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

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

doi:10.1016/j.antiviral.2016.03.001

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.

Authors

Kelly L Warfield¹, Emily M Plummer², Andrew C Sayce³, Dominic S Alonzi⁴, William Tang⁵, Beatrice E Tyrrell⁶, Michelle L Hill⁷, Alessandro T Caputo⁸, Sarah S Killingbeck⁹, P Robert Beatty¹⁰, Eva Harris¹¹, Ren Iwaki¹², Kyoko Kinami¹³, Daisuke Ide¹⁴, J L Kiappes¹⁵, Atsushi Kato¹⁶, Michael D Buck¹⁷, Kevin King¹⁸, William Eddy¹⁹, Mansoora Khaliq²⁰, Aruna Sampath²¹, Anthony M Treston²², Raymond A Dwek²³, Sven G Enterlein²⁴, Joanna L Miller²⁵, Nicole Zitzmann²⁶, Urban Ramstedt²⁷, Sujan Shresta²⁸

Affiliations

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.

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
Receptors, Interferon
interferon receptor, type II
1-Deoxynojirimycin
N-9-methoxynonyldeoxynojirimycin
alpha-Glucosidases

Abstract

Publication types

MeSH terms

Substances

Grants and funding