THE CARBOCYCLIC ANALOG OF 2'-DEOXYGUANOSINE INDUCES A PROLONGED INHIBITION OF DUCK HEPATITIS-B VIRUS-DNA SYNTHESIS IN PRIMARY HEPATOCYTE CULTURES AND IN THE LIVER

The carbocyclic analog of 2'-deoxyguanosine (2'-CDG) is a strong inhib itor of hepatitis B virus (HBV) DNA synthesis in HepG2 cells (P. M. Pr ice, R. Banerjee, and G. Acs, Proc. Natl. Acad. USA 86:8543-8544, 1989 ). We now report that 2'-CDG inhibited duck hepatitis B virus (DHBV) D NA synthesis in primary cultures of duck hepatocytes and in experiment ally infected ducks. Like foscarnet (phosphonoformic acid [PFA]) and 2 '-,3'-dideoxycytidine (ddC), 2'-CDG blocked viral DNA replication in p rimary hepatocyte cultures when present during an infection but failed to inhibit the DNA repair reaction that occurs during the initiation of infection to convert virion relaxed circular DNA to covalently clos ed circular DNA, the template for viral mRNA transcription. Moreover, as for PFA and ddC, viral RNA synthesis was detected when infection wa s initiated in the presence 2'-CDG. In another respect, however, 2'-CD G exhibited antiviral activity unlike that of ddC or PFA: a single 1-d ay treatment of hepatocytes with 2'-CDG blocked initiation of viral DN A synthesis for at least 8 days, irrespective of whether DHBV infectio n was carried out at the time of drug treatment or several days later. Furthermore, orally administered 2'-CDG was long-acting against DHBV in experimentally infected ducklings. Virus replication was delayed by up to 4 days in ducklings infected after administration of 2'-CDG. Th ese observations bf long-lasting efficacy in vitro and in vivo even af ter oral administration suggest that this inhibitor or a nucleoside wi th similar pharmacological properties may be ideal for reducing virus replication in patients with chronic HBV infection.