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Antimicrobial Agents and Chemotherapy, December 1998, p. 3200-3208, Vol. 42, No. 12
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.
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


*
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.
Present address: Schering-Plough Research Institute, Kenilworth, NJ
07033-0539.
Present address: GlaxoWellcome, Research Triangle Park, NC 27709.
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