title: The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication.
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.
authors.affiliation: Harvard Medical School, Department of Microbiology and Immunobiology, Boston, Massachusetts, USA.
authors.forename: Margot
authors.initials: M
authors.lastname: Carocci
authors.affiliation: Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology, Boston, Massachusetts, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hinshaw
authors.affiliation: Harvard Medical School, Department of Microbiology and Immunobiology, Boston, Massachusetts, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Rodgers
authors.affiliation: Harvard Medical School, Department of Microbiology and Immunobiology, Boston, Massachusetts, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Villareal
authors.affiliation: Harvard Medical School, Department of Microbiology and Immunobiology, Boston, Massachusetts, USA.
authors.forename: Dominique J
authors.initials: DJ
authors.lastname: Burri
authors.affiliation: Harvard Medical School, Department of Microbiology and Immunobiology, Boston, Massachusetts, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Pilankatta
authors.affiliation: Harvard Medical School, Department of Microbiology and Immunobiology, Boston, Massachusetts, USA.
authors.forename: Natalya P
authors.initials: NP
authors.lastname: Maharaj
authors.affiliation: Harvard Medical School, Department of Microbiology and Immunobiology, Boston, Massachusetts, USA.
authors.forename: Michaela U
authors.initials: MU
authors.lastname: Gack
authors.affiliation: Integrated Biotherapeutics, Gaithersburg, Maryland, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Stavale
authors.affiliation: Integrated Biotherapeutics, Gaithersburg, Maryland, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Warfield
authors.affiliation: Harvard Medical School, Department of Microbiology and Immunobiology, Boston, Massachusetts, USA priscilla_yang@hms.harvard.edu.
authors.forename: Priscilla L
authors.initials: PL
authors.lastname: Yang
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003715:Dengue / Q000188:drug therapy*; D003716:Dengue Virus / Q000254:growth & development*; D005260:Female; D017313:Fenretinide / Q000627:therapeutic use*; D057809:HEK293 Cells; D016174:Hepacivirus / Q000254:growth & development; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D014709:Vero Cells; D014766:Viremia / Q000188:drug therapy*; D014779:Virus Replication / Q000187:drug effects*; D014902:West Nile virus / Q000254:growth & development
chemical_list: D017382:Reactive Oxygen Species; D017313:Fenretinide