Suppression of pyrimidine biosynthesis by targeting DHODH enzyme robustly inhibits rotavirus replication

Rotavirus infection remains a great health burden worldwide especially in some developing countries. It causes severe dehydrating diarrhea in infants, young children, as well as immunocompromised and organ transplanted patients. Viral replication heavily relies on the host to supply nucleosides. Thu...

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Bibliographic Details
Published in:Antiviral research 2019-07, Vol.167, p.35-44
Main Authors: Chen, Sunrui, Ding, Shihao, Yin, Yuebang, Xu, Lei, Li, Pengfei, Peppelenbosch, Maikel P., Pan, Qiuwei, Wang, Wenshi
Format: Article
Language:English
Subjects:
Antiviral Agents - metabolism
Antiviral Agents - pharmacology
Biphenyl Compounds - metabolism
Biphenyl Compounds - pharmacology
Caco-2 Cells - enzymology
Caco-2 Cells - virology
Drug Development
Enzyme Inhibitors - pharmacology
Humans
Leflunomide - metabolism
Leflunomide - pharmacology
Oxidoreductases Acting on CH-CH Group Donors - metabolism
Primary Cell Culture
Pyrimidine Nucleosides - antagonists & inhibitors
Pyrimidine Nucleosides - biosynthesis
Rotavirus - drug effects
Rotavirus - metabolism
Virus Replication - drug effects
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Summary:Rotavirus infection remains a great health burden worldwide especially in some developing countries. It causes severe dehydrating diarrhea in infants, young children, as well as immunocompromised and organ transplanted patients. Viral replication heavily relies on the host to supply nucleosides. Thus, host enzymes involved in nucleotide biosynthesis represent potential targets for antiviral development. Dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in the de novo biosynthesis pathway of pyrimidines. In this study, we demonstrated that two specific DHODH enzyme inhibitors, brequinar (BQR) and leflunomide (LFM) robustly inhibited rotavirus replication in conventional human intestinal Caco2 cell line as well as in human primary intestinal organoids. The antiviral effect is conserved in both laboratory strain SA11 and rotavirus strain 2011K isolated from clinical sample. Mechanistic study indicated that BQR and LFM exerted their anti-rotavirus effect through targeting DHODH to deplete pyrimidine nucleotide pool. Therefore, targeting pyrimidine biosynthesis represents a potential approach for developing antiviral strategies against rotavirus. •Host enzymes involved in nucleotide biosynthesis represent potential targets for antiviral development.•Dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in the de novo biosynthesis pathway of pyrimidines.•Two specific DHODH enzyme inhibitors, brequinar (BQR) and leflunomide (LFM) robustly inhibited rotavirus replication.•BQR and LFM exerted their anti-rotavirus effect through targeting DHODH to deplete pyrimidine nucleotide pool.
ISSN:0166-3542
1872-9096
DOI:10.1016/j.antiviral.2019.04.005