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...

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Bibliographic Details
Authors: 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.
Format: article
Status:Published version
Publication Date:2019
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/180597
Online Access:http://hdl.handle.net/10261/180597
Access Level:Open access
Keyword:Flavivirus
West Nile virus
Dengue virus
Zika virus
Antivirus
Description
Summary: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.

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