Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models

Emerg Microbes Infect. 2019;8(1):624-636. doi: 10.1080/22221751.2019.1604084.

Abstract

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.

Keywords: Flavivirus; West Nile virus; Zika virus; antivirals; dengue virus.

MeSH terms

  • Acetyl-CoA Carboxylase / antagonists & inhibitors*
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Antiviral Agents / administration & dosage
  • Dengue / drug therapy
  • Dengue / enzymology*
  • Dengue / virology
  • Dengue Virus / drug effects
  • Dengue Virus / genetics
  • Dengue Virus / physiology*
  • Disease Models, Animal
  • Enzyme Inhibitors / administration & dosage*
  • Female
  • Humans
  • Male
  • Mice
  • Virus Replication / drug effects
  • West Nile Fever / drug therapy
  • West Nile Fever / enzymology*
  • West Nile Fever / virology
  • West Nile virus / drug effects
  • West Nile virus / genetics
  • West Nile virus / physiology*
  • Zika Virus / drug effects
  • Zika Virus / genetics
  • Zika Virus / physiology*
  • Zika Virus Infection / drug therapy
  • Zika Virus Infection / enzymology*
  • Zika Virus Infection / virology

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Acetyl-CoA Carboxylase

Grants and funding

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.