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

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 ( N B-DNJ) and N -(9-methoxynonyl)-1deoxynojirimycin (M O N-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 N B-DNJ and 120 mg/kg/day M O N-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 N B-DNJ treated animals surviving and the remaining three showing improved clinical signs. M O N-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with N B-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which N B-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 N B-DNJ and M O N-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 N B-DNJ treated cohort could indicate that N B-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars.