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THU-198
IN VITROAND IN VIVOANTIVIRAL ACTIVITIES OFAB-423 A POTENT
SMALL MOLECULE INHIBITOR OF HEPATITIS B VIRUS CAPSID
ASSEMBLY
N. Mani1, A. Cole2, J. Phelps3, A. Ardzinski1, K. Cobarrubias3,
A. Cuconati1, B. Dorsey2, E. Evangelista4, T. Harasym4, S. Kadhim4,
A. Lee3, H. Liang5, A. Li3, K. McClintock4, S. Majeski4, S. Reid3,
R. Rijnbrand6, S. Tang4, X. Wang1, M. Sofia2,6. 1Virology; 2Chemistry,
Arbutus Biopharma, Doylestown, United States; 3In Vivo Pharmacology
and Macro-Molecular Discovery; 4Drug Metabolism and
Pharmacokinetics, Arbutus Biopharma, Burnaby, Canada; 5Baruch S.
Blumberg Institute; 6Biology, Arbutus Biopharma, Doylestown, United
States
E-mail: [email protected]
Background and Aims: Hepatitis B virus replication is strictly
dependent upon capsid assembly around pregenomic RNA, which
is essential for viral genome (rcDNA) synthesis, infectious virion
production and maintenance of the nuclear cccDNA pool. The capsid
assembly process thus represents a bona fide antiviral target, and
constitutes a novel mechanism that is distinct from the nucleos(t)ide
analogues currently available for clinical use. Here we characterised
the in vitro and in vivo antiviral activities of AB-423, a potent small
molecule inhibitor of capsid assembly.
Methods: Antiviral potency, cytotoxicity and in vitro combination
studies of AB-423were performed using HBV cell culture models and
quantified using dot blot, branched DNA or quantitative PCR assays.
The in vivo antiviral activity of AB-423 alone and in combination with
entecavir and TKM-HBV, an RNAi treatment under development for
chronic hepatitis B, was assessed in a hydrodynamic injection HBV
mouse model.
Results: AB-423 showed potent inhibition of HBV rcDNA production
in a mouse cell line with an average EC50 of 275 nM and CC50 of
>10 μM. In a human hepatoma cell line in which inducible cccDNA
formation is dependent upon capsid assembly and rcDNA
synthesis, similar potency was observed in the inhibition of cccDNA
formation. In primary human hepatocytes isolated from uPA/SCID
chimeric mice and infected in vitro, AB-423 at 1.0 μM concentration
exhibited a ∼1-log reduction in the extracellular HBV DNA pool.
AB-423 inhibited HBV capsid assembly in a biochemical assay
confirming its mechanism of action. In vitro combination studies of
AB-423 with entecavir in the cccDNA formation cell culture system
showed additive/synergistic effects.
AB-423 showed favourable pharmacokinetic properties when dosed
orally in mice and was tested for efficacy in SCID mice that were
hydrodynamically injected with HBV plasmid DNA. AB-423 showed
rapid and strong dose-dependent reduction in serum HBV DNA with
a maximum reduction of ∼2 logs at 200 mg/kg on day 4 that was
maintained through day 7 of the daily b.i.d. dosing period. When
tested in combination with entecavir or TKM-HBV, no antagonism
was detected
Conclusions: AB-423 is a promising antiviral agent that exhibited
potent inhibition of HBV replication in cell culture systems and in
an HBV mouse model both singly as well as in combination with
entecavir or with TKM-HBV. AB-423 is being evaluated for
advancement into clinical development.
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发表于 2016-3-31 15:21
