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1893
In vitro and in vivo anti-HBV activities of the new cyclophilin
inhibitor STG-175
Philippe Gallay; TSRI, La Jolla, CA
BACKGROUND: Over 350 million people are chronically
infected with HBV. Current treatments – IFN and nucleos(t)ide
analogs – eliminate HBV from less than 10% of patients, and
treatment cessation leads to viral rebound. Thus, new treatments
with distinct mechanisms of actions (MoAs) are urgently
needed to eradicate HBV from patients as well as to prevent the
development of liver diseases such as fibrosis and hepatocellular
carcinoma (HCC). Since cyclophilin inhibitors have demonstrated
clinical safety and efficacy against HCV, we examined
the possibility that they could also inhibit HBV replication.
MATERIAL AND METHODS: In this study, we evaluated both
in vitro and in vivo the anti-HBV inhibitory potency of the new
cyclophilin inhibitor STG-175, which previously demonstrated
high efficacy against HCV. RESULTS: We found that STG-175
inhibits two distinct steps of HBV replication. As previously
reported for other cyclophilin inhibitors, we found that STG-
175, by binding to cell surface NTCP, inhibits HBV entry. However,
this entry block is only observed at a high mM range (>10
mM). More interestingly, we found that STG-175 profoundly
reduces HBV replication in HepAD38 cells (EC50 of 155 nM).
Specifically, HBV DNA levels in cell culture supernatants were
diminished by more than 90% after 5 days of drug treatment
without affecting cell toxicity or proliferation. Importantly, this
second STG-175-mediated block occurs post-entry. Moreover,
we found that a 3-week oral treatment with STG-175 (75 mg/
kg/day) reduces by more than 70% the levels of HBV DNA in
the liver of HBV transgenic mice without any signs of toxicities
(body weight, plasma ALT and liver triglyceride levels). CONCLUSIONS:
By demonstrating that the new cyclophilin inhibitor
STG-175 exhibits potent anti-HBV activities both in vitro and
in vivo, our findings strongly indicate that STG-175 represents
an attractive drug partner for IFN-free direct-acting antiviral
regimens for the treatment of hepatitis B.
Disclosures:
The following people have nothing to disclose: Philippe Gallay
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发表于 2016-12-1 11:18
