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Mechanism of Action of Methotrexate Against Zika Virus

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 meth...

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Autores principales: Beck, Sungjun, Zhu, Zhe, Oliveira, Michelli F., Smith, Davey M., Rich, Jeremy N., Bernatchez, Jean A., Siqueira-Neto, Jair L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521145/
https://www.ncbi.nlm.nih.gov/pubmed/30974762
http://dx.doi.org/10.3390/v11040338
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author Beck, Sungjun
Zhu, Zhe
Oliveira, Michelli F.
Smith, Davey M.
Rich, Jeremy N.
Bernatchez, Jean A.
Siqueira-Neto, Jair L.
author_facet Beck, Sungjun
Zhu, Zhe
Oliveira, Michelli F.
Smith, Davey M.
Rich, Jeremy N.
Bernatchez, Jean A.
Siqueira-Neto, Jair L.
author_sort Beck, Sungjun
collection PubMed
description 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.
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spelling pubmed-65211452019-06-03 Mechanism of Action of Methotrexate Against Zika Virus Beck, Sungjun Zhu, Zhe Oliveira, Michelli F. Smith, Davey M. Rich, Jeremy N. Bernatchez, Jean A. Siqueira-Neto, Jair L. Viruses Communication 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. MDPI 2019-04-10 /pmc/articles/PMC6521145/ /pubmed/30974762 http://dx.doi.org/10.3390/v11040338 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Beck, Sungjun
Zhu, Zhe
Oliveira, Michelli F.
Smith, Davey M.
Rich, Jeremy N.
Bernatchez, Jean A.
Siqueira-Neto, Jair L.
Mechanism of Action of Methotrexate Against Zika Virus
title Mechanism of Action of Methotrexate Against Zika Virus
title_full Mechanism of Action of Methotrexate Against Zika Virus
title_fullStr Mechanism of Action of Methotrexate Against Zika Virus
title_full_unstemmed Mechanism of Action of Methotrexate Against Zika Virus
title_short Mechanism of Action of Methotrexate Against Zika Virus
title_sort mechanism of action of methotrexate against zika virus
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521145/
https://www.ncbi.nlm.nih.gov/pubmed/30974762
http://dx.doi.org/10.3390/v11040338
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