Abstract
The kinase C-related kinase 2 (PRK2), which phosphorylates hepatitis C virus (HCV) RNA polymerase, is a proviral factor enhancing HCV replication. Here, we report on the in vivo anti-HCV efficacy of HA1077, which inhibits viral genome replication by targeting PRK2 and displays viral entry inhibitory activity by targeting Rho-associated kinase. HA1077 showed synergistic antiviral activity selectively with nonstructural protein 5 A (NS5A) inhibitors including daclatasvir (DCV). HA1077 oral administration substantially reduced serum viral loads in mice bearing HCV genotype 2a-replicating Huh7 xenografts. When administered with DCV, HA1077 potentiated the antiviral efficacy of DCV and suppressed the generation of DCV resistance-associated variants (RAVs). By deep-sequencing analysis, we uncovered an unprecedented DCV-induced polymorphism at the poly-proline motif (PxxPxxP) of NS5A. Coadministration of HA1077 reduced such a polymorphism. Overall, our results demonstrate the potential therapeutic benefit of combination therapy with HA1077 plus DCV for HCV patients carrying emerging or pre-existing RAVs toward NS5A inhibitors.
Highlights
Hepatitis C virus (HCV) is a major cause of chronic liver diseases and hepatocellular carcinoma
We investigated if there are any synergistic effects by such combinations and analyzed whether HA1077 can suppress the emergence of resistance-associated variants (RAVs) against the most potent anti-hepatitis C virus (HCV) drug targeting nonstructural protein 5 A (NS5A), daclatasvir (DCV; known as BMS-790052 and Daklinza)[6] in a mouse model of HCV replication
Since HA1077 [1-(5-isoquinoline-sulfonyl)-homopiperazine] (Fig. 1a) was originally discovered as a Rho-associated kinase (ROCK) inhibitor it is active against PRK223,24, we were interested in testing the impact of HA1077 on HCV entry
Summary
Hepatitis C virus (HCV) is a major cause of chronic liver diseases and hepatocellular carcinoma. After the clinical application of the first-generation NS3/4 A protease inhibitors telaprevir and boceprevir, during the last decade a number of direct acting antiviral agents (DAAs) targeting viral nonstructural (NS) proteins [e.g., NS3/4 A protease, NS5A, and NS5B RNA-dependent RNA polymerase (RdRp)] have been approved to treat HCV infection and they have been displaying a high sustained virological response (SVR) rate of up to ~90%2–6. Despite their potent antiviral efficacy, most DAAs, when used as a monotherapy, have a lower genetic barrier to resistance[7], because HCV RNA polymerase ensures the survival of the virus due to its low fidelity, which leads to high genetic variation in the HCV genome[8]. We investigated if there are any synergistic effects by such combinations and analyzed whether HA1077 can suppress the emergence of RAVs against the most potent anti-HCV drug targeting NS5A, daclatasvir (DCV; known as BMS-790052 and Daklinza)[6] in a mouse model of HCV replication
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