ML390 inhibits enterovirus 71 replication by targeting de novo pyrimidine biosynthesis pathway

Enterovirus 71 (EV71), a small, single-stranded, positive-sense RNA virus belonging to the enterovirus genus in the family Picornaviridae, causes hand, foot, and mouth disease. Although EV71 seriously threatens to public health, no effective antiviral drugs are available for treating this disease. In this study, we found that ML390, a dihydroorotate dehydrogenase inhibitor, has potential anti-EV71 activity. ML390 dose-dependently inhibited EV71 replication with IC50 and selectivity index values of 0.06601 μM and 156.5, respectively. Supplementation with the downstream product orotate significantly suppressed the ability of ML390 to inhibit EV71 replication. Moreover, an adequate supply of exogenous uridine and cytosine suppressed the anti-EV71 activity of ML390. Thus, the antiviral activity of ML390 is mediated by the inhibition of the pyrimidine synthesis pathway. In an EV71-infected mouse model, ML390 reduced the load of EV71 in the brain, liver, heart, spleen, front legs, and hind legs, and significantly increased the survival rate of the mice infected by EV71. ML390 shows potential for the treatment of hand, foot, and mouth disease caused by EV71 infection.

 

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The study mentioned focuses on the potential antiviral activity of ML390, a dihydroorotate dehydrogenase inhibitor, against Enterovirus 71 (EV71). EV71 is a small, single-stranded, positive-sense RNA virus that belongs to the enterovirus genus in the Picornaviridae family. It is known to cause hand, foot, and mouth disease, which poses a serious threat to public health. Currently, there are no effective antiviral drugs available for treating this disease.

The researchers discovered that ML390 exhibits dose-dependent inhibition of EV71 replication. They determined the IC50 (half-maximal inhibitory concentration) value for ML390 against EV71 to be 0.06601 μM. Additionally, the selectivity index, which represents the therapeutic window of a drug, was found to be 156.5. These values suggest that ML390 has potent antiviral activity against EV71.

Further investigation revealed that the antiviral activity of ML390 is related to its inhibition of the pyrimidine synthesis pathway. The addition of orotate, a downstream product in this pathway, significantly reduced the ability of ML390 to inhibit EV71 replication. Moreover, the presence of exogenous uridine and cytosine, which are other components involved in pyrimidine synthesis, also suppressed the anti-EV71 activity of ML390. These findings suggest that ML390 exerts its antiviral effects by interfering with the production of pyrimidine nucleotides, which are essential for viral replication.

To evaluate the therapeutic potential of ML390, an EV71-infected mouse model was used. The results demonstrated that ML390 reduced the viral load of EV71 in various organs, including the brain, liver, heart, spleen, front legs, and hind legs. Additionally, ML390 significantly increased the survival rate of mice infected with EV71, indicating its efficacy in combating EV71-induced hand, foot, and mouth disease.

In conclusion, the study suggests that ML390, a dihydroorotate dehydrogenase inhibitor, exhibits promising antiviral activity against EV71. By inhibiting the pyrimidine synthesis pathway, ML390 effectively suppresses EV71 replication in vitro and demonstrates therapeutic benefits in an EV71-infected mouse model. These findings highlight the potential of ML390 as a treatment option for hand, foot, and mouth disease caused by EV71 infection.