JP

Biochemistry 1996
32696396 A Small-Scale Medication of Leflunomide as a Treatment of COVID-19 in an Open-Label Blank-Controlled Clinical Trial

Lan, K, Zheng, Z, Hu, K, Zhao, Y, Wang, M, Xu, K, Zhang, Y, Zhao, D, Li, X, Zeng, S, Li, H, Wang, T

Virol Sin 2020
11053058 Leflunomide: mode of action in the treatment of rheumatoid arthritis

Dayer, JM, Breedveld, FC

Ann Rheum Dis 2000
32494856 COVID-19 in teriflunomide-treated patients with multiple sclerosis

Tauhid, S, Maghzi, AH, Freedman, MS, Stankiewicz, JM, Cabot, A, Beretich, BD, Filippi, M, Berriosmorales, I, Schwartz, THW, Weiner, HL, Ionete, C, Preziosa, P, Houtchens, MK, Bakshi, R, Sloane, JA

J Neurol 2020
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