title: A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection.
abstract: BACKGROUND
  Dengue virus (DENV) is estimated to cause 390 million infections each year, but there is no licensed vaccine or therapeutic currently available.
  
  
  METHODS
  We describe a novel, high-throughput screen to identify compounds inhibiting the interaction between DENV nonstructural protein 5 and host nuclear transport proteins. We document the antiviral properties of a lead compound against all 4 serotypes of DENV, antibody-dependent enhanced (ADE) infection, and ex vivo and in vivo DENV infections. In addition, we use quantitative reverse-transcription polymerase chain reaction to examine cellular effects upon compound addition.
  
  
  RESULTS
  We identify N-(4-hydroxyphenyl) retinamide (4-HPR) as effective in protecting against DENV-1-4 and DENV-1 ADE infections, with 50% effective concentrations in the low micromolar range. 4-HPR but not the closely related N-(4-methoxyphenyl) retinamide (4-MPR) could reduce viral RNA levels and titers when applied to an established infection. 4-HPR but not 4-MPR was found to specifically upregulate the protein kinase R-like endoplasmic reticulum kinase arm of the unfolded protein response. Strikingly, 4-HPR but not 4-MPR restricted infection in peripheral blood mononuclear cells and in a lethal ADE-infection mouse model.
  
  
  CONCLUSIONS
  4-HPR is a novel antiviral that modulates the unfolded protein response, effective against DENV1-4 at concentrations achievable in the plasma in a clinical setting, and provides protection in a lethal mouse model.
authors.affiliation: Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University.
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Fraser
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Satoru
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Wing Ki Kitti
authors.initials: WK
authors.lastname: Chan
authors.affiliation: Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University.
authors.forename: Belinda
authors.initials: B
authors.lastname: Maher
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne Department of Microbiology, La Trobe University, Bundoora.
authors.forename: Adam
authors.initials: A
authors.lastname: Lopez-Denman
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hick
authors.affiliation: Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University.
authors.forename: Kylie M
authors.initials: KM
authors.lastname: Wagstaff
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Mackenzie
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
authors.affiliation: Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University.
authors.forename: David A
authors.initials: DA
authors.lastname: Jans
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D003715:Dengue / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D003716:Dengue Virus / Q000145:classification / Q000378:metabolism*; D004195:Disease Models, Animal; D017313:Fenretinide / Q000494:pharmacology; D006801:Humans; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction; D014212:Tretinoin / Q000031:analogs & derivatives / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects*; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D017313:Fenretinide; D014212:Tretinoin; D017361:Viral Nonstructural Proteins; D019892:eIF-2 Kinase; C582223:NS5 protein, dengue virus; C058346:N-(4-methoxyphenyl)retinamide
keywords: antiviral; dengue virus; nuclear transport; unfolded protein response