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  2. HA1077 displays synergistic activity with daclatasvir against hepatitis C virus and suppresses the emergence of NS5A resistance-associated substitutions in mice

HA1077 displays synergistic activity with daclatasvir against hepatitis C virus and suppresses the emergence of NS5A resistance-associated substitutions in mice

  • Sci Rep. 2018 Aug 20;8(1):12469. doi: 10.1038/s41598-018-30460-3.
Seung-Hoon Lee 1 Jae-Su Moon 1 Bo-Yeong Pak 1 Geon-Woo Kim 1 Wooseong Lee 1 Hee Cho 1 SangKyu Kim 2 Seong-Jun Kim 3 Jong-Won Oh 4
Affiliations

Affiliations

  • 1 Department of Biotechnology, Yonsei University, Seoul, 03722, Korea.
  • 2 Department of Systems Immunology, Gangwon National University, Gangwon-do, 24341, Korea.
  • 3 Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea.
  • 4 Department of Biotechnology, Yonsei University, Seoul, 03722, Korea. jwoh@yonsei.ac.kr.
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.

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