Action of celgosivir (6 O-butanoyl castanospermine) against the pestivirus BVDV: implications for the treatment of hepatitis C.
Alpha-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 microM respectively) was shown to be more potent than N-nonyl DNJ (105 and 74 microM), castanospermine (110 and 367 microM) and N-butyl DNJ (> 250 and 550 microM). Of the alpha-glucosidase inhibitors tested, only N-nonyl DNJ showed evidence of toxicity (CC50 > or = 120 microM). Two-way combinations of interferon-alpha, 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 alpha-glucosidase I inhibitors block the production or release of flavivirus particles.
Whitby
Kevin
K
Washington University, St Louis, MO, USA. kwhitby@id.wustl.edu
Taylor
Debra
D
Patel
Dipa
D
Ahmed
Parvin
P
Tyms
A Stanley
AS
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001912:Bovine Virus Diarrhea-Mucosal Disease / Q000188:drug therapy*; D002417:Cattle; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects* / Q000201:enzymology; D004195:Disease Models, Animal; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D065089:Glycoside Hydrolase Inhibitors; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007212:Indolizines / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D014759:Viral Envelope Proteins / Q000378:metabolism; D010948:Viral Plaque Assay; D000520:alpha-Glucosidases; D054836:Indolizidines
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D007212:Indolizines; D016898:Interferon-alpha; D012367:RNA, Viral; D012254:Ribavirin; D014759:Viral Envelope Proteins; D000520:alpha-Glucosidases; C070715:celgosivir; D054836:Indolizidines; C042059:glucosidase I