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

Qingyu Yang1, Chengyuan Wu2, Guangyan Zhu2

  • 1Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan, 430023, China; Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, China.

Antiviral Research
|December 23, 2022
PubMed

Insights

A new study reveals that ML390, a dihydroorotate dehydrogenase inhibitor, effectively inhibits Enterovirus 71 (EV71) replication. This compound shows promise as an antiviral treatment for hand, foot, and mouth disease caused by EV71.

Area of Science:

  • Virology
  • Biochemistry
  • Pharmacology

Background:

  • Enterovirus 71 (EV71) causes hand, foot, and mouth disease, posing a significant public health threat.
  • Currently, no effective antiviral drugs are available for EV71 infections.

Purpose of the Study:

  • To investigate the potential antiviral activity of ML390, a dihydroorotate dehydrogenase inhibitor, against EV71.
  • To elucidate the mechanism of action for ML390's antiviral effects.

Main Methods:

  • Assessing ML390's dose-dependent inhibition of EV71 replication in vitro.
  • Evaluating the impact of orotate, uridine, and cytosine supplementation on ML390's antiviral activity.
  • Testing ML390's efficacy in an EV71-infected mouse model.

Main Results:

  • ML390 demonstrated potent, dose-dependent inhibition of EV71 replication (IC50 = 0.06601 μM) with a high selectivity index (156.5).
  • The antiviral activity of ML390 was linked to the inhibition of the pyrimidine synthesis pathway, as evidenced by the reversal of its effects with orotate and pyrimidine precursors.
  • In vivo, ML390 significantly reduced viral load in multiple organs and increased survival rates in infected mice.

Conclusions:

  • ML390 exhibits significant antiviral activity against Enterovirus 71.
  • ML390's mechanism involves the inhibition of pyrimidine synthesis.
  • ML390 holds potential as a therapeutic agent for treating hand, foot, and mouth disease caused by EV71.
Keywords:
And mouth diseaseAntiviralDihydroorotate dehydrogenaseEnterovirus 71FootHandde novo pyrimidine synthesis pathway

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