Abstract
We previously reported that the non-immunosuppressive cyclophilin inhibitors (CypIs)—cyclosporin A analog CRV431 and sanglifehrin analog NV556—efficiently inhibit HCV replication in vitro. In this study, we asked whether they can also reduce HCV replication in vivo. We found that a single oral administration of CRV431 and NV556 to HCV-infected humanized-liver mice drastically reduced HCV blood levels. The antiviral effect was observed when CRV431 or NV556 were each individually administered with HCV, 3, 6 weeks or even 3 months post-infection when viral replication is robust. These results were confirmed in chimeric mice implanted with human hepatocytes isolated from three distinct donors. Remarkably, no viral rebound was observed 5 months after a single dose administration of 50 mg/kg of CRV431 or NV556 four weeks post-HCV infection, indicating the possibility of suppression of an established viral infection. Since we recently demonstrated that both CRV431 and NV556 also inhibit the development of liver fibrosis and hepatocellular carcinoma in nonviral-induced non-alcoholic steatohepatitis mouse models, our present data suggest that the two entirely structurally different CypIs—CRV431 and NV556—derived from unrelated natural products, represent attractive partners to current direct-acting agent (DAA) regimens for the treatment of hepatitis C and liver diseases.
Highlights
Despite recent therapeutic progress, HCV remains a worldwide health issue with 300,000 deaths per year
We previously showed and reported that the non-immunosuppressive cyclosporin A and sanglifehrin A or B analogs derived from distinct natural products with highly dissimilar structures–CRV431 and NV556 –block HCV replication in vitro [13, 23], we asked in the present study whether they could suppress HCV infection in vivo in humanized-liver chimeric mice
A majority of direct-acting agent (DAA)-treated patients achieve virological cure, HCV resistance to DAAs has a crucial role in the failure of pegylated interferon alpha (pIFNa)-free treatment regimens
Summary
HCV remains a worldwide health issue with 300,000 deaths per year. HCV-infected patients develop cirrhosis (27%) and HCC (25%) [1,2,3]. Earlier than 2011, the standard treatment for HCV infection was the combination of pegylated interferon alpha (pIFNa) and ribavirin (RBV) for 24 or 48 weeks contingent on the HCV genotype [4], resulting in a sustained virologic response (SVR) rate of 40–50%, but associated with major side effects [5,6,7]. Cyclophilin inhibitors inhibit HCV replication in mice provided support in the form of salary for author MH. Hepion Pharmaceuticals provided support in the form of salary for authors PM, DU, and RF. These companies provided the drugs and participated in the revision of the manuscript, but did not have any role in the study design, data collection and analysis, or decision to publish the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section
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