Action of celgosivir (6 O-butanoyl castanospermine) against the pestivirus BVDV: Implications for the treatment of hepatitis C

Abstract

α-Glucosidase I inhibitors have been shown to inhibit the replication of a broad range of enveloped viruses by preventing the correct folding of their envelope glycoproteins. This study assesses the potential of 6 O-butanoyl castanospermine (celgosivir) as a treatment for hepatitis C virus (HCV). In the absence of an adequate culture system for HCV, the closely related virus, bovine viral diarrhoea virus (BVDV), was used as a surrogate model. Using both a plaque assay and a cytopathic effect assay, celgosivir (IC50 16 and 47 μM respectively) was shown to be more potent than N-nonyl DNJ (105 and 74 μM), castanospermine (110 and 367 μM) and N-butyl DNJ (>250 and 550 μM). Of the α-glucosidase inhibitors tested, only N-nonyl DNJ showed evidence of toxicity (CC50 ≥120 μM). Two-way combinations of interferon-α, ribavirin and either celgosivir or castanospermine demonstrated that each could enhance the antiviral efficacy of the others, either additively or synergistically. The observation that the number of viral genomes released from BVDV-infected cells was inhibited by either castanospermine or celgosivir in parallel with the number of infectious units was taken as confirmation that these α-glucosidase I inhibitors block the production or release of flavivirus particles.