title: Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model.
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.
authors.affiliation: Antiviral Research Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.
authors.forename: Joanna L
authors.identifier: http://orcid.org/0000-0002-4383-4641
authors.initials: JL
authors.lastname: Miller
authors.affiliation: Antiviral Research Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.|The Royal Veterinary College, London, United Kingdom.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Spiro
authors.affiliation: Public Health England, Porton Down, Salisbury, United Kingdom.
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Dowall
authors.affiliation: Public Health England, Porton Down, Salisbury, United Kingdom.
authors.forename: Irene
authors.initials: I
authors.lastname: Taylor
authors.affiliation: Public Health England, Porton Down, Salisbury, United Kingdom.
authors.forename: Antony
authors.initials: A
authors.lastname: Rule
authors.affiliation: Antiviral Research Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.
authors.forename: Dominic S
authors.initials: DS
authors.lastname: Alonzi
authors.affiliation: Antiviral Research Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Sayce
authors.affiliation: Viral Pseudotype Unit, Faculty of Science and Technology, University of Westminster, London, United Kingdom.
authors.forename: Edward
authors.initials: E
authors.lastname: Wright
authors.affiliation: Viral Pseudotype Unit, Faculty of Science and Technology, University of Westminster, London, United Kingdom.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Bentley
authors.affiliation: Public Health England, Porton Down, Salisbury, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Thom
authors.affiliation: Public Health England, Porton Down, Salisbury, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Hall
authors.affiliation: Antiviral Research Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.affiliation: Public Health England, Porton Down, Salisbury, United Kingdom.
authors.forename: Roger
authors.initials: R
authors.lastname: Hewson
authors.affiliation: Antiviral Research Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.
authors.forename: Nicole
authors.initials: N
authors.lastname: Zitzmann
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D029043:Ebolavirus; D006168:Guinea Pigs; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy*; D010865:Pilot Projects
chemical_list: D017485:1-Deoxynojirimycin