A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection

Johanna E Fraser, Satoru Watanabe, Chunxiao Wang, Wing K K Chan, Belinda Maher, Adam Lopez-Denman, Caroline A Hick, Kylie M Wagstaff, Jason Murdoch Mackenzie, Patrick M Sexton, Subhash G Vasudevan, David A Jans

Research output: Contribution to journalArticleResearchpeer-review

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 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.
Original languageEnglish
Pages (from-to)1780 - 1791
Number of pages12
JournalJournal of Infectious Diseases
Volume210
Issue number11
DOIs
Publication statusPublished - 2014

Cite this

Fraser, Johanna E ; Watanabe, Satoru ; Wang, Chunxiao ; Chan, Wing K K ; Maher, Belinda ; Lopez-Denman, Adam ; Hick, Caroline A ; Wagstaff, Kylie M ; Mackenzie, Jason Murdoch ; Sexton, Patrick M ; Vasudevan, Subhash G ; Jans, David A. / A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection. In: Journal of Infectious Diseases. 2014 ; Vol. 210, No. 11. pp. 1780 - 1791.
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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 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.",
author = "Fraser, {Johanna E} and Satoru Watanabe and Chunxiao Wang and Chan, {Wing K K} and Belinda Maher and Adam Lopez-Denman and Hick, {Caroline A} and Wagstaff, {Kylie M} and Mackenzie, {Jason Murdoch} and Sexton, {Patrick M} and Vasudevan, {Subhash G} and Jans, {David A}",
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A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection. / Fraser, Johanna E; Watanabe, Satoru; Wang, Chunxiao; Chan, Wing K K; Maher, Belinda; Lopez-Denman, Adam; Hick, Caroline A; Wagstaff, Kylie M; Mackenzie, Jason Murdoch; Sexton, Patrick M; Vasudevan, Subhash G; Jans, David A.

In: Journal of Infectious Diseases, Vol. 210, No. 11, 2014, p. 1780 - 1791.

Research output: Contribution to journalArticleResearchpeer-review

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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.

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