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Minimal in vivo efficacy of iminosugars in a lethal Ebola virus guinea pig model

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posted on 2023-06-09, 11:43 authored by Jens H Kuhn, Joanna L Miller, Simon G Spiro, Stuart D Dowall, Irene Taylor, Antony Rule, Dominic S Alonzi, Andrew C Sayce, Edward WrightEdward Wright, Emma M Bentley, Ruth Thom, Graham Hall, Raymond A Dwek, Roger Hewson, Nicole Zitzmann
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

PLoS ONE

ISSN

1932-6203

Publisher

Public Library of Science

Issue

11

Volume

11

Article number

e0167018

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-01-23

First Open Access (FOA) Date

2018-01-23

First Compliant Deposit (FCD) Date

2018-01-22

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