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

08:00 EDT 8th April 2019 | BioPortfolio

Summary of "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. 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.

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Name: Antiviral research
ISSN: 1872-9096
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Medical and Biotech [MESH] Definitions

An enzyme that, in the course of pyrimidine biosynthesis, catalyzes ring closure by removal of water from N-carbamoylaspartate to yield dihydro-orotic acid. EC 3.5.2.3.

An enzyme which catalyzes an endonucleolytic cleavage near PYRIMIDINE DIMERS to produce a 5'-phosphate product. The enzyme acts on the damaged DNA strand, from the 5' side of the damaged site.

An enzyme that in the course of pyrimidine biosynthesis, catalyzes the oxidation of dihydro-orotic acid to orotic acid utilizing oxygen as the electron acceptor. This enzyme is a flavoprotein which contains both FLAVIN-ADENINE DINUCLEOTIDE and FLAVIN MONONUCLEOTIDE as well as iron-sulfur centers. EC 1.3.3.1.

The enzyme catalyzing the formation of orotidine-5'-phosphoric acid (orotidylic acid) from orotic acid and 5-phosphoribosyl-1-pyrophosphate in the course of pyrimidine nucleotide biosynthesis. EC 2.4.2.10.

An epoxydodecadienamide isolated from several species, including ACREMONIUM, Acrocylindrum, and Helicoceras. It inhibits the biosynthesis of several lipids by interfering with enzyme function.

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