Chronic hepatitis B virus (HBV) infection is a major cause of liver disease. Only interferon-alpha and the nucleosidic inhibitors of the viral polymerase, 3TC and adefovir, are approved for therapy. However, these therapies are limited by the side effects of interferon and the substantial resistance of the virus to nucleosidic inhibitors. Potent new antiviral compounds suitable for monotherapy or combination therapy are highly desired. We describe non-nucleosidic inhibitors of HBV nucleocapsid maturation that possess in vitro and in vivo antiviral activity. These inhibitors have potential for future therapeutic regimens to combat chronic HBV infection.

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The transferase was isolated by means of hydrophobic chromatography and combination of ionexchange and gel filtration at different pH values and ionic strengths. As judged by disc electrophoresis, the enzyme is homogeneous. Electrophoresis in the presence of sodium dodecylsulfate reveals only one band with M , = 49500 f 10 %. In gel filtration the native enzyme has a M , of 200 000. The subunits can be crosslinked by iminothiolane followed by hydrogen peroxide oxidation. In sodium dodecylsulfate electrophoresis this results in a band pattern of integer multiples of SO000 up to 200000 but not higher. The high-M, aggregates disappear on splitting the crosslinks by reduction. Thus the enzyme appears to be composed of four subunits identical or nearly identical in M,.By the dansyl method, only phenylalanine and methionine were found as the amino-terminal residues, suggesting the existence of two different types of subunits.The vitamin-BIZ-dependent 5-methyltetrahydrofolate : homocysteine methyltransferase from Esclzericlzia coli 5-methyltetrahydrofolate + homocysteine BIZ-enzyme, S-adenosylmethionine, FMNHz