title: Inhibition of hepatitis C virus replication by chalepin and pseudane IX isolated from Ruta angustifolia leaves.
abstract: Hepatitis C virus (HCV) infection is highly prevalent among global populations, with an estimated number of infected patients being 170 million. Approximately 70-80% of patients acutely infected with HCV will progress to chronic liver disease, such as liver cirrhosis and hepatocellular carcinoma, which is a substantial cause of morbidity and mortality worldwide. New therapies for HCV infection have been developed, however, the therapeutic efficacies still need to be improved. Medicinal plants are promising sources for antivirals against HCV. A variety of plants have been tested and proven to be beneficial as antiviral drug candidates against HCV. In this study, we examined extracts, their subfractions and isolated compounds of Ruta angustifolia leaves for antiviral activities against HCV in cell culture. We isolated six compounds, chalepin, scopoletin, γ-fagarine, arborinine, kokusaginine and pseudane IX. Among them, chalepin and pseudane IX showed strong anti-HCV activities with 50% inhibitory concentration (IC₅₀) of 1.7 ± 0.5 and 1.4 ± 0.2 μg/ml, respectively, without apparent cytotoxicity. Their anti-HCV activities were stronger than that of ribavirin (2.8 ± 0.4 μg/ml), which has been widely used for the treatment of HCV infection. Mode-of-action analyses revealed that chalepin and pseudane IX inhibited HCV at the post-entry step and decreased the levels of HCV RNA replication and viral protein synthesis. We also observed that arborinine, kokusaginine and γ-fagarine possessed moderate levels of anti-HCV activities with IC₅₀ values being 6.4 ± 0.7, 6.4 ± 1.6 and 20.4 ± 0.4 μg/ml, respectively, whereas scopoletin did not exert significant anti-HCV activities at 30 μg/ml.
authors.affiliation: Division of Microbiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Department of Pharmacognocy and Phytochemistry, Faculty of Pharmacy, Airlangga University, Jl. Dharmawangsa Dalam, Surabaya 60286, Indonesia.
authors.forename: Tutik Sri
authors.initials: TS
authors.lastname: Wahyuni
authors.affiliation: Department of Pharmacognocy and Phytochemistry, Faculty of Pharmacy, Airlangga University, Jl. Dharmawangsa Dalam, Surabaya 60286, Indonesia.
authors.forename: Aty
authors.initials: A
authors.lastname: Widyawaruyanti
authors.affiliation: Institute of Tropical Disease, Airlangga University, Jl. Mulyorejo, Surabaya 60115, Indonesia.
authors.forename: Maria Inge
authors.initials: MI
authors.lastname: Lusida
authors.affiliation: Department of Pharmacognocy and Phytochemistry, Faculty of Pharmacy, Airlangga University, Jl. Dharmawangsa Dalam, Surabaya 60286, Indonesia.
authors.forename: Achmad
authors.initials: A
authors.lastname: Fuad
authors.affiliation: Institute of Tropical Disease, Airlangga University, Jl. Mulyorejo, Surabaya 60115, Indonesia.
authors.lastname: Soetjipto
authors.affiliation: Research Center for Medicinal Plant Resources, National Institute of Biomedical Innovation, 1-2 Hachimandai, Tsukuba, Ibaraki 305-0843, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fuchino
authors.affiliation: Research Center for Medicinal Plant Resources, National Institute of Biomedical Innovation, 1-2 Hachimandai, Tsukuba, Ibaraki 305-0843, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kawahara
authors.affiliation: Division of Infectious Disease Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Division of Microbiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Aoki
authors.affiliation: Division of Microbiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Electronic address: hotta@kobe-u.ac.jp.
authors.forename: Hak
authors.initials: H
authors.lastname: Hotta
mesh_terms: D000998:Antiviral Agents / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D011564:Furocoumarins / Q000302:isolation & purification / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D018515:Plant Leaves / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry; D015363:Quinolones / Q000302:isolation & purification / Q000494:pharmacology*; D032105:Ruta / Q000737:chemistry*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D011564:Furocoumarins; D015363:Quinolones; C000597673:pseudane IX; C031533:chalepin
keywords: Alkaloid; Arborinine (PubChem CID 5281832); Chalepin (PubChem CID 119066); Coumarin; Hepatitis C virus; Kokusaginine (PubChem CID 10227); Post-entry inhibition; Pseudane IX (PubChem data not available); Ruta angustifolia; Rutaceae; Scopoletin (PubChem CID 5280460); γ-Fagarine (PubChem CID 107936)