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Inarigivir Is a Novel Selective Inhibitor of the
HBV Replicase Complex in Vitro
Danni Colledge1, Kathy Jackson1, Vitina Sozzi1, Xin Li1,
Michael R. Beard2, Nicholas Eyre2, Junjie Zhang3, Haitao
Guo3, Nezam H. Afdhal4, Radhakrishnan Iyer4 and Stephen
Locarnini1, (1)Victorian Infectious Disease Reference
Laboratory, (2)University of Adelaide, (3)Department of
Microbiology & Immunology, Indiana University, (4)Spring
Bank Pharmaceuticals, Inc
Background: Inarigivir (SB 9200) is a linear dinucleotide that
activates RIG-I resulting in inhibition of HBV replication via
both direct acting anti-viral effect (DAA) and innate immune
stimulation. DAA effects of Inarigivir are postulated to involve
enhanced RIG-I binding to the 5’-HBV epsilon of pregenomic
(pg) RNA, either by displacing HBV Pol or preventing pgRNA
encapsidation and assembly of the replication complex.
Clinical trials in HCV patients have confirmed the innate
immune activation by Inarigivir for antiviral activity and in
HBV patients have demonstrated significant reduction in HBV
DNA and RNA at low doses of 25 and 50 mg. The aim of this
study was to determine the effect of Inarigivir on packaging
pgRNA into replication complexes and subsequent reverse
transcription. Methods: The well-characterized cell-based
system, HepAD-38 (Ladner et al, 1997 AAC 41:1715) was used
to examine the antiviral effect of Inarigivir on HBV replication
using standard molecular virological techniques. The results
were directly compared to the antiviral effects of the core
protein assembly modifier BAY 41-4109 and the nucleoside
lamivudine (LMV). Results: Incubation of HepAD-38 cultures
with Inarigivir, BAY 41-4109 and LMV resulted in significant
declines in secreted and cell-associated HBV DNA. Using
non-denaturing agarose gel electrophoresis, Inarigivir or LMV
treatment did not affect the assembly of the HBV capsids
whilst these were blocked in a dose-dependent manner by
BAY 41-4109. A similar pattern of a lack of antiviral effect on
core protein translation was observed with Inarigivir and LMV
but not BAY 41-4109 as confirmed by electron microscopy.
Using a differential PCR strategy to detect the 5’-, or 3’-end of
pgRNA, Inarigivir treatment did not affect HBV RNA packaging
into cores. More importantly, however, reverse transcription
into genomic DNA was inhibited within these Inarigivirtreated
replication complexes. Conclusion: The DAA effect
of Inarigivir appears to involve inhibition of HBV replication
at the level of protein priming of the reverse transcription
and/or blocking subsequent primer translocation within the
HBV replication complex. This novel antiviral mechanism of
Inarigivir against HBV is downstream from capsid assembly
yet upstream from or during the reverse transcription process.
Current studies are directed at determining the target of
Inarigivir in HBV replication complex and the role of RIG-I in
the DAA effect of Inarigivir.
Disclosures:
Nezam H. Afdhal – Spring Bank: Management Position; Trio Health care:
Management Position; Gilead: Advisory Committee or Review Panel; Shionogi:
Consulting; EchoSens: Consulting; Ligand: Board Membership; Merck:
Consulting
Stephen Locarnini – SpringBank Pharmaceuticals, Inc.: Consulting; SpringBank
Pharmaceuticals, Inc.: Grant/Research Support; SpringBank Pharmaceuticals,
Inc.: Independent Contractor
The following people have nothing to disclose: Kathy Jackson, Radhakrishnan
Iyer
Disclosure information not available at the time of publication: Danni Colledge,
Vitina Sozzi, Xin Li, Michael R. Beard, Nicholas Eyre, Junjie Zhang, Haitao Guo |
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发表于 2018-10-10 20:38
