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Viruses 2019, 11(4), 338; https://doi.org/10.3390/v11040338

Mechanism of Action of Methotrexate Against Zika Virus

1
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA
2
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA
3
Department of Medicine, Division of Regenerative Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
4
Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA 92093, USA
5
Veterans Affairs San Diego Healthcare System, San Diego, CA 92093, USA
6
Center for Discovery and Innovation in Parasitic Diseases, University of California, San Diego, La Jolla, CA 92093, USA
*
Authors to whom correspondence should be addressed.
Received: 23 March 2019 / Accepted: 5 April 2019 / Published: 10 April 2019
(This article belongs to the Special Issue Emerging Viruses)
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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 10-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 DHFR pathway can be targeted to inhibit replication of ZIKV, similar to other published results showing this effect in related flaviviruses. View Full-Text
Keywords: Zika virus; antivirals; nucleotide metabolism; methotrexate; dihydrofolate reductase Zika virus; antivirals; nucleotide metabolism; methotrexate; dihydrofolate reductase
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Beck, S.; Zhu, Z.; Oliveira, M.F.; Smith, D.M.; Rich, J.N.; Bernatchez, J.A.; Siqueira-Neto, J.L. Mechanism of Action of Methotrexate Against Zika Virus. Viruses 2019, 11, 338.

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