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

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 KhaliqAruna Sampath, Anthony M. Treston, Raymond A. Dwek, Sven G. Enterlein, Joanna L. Miller, Nicole Zitzmann, Urban Ramstedt, Sujan Shresta

^*Corresponding author for this work

Hospital Pharmacy

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

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.

Original language	English
Pages (from-to)	93-98
Number of pages	6
Journal	Antiviral Research
Volume	129
DOIs	https://doi.org/10.1016/j.antiviral.2016.03.001
State	Published - 2016/05/01

Keywords

Antibody-dependent enhancement
Antiviral
Dengue
Glucosidase
Iminosugar
UV-4B

ASJC Scopus subject areas

Pharmacology
Virology

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10.1016/j.antiviral.2016.03.001

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Warfield, K. L., Plummer, E. M., Sayce, A. C., Alonzi, D. S., Tang, W., Tyrrell, B. E., Hill, M. L., Caputo, A. T., Killingbeck, S. S., Beatty, P. R., Harris, E., Iwaki, R., Kinami, K., Ide, D., Kiappes, J. L., Kato, A., Buck, M. D., King, K., Eddy, W., ... Shresta, S. (2016). Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4. Antiviral Research, 129, 93-98. https://doi.org/10.1016/j.antiviral.2016.03.001

@article{41cff5dc7d334d5d8a3e1c0e45576ebf,

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

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",

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

note = "Publisher Copyright: {\textcopyright} 2016 The Authors. Published by Elsevier B.V.",

year = "2016",

month = may,

day = "1",

doi = "10.1016/j.antiviral.2016.03.001",

language = "英語",

volume = "129",

pages = "93--98",

journal = "Antiviral Research",

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Warfield, KL, Plummer, EM, Sayce, AC, Alonzi, DS, Tang, W, Tyrrell, BE, Hill, ML, Caputo, AT, Killingbeck, SS, Beatty, PR, Harris, E, Iwaki, R, Kinami, K, Ide, D, Kiappes, JL, Kato, A, Buck, MD, King, K, Eddy, W, Khaliq, M, Sampath, A, Treston, AM, Dwek, RA, Enterlein, SG, Miller, JL, Zitzmann, N, Ramstedt, U & Shresta, S 2016, 'Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4', Antiviral Research, vol. 129, pp. 93-98. https://doi.org/10.1016/j.antiviral.2016.03.001

TY - JOUR

T1 - Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4

AU - Warfield, Kelly L.

AU - Plummer, Emily M.

AU - Sayce, Andrew C.

AU - Alonzi, Dominic S.

AU - Tang, William

AU - Tyrrell, Beatrice E.

AU - Hill, Michelle L.

AU - Caputo, Alessandro T.

AU - Killingbeck, Sarah S.

AU - Beatty, P. Robert

AU - Harris, Eva

AU - Iwaki, Ren

AU - Kinami, Kyoko

AU - Ide, Daisuke

AU - Kiappes, J. L.

AU - Kato, Atsushi

AU - Buck, Michael D.

AU - King, Kevin

AU - Eddy, William

AU - Khaliq, Mansoora

AU - Sampath, Aruna

AU - Treston, Anthony M.

AU - Dwek, Raymond A.

AU - Enterlein, Sven G.

AU - Miller, Joanna L.

AU - Zitzmann, Nicole

AU - Ramstedt, Urban

AU - Shresta, Sujan

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

KW - Antibody-dependent enhancement

KW - Antiviral

KW - Dengue

KW - Glucosidase

KW - Iminosugar

KW - UV-4B

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U2 - 10.1016/j.antiviral.2016.03.001

DO - 10.1016/j.antiviral.2016.03.001

M3 - 学術論文

C2 - 26946111

AN - SCOPUS:84960364160

SN - 0166-3542

VL - 129

SP - 93

EP - 98

JO - Antiviral Research

JF - Antiviral Research

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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