Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models
Flaviviruses are (re)-emerging RNA viruses strictly dependent on lipid metabolism for infection. In the search for host targeting antivirals, we explored the effect of pharmacological modulation of fatty acid metabolism during flavivirus infection. Considering the central role of acetyl-Coenzyme A c...
| Autores: | , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/180597 |
| Acceso en línea: | http://hdl.handle.net/10261/180597 |
| Access Level: | acceso abierto |
| Palabra clave: | Flavivirus West Nile virus Dengue virus Zika virus Antivirus |
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Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse modelsJiménez de Oya, NereidaEsler, William P.Huard, KimEl-Kattan, Ayman F.Karamanlidis, GeorgiosBlázquez, Ana B.Ramos-Ibeas, PriscilaEscribano-Romero, EstelaLouloudes-Lázaro, AndrésCasas, JosefinaSobrino Castelló, FranciscoHoehn, KyleJames, David E.Gutiérrez-Adán, AlfonsoSaiz Calahorra, Juan CarlosMartín-Acebes, M. A.FlavivirusWest Nile virusDengue virusZika virusAntivirusFlaviviruses are (re)-emerging RNA viruses strictly dependent on lipid metabolism for infection. In the search for host targeting antivirals, we explored the effect of pharmacological modulation of fatty acid metabolism during flavivirus infection. Considering the central role of acetyl-Coenzyme A carboxylase (ACC) on fatty acid metabolism, we analyzed the effect of three small-molecule ACC inhibitors (PF-05175157, PF-05206574, and PF-06256254) on the infection of medically relevant flaviviruses, namely West Nile virus (WNV), dengue virus, and Zika virus. Treatment with these compounds inhibited the multiplication of the three viruses in cultured cells. PF-05175157 induced a reduction of the viral load in serum and kidney in WNV-infected mice, unveiling its therapeutic potential for the treatment of chronic kidney disease associated with persistent WNV infection. This study constitutes a proof of concept of the reliability of ACC inhibitors to become viable antiviral candidates. These results support the repositioning of metabolic inhibitors as broad-spectrum antivirals.This work was supported by Spanish Ministry of Economy and Competitiveness (MINECO) Fondo Europeo de Desarrollo Regional (FEDER) under Grant AGL2014-56518-JIN to M.A.M-A; INIA under Grant RTA2015-009 to J.-C.S.; and the Comunidad Autónoma de Madrid under Grant P2013/ABI-2906 (PLATESA) to J.-C.S and F.S. We thank the Pfizer Compound Transfer Program (Grants WI215864 and WI201531 to M.A.M.-A.) for providing the ACC inhibitors for cell culture and in vivo assays.Peer reviewedTaylor & FrancisMinisterio de Economía y Competitividad (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192019info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/180597reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/AGL2014-56518-JINhttps://doi.org/10.1080/22221751.2019.1604084Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1805972026-05-22T06:33:51Z |
| dc.title.none.fl_str_mv |
Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models |
| title |
Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models |
| spellingShingle |
Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models Jiménez de Oya, Nereida Flavivirus West Nile virus Dengue virus Zika virus Antivirus |
| title_short |
Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models |
| title_full |
Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models |
| title_fullStr |
Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models |
| title_full_unstemmed |
Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models |
| title_sort |
Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models |
| dc.creator.none.fl_str_mv |
Jiménez de Oya, Nereida Esler, William P. Huard, Kim El-Kattan, Ayman F. Karamanlidis, Georgios Blázquez, Ana B. Ramos-Ibeas, Priscila Escribano-Romero, Estela Louloudes-Lázaro, Andrés Casas, Josefina Sobrino Castelló, Francisco Hoehn, Kyle James, David E. Gutiérrez-Adán, Alfonso Saiz Calahorra, Juan Carlos Martín-Acebes, M. A. |
| author |
Jiménez de Oya, Nereida |
| author_facet |
Jiménez de Oya, Nereida Esler, William P. Huard, Kim El-Kattan, Ayman F. Karamanlidis, Georgios Blázquez, Ana B. Ramos-Ibeas, Priscila Escribano-Romero, Estela Louloudes-Lázaro, Andrés Casas, Josefina Sobrino Castelló, Francisco Hoehn, Kyle James, David E. Gutiérrez-Adán, Alfonso Saiz Calahorra, Juan Carlos Martín-Acebes, M. A. |
| author_role |
author |
| author2 |
Esler, William P. Huard, Kim El-Kattan, Ayman F. Karamanlidis, Georgios Blázquez, Ana B. Ramos-Ibeas, Priscila Escribano-Romero, Estela Louloudes-Lázaro, Andrés Casas, Josefina Sobrino Castelló, Francisco Hoehn, Kyle James, David E. Gutiérrez-Adán, Alfonso Saiz Calahorra, Juan Carlos Martín-Acebes, M. A. |
| author2_role |
author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Ministerio de Economía y Competitividad (España) Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
Flavivirus West Nile virus Dengue virus Zika virus Antivirus |
| topic |
Flavivirus West Nile virus Dengue virus Zika virus Antivirus |
| description |
Flaviviruses are (re)-emerging RNA viruses strictly dependent on lipid metabolism for infection. In the search for host targeting antivirals, we explored the effect of pharmacological modulation of fatty acid metabolism during flavivirus infection. Considering the central role of acetyl-Coenzyme A carboxylase (ACC) on fatty acid metabolism, we analyzed the effect of three small-molecule ACC inhibitors (PF-05175157, PF-05206574, and PF-06256254) on the infection of medically relevant flaviviruses, namely West Nile virus (WNV), dengue virus, and Zika virus. Treatment with these compounds inhibited the multiplication of the three viruses in cultured cells. PF-05175157 induced a reduction of the viral load in serum and kidney in WNV-infected mice, unveiling its therapeutic potential for the treatment of chronic kidney disease associated with persistent WNV infection. This study constitutes a proof of concept of the reliability of ACC inhibitors to become viable antiviral candidates. These results support the repositioning of metabolic inhibitors as broad-spectrum antivirals. |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019 2019 2019 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/180597 |
| url |
http://hdl.handle.net/10261/180597 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
#PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/AGL2014-56518-JIN https://doi.org/10.1080/22221751.2019.1604084 Sí |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
| dc.publisher.none.fl_str_mv |
Taylor & Francis |
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Taylor & Francis |
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reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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Consejo Superior de Investigaciones Científicas (CSIC) |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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15,811543 |