Peroxisome proliferator-activated receptor delta antagonists inhibit hepatitis C virus RNA replication

Shintaro Ban, Youki Ueda, Masao Ohashi, Kenji Matsuno, Masanori Ikeda, Nobuyuki Kato, Hiroyuki Miyachi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

It has been reported that ligand-mediated transcription factor peroxisome proliferator-activated receptor alpha (hPPARα) is involved in hepatitis C virus (HCV) RNA replication, whereas hPPARγ is not, and the effect of hPPARδ is unknown. Here, we show that hPPARδ-selective antagonists effectively inhibit HCV RNA replication. We describe the design, synthesis and pharmacological evaluation of a series of biphenyl-4-carboxylic acid-type hPPARδ antagonists, including previously reported compounds, as candidate anti-HCV agents. A representative compound (4c) dose-dependently inhibited HCV RNA replication (EC50 0.22 μM), while exhibiting relatively weak cytotoxicity to the host cells (CC50 2.5 μM). It also showed an additive and dose-dependent effect on the inhibition of HCV RNA replication by pegylated interferon alpha (Peg-IFNα) alone and by both Peg-IFNα and ribavirin (currently the clinical treatment of choice for HCV infection). Thus, combination of a hPPARδ antagonist with current therapy may improve the efficacy of treatment for HCV infection.

Original languageEnglish
Pages (from-to)4774-4778
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number17
DOIs
Publication statusPublished - Sep 1 2013

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Keywords

  • Biphenyl-4-carboxylic acid
  • HCV RNA replication
  • PPAR delta
  • PPAR delta antagonist

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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