Glucosidase inhibitors as antiviral agents for hepatitis B and C

HBV and HCV infections are a major public health concern. New antiviral drugs are urgently needed with improved efficacy. Compounds that specifically target viral enzymes are the most attractive in terms of drug development and are therefore the most studied. However, antiviral strategies based entirely on this class of compounds encounter problems caused by the emergence of viral escape mutants, as already widely described for HIV. One way to prevent or delay viral resistance is to combine antiviral agents that target different steps of the virus life cycle. Future therapy may also combine such virus-specific antivirals with compounds targeting host proteins or functions. In this respect, viral morphogenesis and infectivity represent interesting, and still unexploited, novel molecular targets. Endoplasmic reticulum glucosidase inhibitors have demonstrated anti-HBV and anti-HCV properties by inhibiting viral morphogenesis and infectivity. One such compound, celgosivir, is currently being evaluated in clinical trials against HCV infection, and encouraging phase IIa data have been disclosed. This review will discuss HBV and HCV morphogenesis, with a particular focus on the role of N-glycosylation for viral protein folding and assembly, and will present the antiviral properties of glucosidase inhibitors.