Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model

PLoS One. 2016 Nov 23;11(11):e0167018. doi: 10.1371/journal.pone.0167018. eCollection 2016.

Abstract

The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars.

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / pharmacology*
  • Animals
  • Disease Models, Animal
  • Ebolavirus*
  • Guinea Pigs
  • Hemorrhagic Fever, Ebola / drug therapy*
  • Pilot Projects

Substances

  • 1-Deoxynojirimycin

Grant support

This work has been supported by Oxford Glycobiology Institute Endowment and a research grant from Emergent BioSolutions, Inc. (formerly Unither Virology LLC). ACS was funded by a Clarendon Fund Scholarship and a Santander Graduate Scholarship from Pembroke College, Oxford. SGS was funded by the Wellcome Trust, grant 092872/Z/10/Z. NZ is a Fellow of Merton College, Oxford. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.