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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.
- Source :
-
Antiviral research [Antiviral Res] 2016 May; Vol. 129, pp. 93-98. Date of Electronic Publication: 2016 Mar 03. - Publication Year :
- 2016
-
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.<br /> (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- 1-Deoxynojirimycin administration & dosage
1-Deoxynojirimycin pharmacology
1-Deoxynojirimycin therapeutic use
Animals
Antibodies, Viral blood
Antibody-Dependent Enhancement drug effects
Antiviral Agents administration & dosage
Antiviral Agents therapeutic use
Cells, Cultured
Chlorocebus aethiops
Clinical Trials as Topic
Disease Models, Animal
Drugs, Investigational
Endoplasmic Reticulum drug effects
Endoplasmic Reticulum enzymology
Glycoside Hydrolase Inhibitors administration & dosage
Glycoside Hydrolase Inhibitors chemistry
Glycoside Hydrolase Inhibitors therapeutic use
Humans
Inhibitory Concentration 50
Mice
Monocytes virology
Receptors, Interferon deficiency
Serogroup
Severe Dengue virology
Vero Cells
1-Deoxynojirimycin analogs & derivatives
Antiviral Agents pharmacology
Dengue Virus drug effects
Glycoside Hydrolase Inhibitors pharmacology
Severe Dengue drug therapy
alpha-Glucosidases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1872-9096
- Volume :
- 129
- Database :
- MEDLINE
- Journal :
- Antiviral research
- Publication Type :
- Academic Journal
- Accession number :
- 26946111
- Full Text :
- https://doi.org/10.1016/j.antiviral.2016.03.001