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- 2009-10-5
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- 2022-12-28
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15
Identification and Characterization of QL-0A6A, A
Novel HBV Capsid Inhibitor
For the Treatment of Chronic Hepatitis B
Qiong Zhou1, Shibo He1, Huangtao Jin1, Pengcheng Li1, Ya Sun1,
Jie Li1, Hongbo Wang1, Fubiao Xiao1, Kai Zhou1, Xiaolin Li1,
Haiying He1, Liang Shen1, Lijuan Hou1, Jian Li1, Shuhui Chen1,
Zhengxian Gu1, Zhe Cheng2, Chunyan Sun2, Long Zhang2,
Shuyong Zhao2; 1WuXi AppTec (Shanghai) Co., Ltd, 288 FuTe
Zhong Road, Shanghai 200131, P.R. China, Shanghai, China;
2Shandong Provincial Key Laboratory of Small Molecular Targeted
Drugs, Qilu Pharmaceutical Co., Ltd. No. 243 Gong Ye Bei Road,
Jinan, Shandong Province, 250100, P.R. China, Shandong, China
Background: Chronic HBV infection (CHB) is a world-wide
prevalent disease, the current standard care for the CHB, interferon
alpha and nucleos(t)ide analogs, can efficiently inhibit
HBV replication, but they are rare to cure CHB. Therefore, it
is necessary to discover novel anti-HBV agents. QL-0A6A is a
potent and selective HBV capsid inhibitor that inhibits HBV replication
in the cell-based assays and mouse models. Methods:
QL-0A6A was tested for interruption of the virus core protein
assembly in an HBV capsid assembly quenching assay, inhibition
of HBV replication in HepG2.2.15 cells, and HepG2 cells
transiently transfected with HBV replication-competent DNA
by qPCR. The in vivo activity of QL-0A6A against HBV replication
was evaluated in the hydrodynamic injection (HDI) and
humanized FRG™ (Fah-/-/Rag2-/-/Il2rg-/-) mouse models. In
the HDI model, the BALB/C mice were injected with the replication-
competent HBV plasmid DNA via tail veins, and orally
administered with QL-0A6A at doses of 15, 50, 150 mpk, BID,
for 7 days. In the humanized FRG™ mouse model, the mice
were infected with HBV derived from a CHB patient serum, and
orally administered with QL-0A6A from100 to 200 mpk, BID,
for 30 days. HBV DNA in the plasma and livers was measured
by qPCR in both the HDI and FRG models. Effect of QL-0A6A
on HBsAg was monitored in the plasma and livers in the FRG
mouse study. Results: QL-0A6A showed interruption of HBV
capsid assembly in the biochemical assay with low nanomolar
activity against HBV replication in HepG2.2.15 cells. QL-0A6A
exhibited broad spectrum against different genotypes of HBV,
and favorable combination effects on inhibition of HBV replication
in combination with nucleos(t)ide analogs in the cellbased
HBV assays. QL-0A6A remained full activity against the
nuc-resistant HBV mutants. QL-0A6A had statistically significant
(p<0.01) and dose-dependent inhibition of HBV replication
in the HDI model. In the FRG mouse model, QL-0A6A had a
maximal reduction of plasma HBV DNA by 3.71 log, and significant
decrease of liver HBV DNA determined by both qPCR
and Southern blot. QL-0A6A showed higher activity against
HBV than tenofovir in the FRG study. In both the HDI and FRG
mouse studies, QL-0A6A was well tolerated, and did not affect
the mouse body weight. Conclusions: QL-0A6A is a potent and
selective HBV capsid assembly inhibitor. QL-0A6A has no cross
resistance but favorable synergy effect with the nucleos(t)ide
analogs. QL-0A6A demonstrates potent activity against HBV
replication in the mouse models. Therefore, QL-0A6A warrants
to be developed for a therapy of chronic HBV infection.
Disclosures:
Zhengxian Gu - Employment: WuXi AppTec
The following people have nothing to disclose: Qiong Zhou, Shibo He, Huangtao
Jin, Pengcheng Li, Ya Sun, Jie Li, Hongbo Wang, Fubiao Xiao, Kai Zhou,
Xiaolin Li, Haiying He, Liang Shen, Lijuan Hou, Jian Li, Shuhui Chen, Zhe Cheng,
Chunyan Sun, Long Zhang, Shuyong Zhao
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发表于 2016-10-3 15:09
