title: Liver-specific mono-unsaturated fatty acid synthase-1 inhibitor for anti-hepatitis C treatment.
abstract: Recently, direct antiviral agents against hepatitis C virus (HCV) infection have been developed as highly effective anti-HCV drugs. However, the appearance of resistant viruses against direct anti-viral agents is an unsolved problem. One of the strategies considered to suppress the emergence of the drug-resistant viruses is to use drugs inhibiting the host factor, which contributes to HCV proliferation, in combination with direct anti-viral agents. The replication complex was reported to be present in the membranous compartment in the cells. Thus, lipid metabolism modulators are good candidates to regulate virus assembly and HCV replication. Recent studies have shown that stearoyl-CoA desaturase (SCD), an enzyme for long-chain mono-unsaturated fatty acid (LCMUFA) synthesis, is a key factor that defines HCV replication efficiency. Systemic exposure to SCD-1 inhibor induces some side effects in the eyes and skin. Thus, systemic SCD-1 inhibitors are considered inappropriate for HCV therapy. To avoid the side effects of systemic SCD-1 inhibitors, the liver-specific SCD-1 inhibitor, MK8245, was synthesized; it showed antidiabetic effects in diabetic model mice with no side effects. In the phase 1 clinical study on measurement of MK8245 tolerability, no significant side effects were reported (ClinicalTrials.gov Identifier: NCT00790556). Therefore, we thought liver-specific SCD-1 inhibitors would be suitable agents for HCV-infected patients. MK8245 was evaluated using recombinant HCV culture systems. Considering current HCV treatments, to avoid the emergence of direct anti-viral agents-resistant viruses, combination therapy with direct anti-viral agents and host-targeted agents would be optimal. With this viewpoint, we confirmed MK8245's additive or synergistic anti-HCV effects on current direct anti-viral agents and interferon-alpha therapy. The results suggest that MK8245 is an option for anti-HCV multi-drug therapy with a low risk of emergence of drug-resistant HCV without significant side effects.
authors.affiliation: Takeda Pharmaceutical Company Limited, Pharmaceutical Research Division, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yasunori.nio@takeda.com.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Nio
authors.affiliation: Laboratory of Human Tumor Viruses, The Institute for Virus Research, Kyoto University, 53 Kawaharacho, Shogoin, Sakyoku, Kyoto 606-8507, Japan; Grad. Sch. of Biostudies, Kyoto University, 53 Kawaharacho, Shogoin, Sakyoku, Kyoto 606-8507, Japan.
authors.forename: Hikari
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Laboratory of Human Tumor Viruses, The Institute for Virus Research, Kyoto University, 53 Kawaharacho, Shogoin, Sakyoku, Kyoto 606-8507, Japan; Grad. Sch. of Biostudies, Kyoto University, 53 Kawaharacho, Shogoin, Sakyoku, Kyoto 606-8507, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Okamura
authors.affiliation: Laboratory of Human Tumor Viruses, The Institute for Virus Research, Kyoto University, 53 Kawaharacho, Shogoin, Sakyoku, Kyoto 606-8507, Japan; Grad. Sch. of Biostudies, Kyoto University, 53 Kawaharacho, Shogoin, Sakyoku, Kyoto 606-8507, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyayama
authors.affiliation: Laboratory of Human Tumor Viruses, The Institute for Virus Research, Kyoto University, 53 Kawaharacho, Shogoin, Sakyoku, Kyoto 606-8507, Japan; Grad. Sch. of Biostudies, Kyoto University, 53 Kawaharacho, Shogoin, Sakyoku, Kyoto 606-8507, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Akahori
authors.affiliation: Laboratory of Human Tumor Viruses, The Institute for Virus Research, Kyoto University, 53 Kawaharacho, Shogoin, Sakyoku, Kyoto 606-8507, Japan; Grad. Sch. of Biostudies, Kyoto University, 53 Kawaharacho, Shogoin, Sakyoku, Kyoto 606-8507, Japan. Electronic address: mhijikat@virus.kyoto-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hijikata
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D053898:Biosynthetic Pathways / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D012367:RNA, Viral; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: C561635:(5-(3-(4-(2-bromo-5-fluorophenoxy)piperidin-1-yl)isoxazol-5-yl)-2H-tetrazol-2-yl)acetic acid; D000085:Acetates; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D012367:RNA, Viral; D013777:Tetrazoles; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase
keywords: Fatty acid synthesis; Hepatitis C virus; Liver-specific SCD-1 inhibitor MK8245; SCD