TY - JOUR
T1 - A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection
AU - Fraser, Johanna E
AU - Watanabe, Satoru
AU - Wang, Chunxiao
AU - Chan, Wing K K
AU - Maher, Belinda
AU - Lopez-Denman, Adam
AU - Hick, Caroline A
AU - Wagstaff, Kylie M
AU - Mackenzie, Jason Murdoch
AU - Sexton, Patrick M
AU - Vasudevan, Subhash G
AU - Jans, David A
PY - 2014
Y1 - 2014
N2 - 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 non-structural 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 infection (ADE), ex vivo and in vivo DENV infections. In addition we use qRT-PCR 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 (EC50s) in the low muM range. 4-HPR, but not closely related N-(4-methoxyphenyl) retinamide (4-MPR), could reduce viral RNA levels and titres when applied to an established infection. 4-HPR, but not 4-MPR, was found to specifically up-regulate the PKR-like ER kinase (PERK) arm of the unfolded protein response (UPR). Strikingly, 4-HPR but not 4-MPR restricted infection in peripheral blood mononuclear cells, and in a lethal ADE mouse model. CONCLUSIONS: 4HPR is a novel antiviral that modulates the UPR, effective against DENV1-4 at concentrations achievable in the plasma in a clinical setting, and provides protection in a lethal mouse model.
AB - 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 non-structural 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 infection (ADE), ex vivo and in vivo DENV infections. In addition we use qRT-PCR 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 (EC50s) in the low muM range. 4-HPR, but not closely related N-(4-methoxyphenyl) retinamide (4-MPR), could reduce viral RNA levels and titres when applied to an established infection. 4-HPR, but not 4-MPR, was found to specifically up-regulate the PKR-like ER kinase (PERK) arm of the unfolded protein response (UPR). Strikingly, 4-HPR but not 4-MPR restricted infection in peripheral blood mononuclear cells, and in a lethal ADE mouse model. CONCLUSIONS: 4HPR is a novel antiviral that modulates the UPR, effective against DENV1-4 at concentrations achievable in the plasma in a clinical setting, and provides protection in a lethal mouse model.
UR - http://jid.oxfordjournals.org/content/210/11/1780.full.pdf+html
U2 - 10.1093/infdis/jiu319
DO - 10.1093/infdis/jiu319
M3 - Article
SN - 0022-1899
VL - 210
SP - 1780
EP - 1791
JO - The Journal of Infectious Diseases
JF - The Journal of Infectious Diseases
IS - 11
ER -