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
  • 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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