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- 2022-12-28
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Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured
hepatocytes through targeting a membrane transporter NTCP
Koichi Watashi1,*,
Ann Sluder2,
Takuji Daito1,2,
Satoko Matsunaga3,
Akihide Ryo3,
Shushi Nagamori4,
Masashi Iwamoto1,
Syo Nakajima1,
Senko Tsukuda1,5,
Katyna Borroto-Esoda2,
Masaya Sugiyama6,
Yasuhito Tanaka7,
Yoshikatsu Kanai4,
Hiroyuki Kusuhara8,
Masashi Mizokami6,
Takaji Wakita1
DOI: 10.1002/hep.26982
Abstract
Chronic hepatitis B virus (HBV) infection is a major public health problem
worldwide. Although nucleos(t)ide analogs inhibiting viral reverse
transcriptase are clinically available as anti-HBV agents, emergence of
drug resistant virus highlights the need for new anti-HBV agents
interfering with other targets. Here we report that cyclosporin A (CsA) can
inhibit HBV entry into cultured hepatocytes. The anti-HBV effect of CsA
was independent of binding to cyclophilin and calcineurin. Rather, blockade
of HBV infection correlated with the ability to inhibit the transporter
activity of sodium taurocholate cotransporting polypeptide (NTCP). We also
found that HBV infection susceptible cells, differentiated HepaRG cells and
primary human hepatocytes expressed NTCP, while non-susceptible cell lines
did not. A series of compounds targeting NTCP could inhibit HBV infection.
CsA inhibited the binding between NTCP and large envelope protein in
vitro. Evaluation of CsA analogs identified a compound with higher anti-HBV
potency, having an IC50 < 0.2 μM. This study provides a proof of concept
for the novel strategy to identify anti-HBV agents by targeting the
candidate HBV receptor, NTCP, utilizing CsA as a structural platform.
(Hepatology 2013;)
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发表于 2013-12-28 16:03
