HA1077 displays synergistic activity with daclatasvir against hepatitis C virus and suppresses the emergence of NS5A resistance-associated substitutions in mice
| Autor: | Seongjun Kim, Wooseong Lee, Seung Hoon Lee, Jong Won Oh, Hee Cho, Geon-Woo Kim, Bo Yeong Pak, Jae Su Moon, Sang-Kyu Kim |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pyrrolidines Daclatasvir Genotype viruses Hepatitis C virus lcsh:Medicine Hepacivirus Mice SCID Viral Nonstructural Proteins Biology Virus Replication medicine.disease_cause Antiviral Agents Article Mice 03 medical and health sciences Mice Inbred NOD Viral entry 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Cell Line Tumor Drug Resistance Viral medicine Animals Humans lcsh:Science NS5A Multidisciplinary Kinase lcsh:R Imidazoles virus diseases Valine Hepatitis C Hepatitis C Chronic medicine.disease Virology digestive system diseases 030104 developmental biology Drug Therapy Combination lcsh:Q Carbamates Viral genome replication Viral load medicine.drug |
| Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-13 (2018) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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