Potent antiviral activity of brequinar against the emerging Cantagalo virus in cell culture

Abstract

In the present work, the antiviral activity of brequinar (BQR) against the replication of Cantagalo virus was evaluated. BQR is a potent inhibitor of cellular dihydroorotate dehydrogenase, an enzyme of the de novo pyrimidine biosynthetic pathway. Infection in the presence of 0.5μM BQR reduced virus progeny production by >90%, revealing an EC(50) (drug concentration required to inhibit 50% of virus replication) of 0.017μM. Replication of other orthopoxviruses was also inhibited by BQR at similar levels. In the presence of the drug, virus early proteins accumulated to control levels, whereas late gene expression was severely impaired. This result was confirmed by indirect immunofluorescence assays and analysis of time-regulated expression of a reporter gene under the control of a virus promoter. Both assays revealed nearly 90% inhibition of late gene expression. BQR also blocked virus DNA replication, which accounted for the subsequent inhibition of virus late gene expression. The ablation of virus DNA replication, late gene expression and infectious progeny production was restored to control levels when infected cells were co-treated with uridine (URD) and BQR. These data demonstrated that BQR targeted virus DNA synthesis by depleting the cellular pyrimidine pool, which was bypassed by the salvage pathway when URD was added to the cell cultures.

D282, a Non-Nucleoside Inhibitor of Influenza Virus Infection that Interferes with de novo Pyrimidine Biosynthesis

“…Immunosuppression during certain infections such as those caused by vaccinia results in exacerbation of disease [40,41]. To avoid this problem, Schnellrath and Damasco [42] suggested that brequinar, a pyrimidine pathway inhibitor, might be used topically against cutaneous vaccinia infections.…”

The Antiviral Effect of Baicalin on Enterovirus 71 In Vitro

“…Virus infection analysis was performed by plaque reduction assay as described previously [ 22 ] with some modifications. Briefly, a total of RD cells (3 × 10 5 ) were seeded into six-well plates and cultured until 80% confluency.…”

“…To investigate the anti-EV71 activity of the baicalin, the experiments were performed according to the previously described method [ 22 ]. Baicalin was diluted in serum-free DMEM to 0, 6.25, 12.5, 25, and 50 μg/mL.…”

Identification of Inhibitors of ZIKV Replication

“…Group E included Brequinar, a known inhibitor of dihydroorotate dehydrogenase (DHODH). Brequinar has been described to have broad-spectrum antiviral activity against a large number of viruses ( Table 7 ) [ 52 , 53 , 54 , 55 , 56 , 57 ]. Brequinar has also been shown to have anti-ZIKV activity in Vero cells infected with ZIKV MR-766 and PRVABC59 (EC 50 of 0.08 and 0.08 µM, respectively), and in Vero cells infected with ZIKV MR-766 in pre-treatment conditions (EC 50 of 0.3 µM) [ 34 , 56 ].…”