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

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

Author information

1
Emergent Virology LLC, Gaithersburg, MD 20879, USA. Electronic address: warfieldk@ebsi.com.
2
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: Emily.plummer@gmail.com.
3
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: andrew.sayce@bioch.ox.ac.uk.
4
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: dominic.alonzi@bioch.ox.ac.uk.
5
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: wtang@lji.org.
6
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: beatrice.tyrrell@bioch.ox.ac.uk.
7
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: michelle.hill@bioch.ox.ac.uk.
8
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: alessandro.caputo@stx.ox.ac.uk.
9
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California-Berkeley, Berkeley, CA, USA. Electronic address: sskillingbeck@ucdavis.edu.
10
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California-Berkeley, Berkeley, CA, USA. Electronic address: prbeatty@berkeley.edu.
11
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California-Berkeley, Berkeley, CA, USA. Electronic address: eharris@berkeley.edu.
12
Department of Hospital Pharmacy, University of Toyama, Toyama, Japan. Electronic address: r-iwaki@fujichemical.co.jp.
13
Department of Hospital Pharmacy, University of Toyama, Toyama, Japan. Electronic address: s1160215@ems.u-toyama.ac.jp.
14
Department of Hospital Pharmacy, University of Toyama, Toyama, Japan. Electronic address: s1260204@ems.u-toyama.ac.jp.
15
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: john.kiappes@bioch.ox.ac.uk.
16
Department of Hospital Pharmacy, University of Toyama, Toyama, Japan. Electronic address: kato@med.u-toyama.ac.jp.
17
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: mdsbuck@gmail.com.
18
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: kevindalesamuelking@gmail.com.
19
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: william.e.eddy@gmail.com.
20
Emergent Virology LLC, Gaithersburg, MD 20879, USA. Electronic address: khlaliqm@ebsi.com.
21
Emergent Virology LLC, Gaithersburg, MD 20879, USA. Electronic address: sampatha1@ebsi.com.
22
Emergent Virology LLC, Gaithersburg, MD 20879, USA. Electronic address: trestona@ebsi.com.
23
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: raymond.dwek@exeter.ox.ac.uk.
24
Integrated Biotherapeutics, Gaithersburg, MD 20878, USA. Electronic address: sven@integratedbiotherapeutics.com.
25
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: joanna.miller@bioch.ox.ac.uk.
26
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: nicole.zitzmann@bioch.ox.ac.uk.
27
Unither Virology LLC, Silver Spring, MD 20910, USA. Electronic address: urban_ramstedt@yahoo.com.
28
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: sujan@lji.org.

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

PMID:
26946111
PMCID:
PMC5064435
DOI:
10.1016/j.antiviral.2016.03.001
[Indexed for MEDLINE]
Free PMC Article

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