Assessment of the potential for host-targeted iminosugars UV-4 and UV-5 activity against filovirus infections in vitro and in vivo

Kelly L. Warfield, Travis K. Warren, Xiangguo Qiu, Jay Wells, Chad Mire, Joan B. Geisbert, Kelly S. Stuthman, Nicole L. Garza, Sean A. Van Tongeren, Amy C. Shurtleff, Krystle N. Agans, Gary Wong, Michael V. Callahan, Thomas Geisbert, Brennan Klose, Urban Ramstedt, Anthony M. Treston

Research output: Contribution to journalArticle

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Abstract

Iminosugars are host-directed antivirals with broad-spectrum activity. The iminosugar, N-butyl-deoxynojirimycin (NB-DNJ or Miglustat®), is used in humans for treatment of Gaucher's disease and has mild antiviral properties. More potent analogs of NB-DNJ have been generated and have demonstrated activity against a variety of viruses including flaviviruses, influenza, herpesviruses and filoviruses. In the current study, a panel of analogs based on NB-DNJ was analyzed for activity against Ebola (EBOV) and Marburg viruses (MARV). The antiviral activity of NB-DNJ (UV-1), UV-2, UV-3, UV-4 and UV-5 against both EBOV and MARV was demonstrated in Vero cells. Subsequent studies to examine the activity of UV-4 and UV-5 using rodent models of EBOV and MARV were performed. In vivo efficacy studies provided inconsistent data following treatment with iminosugars using filovirus mouse models. A tolerability study in nonhuman primates demonstrated that UV-4 could be administered at much higher dose levels than rodents. Since UV-4 was active in vitro, had been demonstrated to be active against influenza and dengue in vivo, and was being tested in a Phase 1 clinical trial, a small proof-of-concept nonhuman primate trial was performed to determine whether this antiviral candidate could provide clinical benefit to EBOV-infected individuals. Administration of UV-4B did not provide a clinical or survival benefit to macaques infected with EBOV–Makona; however, dosing of animals was not optimal in this study. Efficacy may be improved by thrice daily dosing (e.g. by nasogastric tube feeding) to match the efficacious dosing regimens demonstrated against dengue and influenza viruses.

Original languageEnglish (US)
Pages (from-to)22-31
Number of pages10
JournalAntiviral Research
Volume138
DOIs
StatePublished - Feb 1 2017

Fingerprint

Marburgvirus
Antiviral Agents
Infection
Primates
Human Influenza
Rodentia
Ebolavirus
Flavivirus
Gaucher Disease
Clinical Trials, Phase I
Dengue Virus
Vero Cells
Dengue
Herpesviridae
Macaca
Enteral Nutrition
Orthomyxoviridae
Viruses
Survival
N-(9-methoxynonyl)-1-deoxynojirimycin

Keywords

  • Antiviral
  • Ebola virus
  • Glucosidase
  • Iminosugar
  • Marburg virus
  • UV-4B

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Cite this

Assessment of the potential for host-targeted iminosugars UV-4 and UV-5 activity against filovirus infections in vitro and in vivo. / Warfield, Kelly L.; Warren, Travis K.; Qiu, Xiangguo; Wells, Jay; Mire, Chad; Geisbert, Joan B.; Stuthman, Kelly S.; Garza, Nicole L.; Van Tongeren, Sean A.; Shurtleff, Amy C.; Agans, Krystle N.; Wong, Gary; Callahan, Michael V.; Geisbert, Thomas; Klose, Brennan; Ramstedt, Urban; Treston, Anthony M.

In: Antiviral Research, Vol. 138, 01.02.2017, p. 22-31.

Research output: Contribution to journalArticle

Warfield, KL, Warren, TK, Qiu, X, Wells, J, Mire, C, Geisbert, JB, Stuthman, KS, Garza, NL, Van Tongeren, SA, Shurtleff, AC, Agans, KN, Wong, G, Callahan, MV, Geisbert, T, Klose, B, Ramstedt, U & Treston, AM 2017, 'Assessment of the potential for host-targeted iminosugars UV-4 and UV-5 activity against filovirus infections in vitro and in vivo', Antiviral Research, vol. 138, pp. 22-31. https://doi.org/10.1016/j.antiviral.2016.11.019
Warfield, Kelly L. ; Warren, Travis K. ; Qiu, Xiangguo ; Wells, Jay ; Mire, Chad ; Geisbert, Joan B. ; Stuthman, Kelly S. ; Garza, Nicole L. ; Van Tongeren, Sean A. ; Shurtleff, Amy C. ; Agans, Krystle N. ; Wong, Gary ; Callahan, Michael V. ; Geisbert, Thomas ; Klose, Brennan ; Ramstedt, Urban ; Treston, Anthony M. / Assessment of the potential for host-targeted iminosugars UV-4 and UV-5 activity against filovirus infections in vitro and in vivo. In: Antiviral Research. 2017 ; Vol. 138. pp. 22-31.
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