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• W2074750922 abstract "Dengue virus (DENV), a member of the Flaviviridae family, is a mosquito-borne pathogen and the cause of dengue fever. The increasing prevalence of DENV worldwide heightens the need for an effective vaccine and specific antivirals. Due to the dependence of DENV upon the lipid biosynthetic machinery of the host cell, lipid signaling and metabolism present unique opportunities for inhibiting viral replication. We screened a library of bioactive lipids and modulators of lipid metabolism and identified 4-hydroxyphenyl retinamide (4-HPR) (fenretinide) as an inhibitor of DENV in cell culture. 4-HPR inhibits the steady-state accumulation of viral genomic RNA and reduces viremia when orally administered in a murine model of DENV infection. The molecular target responsible for this antiviral activity is distinct from other known inhibitors of DENV but appears to affect other members of the Flaviviridae, including the West Nile, Modoc, and hepatitis C viruses. Although long-chain ceramides have been implicated in DENV replication, we demonstrate that DENV is insensitive to the perturbation of long-chain ceramides in mammalian cell culture and that the effect of 4-HPR on dihydroceramide homeostasis is separable from its antiviral activity. Likewise, the induction of reactive oxygen species by 4-HPR is not required for the inhibition of DENV. The inhibition of DENV in vivo by 4-HPR, combined with its well-established safety and tolerability in humans, suggests that it may be repurposed as a pan-Flaviviridae antiviral agent. This work also illustrates the utility of bioactive lipid screens for identifying critical interactions of DENV and other viral pathogens with host lipid biosynthesis, metabolism, and signal transduction." @default.
• W2074750922 created "2016-06-24" @default.
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• W2074750922 date "2015-01-01" @default.
• W2074750922 modified "2023-10-01" @default.
• W2074750922 title "The Bioactive Lipid 4-Hydroxyphenyl Retinamide Inhibits Flavivirus Replication" @default.
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• W2074750922 doi "https://doi.org/10.1128/aac.04177-14" @default.
• W2074750922 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4291433" @default.
• W2074750922 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25313218" @default.
• W2074750922 hasPublicationYear "2015" @default.
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