Abstract
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.
Highlights
The genus Flavivirus includes 53 closely related species of positive-strand RNA viruses transmitted by vectors [1]
The recent increase on the information relative to the involvement of lipids in flavivirus infection [38,39,40], there are limited data supporting the role of host lipids during flavivirus infection in vivo, and only the relevance of cholesterol and sphingolipids has been demonstrated in animal models [41,42,43,44]
Taking advantage of a series of small-molecule acetyl-CoA carboxylase (ACC) inhibitors recently developed to treat human disorders, we have investigated the significance of fatty acid metabolism in the infection of three different flaviviruses (WNV, dengue virus (DENV), and Zika virus (ZIKV)) in cell culture
Summary
The genus Flavivirus includes 53 closely related species of positive-strand RNA viruses transmitted by vectors (mosquitoes and ticks) [1]. West Nile virus (WNV) provokes outbreaks of febrile illness, encephalitis, acute flaccid-paralysis and can induce long lasting sequelae and a chronic renal disease associated with persistent infection, dengue virus (DENV) causes about 100 million cases of disease each year including hemorrhagic fevers, and Zika virus (ZIKV) is responsible for birth defects (microcephaly) and neurological syndromes [2,3,4,5]. The increase in worldwide travel and trade, global warming, and urbanization are facilitating the colonization of new territories by pathogenic flaviviruses, putting human and animal health at risk. This can be exemplified by the emergence of WNV and ZIKV in the Americas from 1999 and 2015, respectively. There is an urgent need for effective therapies against recognized pathogenic flaviviruses, and potentially suitable against future flaviviral threats
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