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

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.
Kelly L Warfield 1,  Emily M Plummer 2,  Andrew C Sayce 3,  Dominic S Alonzi 4,  William Tang 5,  Beatrice E Tyrrell 6,  Michelle L Hill 7,  Alessandro T Caputo 8,  Sarah S Killingbeck 9,  P Robert Beatty 10,  Eva Harris 11,  Ren Iwaki 12,  Kyoko Kinami 13,  Daisuke Ide 14,  J L Kiappes 15,  Atsushi Kato 16,  Michael D Buck 17,  Kevin King 18,  William Eddy 19,  Mansoora Khaliq 20,  Aruna Sampath 21,  Anthony M Treston 22,  Raymond A Dwek 23,  Sven G Enterlein 24,  Joanna L Miller 25,  Nicole Zitzmann 26,  Urban Ramstedt 27,  Sujan Shresta 28
Affiliations

Affiliations

  • 1 Emergent Virology LLC, Gaithersburg, MD 20879, USA. Electronic address: [email protected].
  • 2 La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 3 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: [email protected].
  • 4 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: [email protected].
  • 5 La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 6 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: [email protected].
  • 7 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: [email protected].
  • 8 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: [email protected].
  • 9 Division of Infectious Diseases and Vaccinology, School of Public Health, University of California-Berkeley, Berkeley, CA, USA. Electronic address: [email protected].
  • 10 Division of Infectious Diseases and Vaccinology, School of Public Health, University of California-Berkeley, Berkeley, CA, USA. Electronic address: [email protected].
  • 11 Division of Infectious Diseases and Vaccinology, School of Public Health, University of California-Berkeley, Berkeley, CA, USA. Electronic address: [email protected].
  • 12 Department of Hospital Pharmacy, University of Toyama, Toyama, Japan. Electronic address: [email protected].
  • 13 Department of Hospital Pharmacy, University of Toyama, Toyama, Japan. Electronic address: [email protected].
  • 14 Department of Hospital Pharmacy, University of Toyama, Toyama, Japan. Electronic address: [email protected].
  • 15 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: [email protected].
  • 16 Department of Hospital Pharmacy, University of Toyama, Toyama, Japan. Electronic address: [email protected].
  • 17 La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 18 La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 19 La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 20 Emergent Virology LLC, Gaithersburg, MD 20879, USA. Electronic address: [email protected].
  • 21 Emergent Virology LLC, Gaithersburg, MD 20879, USA. Electronic address: [email protected].
  • 22 Emergent Virology LLC, Gaithersburg, MD 20879, USA. Electronic address: [email protected].
  • 23 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: [email protected].
  • 24 Integrated Biotherapeutics, Gaithersburg, MD 20878, USA. Electronic address: [email protected].
  • 25 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: [email protected].
  • 26 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: [email protected].
  • 27 Unither Virology LLC, Silver Spring, MD 20910, USA. Electronic address: [email protected].
  • 28 La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: [email protected].
PMID: 26946111 DOI: 10.1016/j.antiviral.2016.03.001
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.

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