DOI: 10.1101/481440Nov 29, 2018Paper

Mechanism of action of methotrexate against Zika virus

BioRxiv : the Preprint Server for Biology
Sung BeckJair L. Siqueira-Neto

Abstract

Zika virus (ZIKV), which is associated with microcephaly in infants and Guillain-Barré syndrome, reemerged as a serious public health threat in Latin America in recent years. Previous high-throughput screening (HTS) campaigns have revealed several potential hit molecules against ZIKV, including methotrexate (MTX), which is clinically used as an anti-cancer chemotherapy and anti-rheumatoid agent. We studied the mechanism of action of MTX against ZIKV in relation to its inhibition of dihydrofolate reductase (DHFR) in vitro using Vero and human neural stem cells (hNSCs). As expected, an antiviral effect for MTX against ZIKV was observed, showing up to ten-fold decrease in virus titer during MTX treatment. We also observed that addition of leucovorin (a downstream metabolite of DHFR pathway) rescued the ZIKV replication impaired by MTX treatment in ZIKV-infected cells, explaining the antiviral effect of MTX through inhibition of DHFR. We also found that addition of adenosine to ZIKV-infected cells was able to rescue ZIKV replication inhibited by MTX, suggesting that restriction of de novo synthesis adenosine triphosphate (ATP) pools suppresses viral replication. These results confirm that the DFHR pathway can be targeted to inhibit...Continue Reading

Related Concepts

Adenosine
Antiviral Agents
Flavivirus
Guillain-Barre Syndrome
Leucovorin
Methotrexate
Virus Replication
Virus
diadenosine triphosphate
Zika virus (organism)

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