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Antimicrobial Agents and Chemotherapy, December 1998, p. 3200-3208, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

In Vitro Inhibition of Hepadnavirus Polymerases by the Triphosphates of BMS-200475 and Lobucavir

Maria Seifer,dagger Robert K. Hamatake,Dagger Richard J. Colonno, and David N. Standring*

Pharmaceutical Research Institute, Bristol-Myers Squibb, Wallingford, Connecticut 06492

Received 3 February 1998/Returned for modification 1 May 1998/Accepted 15 September 1998

The guanosine analogs BMS-200475 and lobucavir have previously been shown to effectively suppress propagation of the human hepatitis B virus (HBV) and woodchuck hepatitis virus (WHV) in 2.2.15 liver cells and in the woodchuck animal model system, respectively. This repression was presumed to occur via inhibition of the viral polymerase (Pol) by the triphosphate (TP) forms of BMS-200475 and lobucavir which are both produced in mammalian cells. To determine the exact mode of action, BMS-200475-TP and lobucavir-TP, along with several other guanosine analog-TPs and lamivudine-TP were tested against the HBV, WHV, and duck hepatitis B virus (DHBV) polymerases in vitro. Estimates of the 50% inhibitory concentrations revealed that BMS-200475-TP and lobucavir-TP inhibited HBV, WHV, and DHBV Pol comparably and were superior to the other nucleoside-TPs tested. More importantly, both analogs blocked the three distinct phases of hepadnaviral replication: priming, reverse transcription, and DNA-dependent DNA synthesis. These data suggest that the modest potency of lobucavir in 2.2.15 cells may be the result of poor phosphorylation in vivo. Kinetic studies revealed that BMS-200475-TP and lobucavir-TP competitively inhibit HBV Pol and WHV Pol with respect to the natural dGTP substrate and that both drugs appear to bind to Pol with very high affinities. Endogenous sequencing reactions conducted in replicative HBV nucleocapsids suggested that BMS-200475-TP and lobucavir-TP are nonobligate chain terminators that stall Pol at sites that are distinct yet characteristically two to three residues downstream from dG incorporation sites.

* Corresponding author. Present mailing address: Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033-0539. Phone: (908) 740-7446. Fax: (908) 740-3918. E-mail: david.standring{at}spcorp.com.

dagger Present address: Schering-Plough Research Institute, Kenilworth, NJ 07033-0539.

Dagger Present address: GlaxoWellcome, Research Triangle Park, NC 27709.

Antimicrobial Agents and Chemotherapy, December 1998, p. 3200-3208, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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