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: Johanna E Fraser, Satoru Watanabe, Chunxiao Wang, Wing Ki Kitti Chan, Belinda Maher, Adam Lopez-Denman, Caroline Hick, Kylie M Wagstaff, Jason M Mackenzie, Patrick M Sexton, Subhash G Vasudevan, David A Jans
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 210 Issue 11 Pg. 1780-91 (Dec 01 2014) ISSN: 1537-6613 [Electronic] United States
• PMID: 24903662 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Antiviral Agents
• Carrier Proteins
• NS5 protein, dengue virus
• Viral Nonstructural Proteins
• Fenretinide
• Tretinoin
• N-(4-methoxyphenyl)retinamide
• PERK kinase
• eIF-2 Kinase

Topics

• Active Transport, Cell Nucleus (drug effects)
• Animals
• Antiviral Agents (pharmacology)
• Carrier Proteins (metabolism)
• Cell Line
• Dengue (drug therapy, metabolism, virology)
• Dengue Virus (classification, metabolism)
• Disease Models, Animal
• Fenretinide (pharmacology)
• Humans
• Mice
• Protein Binding (drug effects)
• Protein Transport (drug effects)
• Signal Transduction
• Tretinoin (analogs & derivatives, pharmacology)
• Unfolded Protein Response (drug effects)
• Viral Nonstructural Proteins (metabolism)
• Virus Replication (drug effects)
• eIF-2 Kinase (metabolism)