title: An orally available, small-molecule interferon inhibits viral replication.
abstract: Most acute hepatitis C virus (HCV) infections become chronic and some progress to liver cirrhosis or hepatocellular carcinoma. Standard therapy involves an interferon (IFN)-α-based regimen, and efficacy of therapy has been significantly improved by the development of protease inhibitors. However, several issues remain concerning the injectable form and the side effects of IFN. Here, we report an orally available, small-molecule type I IFN receptor agonist that directly transduces the IFN signal cascade and stimulates antiviral gene expression. Like type I IFN, the small-molecule compound induces IFN-stimulated gene (ISG) expression for antiviral activity in vitro and in vivo in mice, and the ISG induction mechanism is attributed to a direct interaction between the compound and IFN-α receptor 2, a key molecule of IFN-signaling on the cell surface. Our study highlights the importance of an orally active IFN-like agent, both as a therapy for antiviral infections and as a potential IFN substitute.
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co. Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Konishi
authors.forename: Koichi
authors.initials: K
authors.lastname: Okamoto
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohmori
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohmori
authors.forename: Motooki
authors.initials: M
authors.lastname: Ashihara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hirata
authors.forename: Atsunori
authors.initials: A
authors.lastname: Ohta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Natsuko
authors.initials: N
authors.lastname: Hada
authors.forename: Asao
authors.initials: A
authors.lastname: Katsume
authors.forename: Michinori
authors.initials: M
authors.lastname: Kohara
authors.forename: Kazumi
authors.initials: K
authors.lastname: Morikawa
authors.forename: Takuo
authors.initials: T
authors.lastname: Tsukuda
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
authors.forename: Graham R
authors.initials: GR
authors.lastname: Foster
authors.forename: William
authors.initials: W
authors.lastname: Alazawi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Mikio
authors.initials: M
authors.lastname: Arisawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sudoh
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015153:Blotting, Western; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D007370:Interferon Type I / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D007370:Interferon Type I