ABSTRACT FINAL ID: 1893
TITLE: In vitro and in vivo anti-HBV activities of the new cyclophilin inhibitor STG-175
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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 µM range (>10 µM). 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.