Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4

Antiviral Res. 2016 May;129:93-98. doi: 10.1016/j.antiviral.2016.03.001. Epub 2016 Mar 3.

Abstract

The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10-20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection. UV-4B also reduced infectious virus production in in vitro antiviral activity assays against all four DENV serotypes, including clinical isolates. A set of purified enzyme, in vitro, and in vivo studies demonstrated that inhibition of endoplasmic reticulum (ER) α-glucosidases and not the glycosphingolipid pathway appears to be responsible for the antiviral activity of UV-4B against DENV. Along with a comprehensive safety package, these and previously published data provided support for an Investigational New Drug (IND) filing and Phases 1 and 2 clinical trials for UV-4B with an indication of acute dengue disease.

Keywords: Antibody-dependent enhancement; Antiviral; Dengue; Glucosidase; Iminosugar; UV-4B.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Deoxynojirimycin / administration & dosage
  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / pharmacology
  • 1-Deoxynojirimycin / therapeutic use
  • Animals
  • Antibodies, Viral / blood
  • Antibody-Dependent Enhancement / drug effects
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Cells, Cultured
  • Chlorocebus aethiops
  • Clinical Trials as Topic
  • Dengue Virus / drug effects*
  • Disease Models, Animal
  • Drugs, Investigational
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / enzymology
  • Glycoside Hydrolase Inhibitors / administration & dosage
  • Glycoside Hydrolase Inhibitors / chemistry
  • Glycoside Hydrolase Inhibitors / pharmacology*
  • Glycoside Hydrolase Inhibitors / therapeutic use
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Monocytes / virology
  • Receptors, Interferon / deficiency
  • Serogroup
  • Severe Dengue / drug therapy*
  • Severe Dengue / virology
  • Vero Cells
  • alpha-Glucosidases / metabolism*

Substances

  • Antibodies, Viral
  • Antiviral Agents
  • Drugs, Investigational
  • Glycoside Hydrolase Inhibitors
  • N-(9-methoxynonyl)-1-deoxynojirimycin
  • Receptors, Interferon
  • interferon receptor, type II
  • 1-Deoxynojirimycin
  • alpha-Glucosidases