|
- 现金
- 62111 元
- 精华
- 26
- 帖子
- 30437
- 注册时间
- 2009-10-5
- 最后登录
- 2022-12-28
|
EASL 2018 PS-032
Discovery of a novel core inhibitor EP-027367 with potent
antiviral activity both in vitro and in a humanized mouse model
M. Vaine1, S. Clugston1, J. Kass1, X. Gao1, H. Cao1, W. Li1, X. Peng1,
L. Jiang1, K. Daniels1, Y.-L. Qiu1, Y.S. Or1, K. Lin2. 1Enanta
Pharmaceuticals; 2Enanta Pharmaceuticals, Watertown, United States
Email: [email protected]
Background and Aims: Current therapies for hepatitis B virus (HBV)
using nucleos(t)ides and IFN can effectively suppress viral replication
but rarely lead to a functional cure, which necessitates the
development of new antiviral drugs. Core inhibitors or capsid
assembly modulators are a new class of HBV inhibitors which
misdirect the assembly and function of the viral capsid. We have
identified EP-027367 as a novel core inhibitor with a favorable
antiviral, pharmacokinetic, and safety profile to treat HBV infection.
Method: The effect of EP-027367 on viral capsid assembly was
determined in vitro. Its anti-HBV activities at different stages of the
viral lifecyclewere characterized in HepG2.2.15, HepAD38, HepDE19,
HepaRG, and primary human hepatocytes. In vivo efficacy of EP-
027367 was evaluated in a humanized mouse model consisting of
uPA/SCID mice with livers repopulated by human hepatocytes and
infected with a genotype C HBV.
Results: EP-027367 modulates HBV capsid assembly and blocks viral
pgRNA encapsidation in vitro. It inhibits the production of HBV rcDNA
with EC50s of 20, 24 and 40 nM in HepG2.2.15, HepAD38, and
HepDE19 cells, respectively. It is active across HBV genotypes A-H
with potencies ranging from 7 to 50 nMand is not affected by known
nucleos(t)ide resistant variants. Combinations of EP-027367 with
other HBV inhibitors display additive to synergistic antiviral activity
in vitro. Additionally, EP-027367 can prevent de novo infection of
susceptible cell lines at sub-micromolar concentrations by inhibiting
the formation of new cccDNA. In a human liver chimeric mouse
model, EP-027367, given orally at 50, 100 and 200 mg/kg BID for 28
days, reduced HBV DNA level by 2.2, 2.7 and 3.0 logs from baseline,
respectively.
Conclusion: EP-027367, a novel HBV core inhibitor with potent
antiviral activities both in vitro and in vivo, represents a promising
new therapeutic candidate for treating HBV infection.
|
|
发表于 2018-4-1 23:30
