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

  • Author(s): Warfield, Kelly L
  • Plummer, Emily M
  • Sayce, Andrew C
  • Alonzi, Dominic S
  • Tang, William
  • Tyrrell, Beatrice E
  • Hill, Michelle L
  • Caputo, Alessandro T
  • Killingbeck, Sarah S
  • Beatty, P Robert
  • Harris, Eva
  • Iwaki, Ren
  • Kinami, Kyoko
  • Ide, Daisuke
  • Kiappes, JL
  • Kato, Atsushi
  • Buck, Michael D
  • King, Kevin
  • Eddy, William
  • Khaliq, Mansoora
  • Sampath, Aruna
  • Treston, Anthony M
  • Dwek, Raymond A
  • Enterlein, Sven G
  • Miller, Joanna L
  • Zitzmann, Nicole
  • Ramstedt, Urban
  • Shresta, Sujan
  • et al.
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.

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