Aty Widyawaruyanti1,2, Mulyadi Tanjung2,3, Adita Ayu Permanasari2, Ratih Saputri2,3, Lidya Tumewu2, Myrna Adianti2, Chie Aoki-Utsubo4, Hak Hotta5, Achmad Fuad Hafid1,2, Tutik Sri Wahyuni6,7. 1. Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Universitas Airlangga, Jl. Mulyorejo, Surabaya, 60115, Indonesia. 2. Institute of Tropical Disease, Universitas Airlangga, Jl. Mulyorejo, Surabaya, 60115, Indonesia. 3. Department of Chemistry, Faculty of Science and Technology, Universitas Airlangga, Jl. Mulyorejo, Surabaya, 60115, Indonesia. 4. Department of Public Health, Kobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, 654-0142, Japan. 5. Faculty of Clinical Nutrition and Dietetics, Konan Women's University, 6-2-23 Morikita-machi, Higashinada-ku, Kobe, 658-0001, Japan. 6. Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Universitas Airlangga, Jl. Mulyorejo, Surabaya, 60115, Indonesia. tutik-s-w@ff.unair.ac.id. 7. Institute of Tropical Disease, Universitas Airlangga, Jl. Mulyorejo, Surabaya, 60115, Indonesia. tutik-s-w@ff.unair.ac.id.
Abstract
BACKGROUND: New agents for developing alternative or complementary medicine to treat the hepatitis C virus (HCV) are still needed due to high rates of HCV infection globally and the current limitations of available treatments. Treatment of HCV with a combination of direct acting antivirals have been shown to be approximately 90% effective but will be limited in the future due to the emergence of drug resistance and high cost. The leaves of Melicope latifolia have previously been reported to have anti-HCV activity and are a potential source of bioactive compounds for future novel drug development. This study aimed to evaluate the efficacy of the extract of M. latifolia fruit to treat HCV and to isolate its active compounds. METHOD: M. latifolia fruit was extracted using methanol and purified using vacuum liquid chromatography (VLC) and Radial Chromatography. The anti-HCV activity was analyzed using cell culture lines Huh7it-1 and JFH1 (genotype 2a). Time-of-addition and immunoblotting studies were performed to identify the mode of action of the isolated active compounds. The structures of the active compounds were determined using nuclear magnetic resonance (NMR) spectra, UV, IR, and Mass Spectra. RESULTS: Six known compounds were isolated from M. latifolia fruit: O-methyloktadrenolon, alloevodionol, isopimpinellin, alloxanthoxyletin, methylevodionol, and N-methylflindersine. N-methylflidersine was the most active compound with IC50 value of 3.8 μg/ml while methylevodionol, isopimpinellin, and alloevodionol were less active. O-methyloktadrenolon and alloxanthoxyletin were moderately active with IC50 values of 10.9 and 21.72 μg/ml, respectively. N-methylflidersine decreased level of HCV NS3 protein expression in the cells. CONCLUSION: The alkaloid compound, N-methylflindersine which was isolated from M. latifolia possesses anti-HCV activity through post-entry inhibition and suppressed NS3 protein expression.
BACKGROUND: New agents for developing alternative or complementary medicine to treat the hepatitis C virus (HCV) are still needed due to high rates of HCV infection globally and the current limitations of available treatments. Treatment of HCV with a combination of direct acting antivirals have been shown to be approximately 90% effective but will be limited in the future due to the emergence of drug resistance and high cost. The leaves of Melicope latifolia have previously been reported to have anti-HCV activity and are a potential source of bioactive compounds for future novel drug development. This study aimed to evaluate the efficacy of the extract of M. latifolia fruit to treat HCV and to isolate its active compounds. METHOD:M. latifolia fruit was extracted using methanol and purified using vacuum liquid chromatography (VLC) and Radial Chromatography. The anti-HCV activity was analyzed using cell culture lines Huh7it-1 and JFH1 (genotype 2a). Time-of-addition and immunoblotting studies were performed to identify the mode of action of the isolated active compounds. The structures of the active compounds were determined using nuclear magnetic resonance (NMR) spectra, UV, IR, and Mass Spectra. RESULTS: Six known compounds were isolated from M. latifolia fruit: O-methyloktadrenolon, alloevodionol, isopimpinellin, alloxanthoxyletin, methylevodionol, and N-methylflindersine. N-methylflidersine was the most active compound with IC50 value of 3.8 μg/ml while methylevodionol, isopimpinellin, and alloevodionol were less active. O-methyloktadrenolon and alloxanthoxyletin were moderately active with IC50 values of 10.9 and 21.72 μg/ml, respectively. N-methylflidersine decreased level of HCVNS3 protein expression in the cells. CONCLUSION: The alkaloid compound, N-methylflindersine which was isolated from M. latifolia possesses anti-HCV activity through post-entry inhibition and suppressed NS3 protein expression.
Entities:
Keywords:
Alkaloids; Benzopyrans; Hepatitis C virus; Melicope latifolia
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