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- 2022-12-28
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PS-073
Preclinical profile of HBV core protein inhibitor, ABI-H3733, a
potent inhibitor of cccDNA generation in HBV infected cells
Qi Huang1, Simon Haydar1, Yi Zhou1, Dawei Cai1, Xiang Xu1, Ran Yan1,
Lida Guo1, Esteban Carabajal1, Xuman Tang1, Michael Walker1,
Roopa Rai1, Mark Bures1, Leping Li1, Richard Colonno1. 1Assembly
Biosciences, San Francisco, United States
Email: [email protected]
Background and aims: Clinical cure remains elusive in chronic HBV
(CHB) patients, despite prolonged treatment with current therapies.
Core protein Inhibitors (CPIs) represent a novel class of direct acting
antivirals that target multiple aspects of the viral life cycle. Here we
characterize a newly identified CPI with enhanced potency in
blocking cccDNA establishment.
Method: Antiviral activities were determined using the induced
HepAD38 cell line (Gt D), and infection of HepG2-NTCP cells
and Primary Human Hepatocytes (PHH). Pan-genotypic activity was
established using transient transfection assays or HBV stable cell
lines. Combination studies were performed using a range of
inhibitory concentrations in HepAD38 cells. HBV DNAwas quantified
by Taqman PCR (qPCR) using primers and a probe specific to the HBV
core gene. HBeAg and HBsAg were quantified by ELISA. HBV total
RNA/encapsidated pgRNA, capsids and capsid-associated core DNA
were detected by either RT-qPCR, Northern Blot or b-DNA, Western
Blot, Enzyme Immunoassay (EIA) and Southern Blot, respectively, as
previously described.
Results: ABI-H3733 exhibited potent inhibition of viral DNA replication
in HepAD38 cells and PHH (EC50 5 and 12 nM, respectively),
and reductions in HBeAg, HBsAg and pgRNA in infected HepG2-NTCP
cells and PHH (EC50 43 and 61 nM, respectively). ABI-H3733
antiviral activity was pan-genotypic and activity was retained
against a panel of known CPI resistant variants. No significant activitywas observed against other viruses (EC50s > 10 μM) or in cytotoxicity
assays (CC50s > 10 μM). Combination studies predict additive to
synergistic inhibition when combined with Nuc therapy. ABI-H3733
possesses promising physical properties, low drug-drug interaction
potential and favorable PK profiles in multiple species. Mechanism of
action studies suggest enhanced potency in blocking encapsidation
of pgRNA, and disruption of pre-formed capsids (EC50 133 nM),
leading to premature disassembly during trafficking of rcDNA
containing capsids to the nucleus during infection. Using Southern
blot analysis, ABI-H3733 inhibited cccDNA formation with an EC50 of
125 nM.
Conclusion: ABI-H3733 is a novel CPI, derived from a new chemical
scaffold. It possesses potent inhibitory activity against multiple steps
in the HBV infectious cycle, particularly those related to cccDNA
generation. The enhanced potency and favorable preclinical profile
support advancement of this next generation CPI into clinical
development. |
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发表于 2019-3-30 15:12