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Antiviral and molecular docking analysis of methoxyflavones isolated from Melicope latifolia leaves against HCV

Yıl 2023, Cilt: 27 Sayı: 3, 1301 - 1312, 28.06.2025

Aty Widyawaruyanti Lidya Tumewu Achmad F. Hafid Tutik S. Wahyun Adita A. Permanasari Myrna Adianti Maria I. Lusida Soetjipto Soetjipto Hiroyuki Fuchino Nobuo Kawahara Chie Aoki-utsubo Tri Widiandani Hak Hotta

Öz

Treatments of hepatitis C virus have been developed and increased the sustained virology response (SVR),
however, there are several reports of drug resistance, high-cost issue, and limited access to current hepatitis C virus
(HCV) treatment that remain become a problem. This necessitates to search for complementary and alternative drugs
against HCV, therefore the investigation of active compounds from plant extracts such as Melicope latifolia, a plant that
has been reported as anti-HCV, will be provided in this study. The anti-HCV activities were tested using in vitro
cultured cells of hepatocyte cell line Huh 7.5 and HCV genotype 2a (J6/JFH1). Ethanol extract of M. latifolia leaves was
separated by chromatographic methods and the chemical structures of the isolated compounds were established based
on mass spectrometry, 1D, and 2D nuclear magnetic resonance spectral data, as well as comparison with reported data.
The interaction of the compound with the protein, which involves to HCV activity, was determined by docking analysis.
Three known methoxyflavone compounds identified as 5,4'-dihydroxy-7-prenyloxy-3,8,5’-trimethoxyflavone (1); 5,3'-
dihydroxy-3,7,8,4'-tetramethoxyflavone (2); and 5-hydroxy-3,7,8,3',4'-pentamethoxyflavone (3) were isolated from the
ethanolic extract of M. latifolia leaves. Anti-HCV activities revealed that compound (1) strongly inhibited HCV J6/JFH1
with a 50% inhibitory concentration (IC50) value of 6.7±0.4 µg/mL and 50% cytotoxic concentration (CC50) of 19.3
µg/mL. The docking analysis revealed an interaction with the 4GAG, a protein that involves in the entry step of HCV,
and the 4EAW protein which plays an important role during HCV replication.

Anahtar Kelimeler

AntiHCV Infectious disease Melicope latifolia medicine hepatitis health

Kaynakça

  • [1] Lindenbach BD, Evans MJ, Syder AJ, Wölk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, Rice CM. Complete replication of hepatitis C virus in cell culture. Science. 2005;309(5734):623-626. https://doi.org/10.1126/science.1114016.
  • [2] Ireton RC, Gale M Jr. Pushing to a cure by harnessing innate immunity against hepatitis C virus. Antiviral Res. 2014;108:156-164. https://doi.org/10.1016/j.antiviral.2014.05.012
  • [3] Gonzalez-Grande R, Jimenez-Perez M, Gonzalez Arjona C, Mostazo Torres J. New approaches in the treatment of hepatitis C. World J Gastroenterol. 2016;22(4):1421-1432. https://doi.org/10.3748/wjg.v22.i4.1421
  • [4] Kiser JJ, Flexner C. Direct-acting antiviral agents for hepatitis C virus infection. Annu Rev Pharmacol Toxicol. 2013;53:427-449. https://doi.org/10.1146%2Fannurev-pharmtox-011112-140254
  • [5] Hussein G, Miyashiro H, Nakamura N, Hattori M, Kakiuchi N, Shimotohno K. Inhibitory effects of Sudanese medicinal plant extracts on hepatitis C virus (HCV) protease. Phytother Res. 2000;14(7):510-516. https://doi.org/10.1002/1099-1573(200011)14:7<510::AID-PTR646>3.0.CO;2-B
  • [6] Calland N, Dubuisson J, Rouille Y, Seron K. Hepatitis C virus and natural compounds: A new antiviral approach? Viruses. 2012;4(10):2197-2217. https://doi.org/10.3390%2Fv4102197
  • [7] Ashfaq UA, Idrees S. Medicinal plants against hepatitis C virus. World J Gastroenterol. 2014;20(11):2941-2947. https://doi.org/10.3748/wjg.v20.i11.2941
  • [8] Khachatoorian R, Arumugaswami V, Raychaudhuri S, Yeh GK, Maloney EM, Wang J, Dasgupta A, French SW. Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle. Virology. 2012;433(2):346-355. https://doi.org/10.1016/j.virol.2012.08.029
  • [9] Shibata C, Ohno M, Otsuka M, Kishikawa T, Goto K, Muroyama R, Kato N, Yoshikawa T, Takata A, Koike K. The flavonoid apigenin inhibits hepatitis C virus replication by decreasing mature microRNA122 levels. Virology. 2014;462-463:42-48. https://doi.org/10.1016/j.virol.2014.05.024
  • [10] Nahmias Y, Goldwasser J, Casali M, van Poll D, Wakita T, Chung RT, Yarmush ML. Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology. 2008;47(5):1437-45. https://doi.org/10.1002/hep.22197
  • [11] Bachmetov L, Gal-Tanamy M, Shapira A, Vorobeychik M, Giterman-Galam T, Sathiyamoorthy P, Golan-Goldhirsh A, Benhar I, Tur-Kaspa R, Zemel R. Suppression of hepatitis C virus by the flavonoid quercetin is mediated by inhibition of NS3 protease activity. J Viral Hepat. 2012;19(2):e81-88. https://doi.org/10.1111/j.1365-2893.2011.01507.x
  • [12] Adianti M, Aoki C, Komoto M, Deng L, Shoji I, Wahyuni TS, Lusida MI, Soetjipto, Fuchino H, Kawahara N, Hotta H. Anti-hepatitis C virus compounds obtained from Glycyrrhiza uralensis and other Glycyrrhiza species. Microbiol Immunol. 2014;58(3):180-187. https://doi.org/10.1111/1348-0421.12127
  • [13] Ratnoglik SL, Aoki C, Sudarmono P, Komoto M, Deng L, Shoji I, Fuchino H, Kawahara N, Hotta H. Antiviral activity of extracts from Morinda citrifolia leaves and chlorophyll catabolites, pheophorbide a and pyropheophorbide a, against hepatitis C virus. Microbiol Immunol. 2014;58(3):188-194. https://doi.org/10.1111/1348-0421.12133
  • [14] Wahyuni TS, Tumewu L, Permanasari AA, Apriani E, Adianti M, Rahman A, Widyawaruyanti A, Lusida MI, Fuad A, Soetjipto, Nasronudin, Fuchino H, Kawahara N, Shoji I, Deng L, Aoki C, Hotta H. Antiviral activities of Indonesian medicinal plants in the East Java region against hepatitis C virus. Virol J. 2013;10:259. https://doi.org/10.1186/1743-422X-10-259
  • [15] Lange CM, Jacobson IM, Rice CM, Zeuzem S. Emerging therapies for the treatment of hepatitis C. EMBO Mol Med. 2014;6(1):4-15. https://doi.org/10.1002/emmm.201303131
  • [16] Keyvani H, Fazlalipour M, Monavari SH, Mollaie HR. Hepatitis C virus--proteins, diagnosis, treatment and new approaches for vaccine development. Asian Pac J Cancer Prev. 2012;13(12):5931-5949. https://doi.org/10.7314/APJCP.2012.13.12.5917
  • [17] Sagir A, Avci A, Erhardt A, Lorke J, Heintges T, Haussinger D. New approaches in the treatment of hepatitis B. Dtsch Med Wochenschr. 2004;129(21):1203-1208. https://doi.org/10.3390%2Fjcm9103187
  • [18] Abe H, Hayes CN, Hiraga N, Imamura M, Tsuge M, Miki D, Takahashi S, Ochi H, Chayama K. A translational study of resistance emergence using sequential direct-acting antiviral agents for hepatitis C using ultra-deep sequencing. Am J Gastroenterol. 2013;108(9):1464-1472. https://doi.org/10.1038/ajg.2013.205
  • [19] Ahsan M, Amstrong JA, Gibbons S, Gray AI, Waterman PG. Novel O-Prenylated flavonoid from two varieties of Boronia coerulescens. Phytochemistry. 1994;37(1):259-266. https://doi.org/10.1016/0031-9422(94)85037-2
  • [20] Wollenweber E, Fischer R, Dörr M, Irvine K, Pereira C, Stevens J. Chemodiversity of exudate flavonoids in Cassinia and Ozothamnus (Asteraceae, Gnaphalieae). Z Naturforsch C. 2008;63(9-10):731-739. https://doi.org/10.1515/znc-2008-9-1019
  • [21] Li S, Lo C-Y, Ho C-T. Hydroxylated polymethoxyflavones and methylated flavonoids in sweet orange (Citrus sinensis) peel. J Agric Food Chem. 2006;54(12):4176-4185. https://doi.org/10.1021/jf060234n
  • [22] George S, Ajikumaran Nair S, Johnson AJ, Venkataraman R, Baby S. O-prenylated flavonoid, an antidiabetes constituent in Melicope lunuankenda. J Ethnopharmacol. 2015;168:158-163. https://doi.org/10.1016/j.jep.2015.03.060
  • [23] Yang X, Yang J, Jiang Y, Yang H, Yun Z, Rong W, Yang B. Regiospecific synthesis of prenylated flavonoids by a prenyltransferase cloned from Fusarium oxysporum. Sci Rep. 2016;6:24819. https://doi.org/10.1038/srep24819
  • [24] Chen X, Mukwaya E, Wong MS, Zhang Y. A systematic review on biological activities of prenylated flavonoids. Pharm Biol. 2014;52(5):655-660. https://doi.org/10.3109/13880209.2013.853809
  • [25] Qian XJ, Zhu YZ, Zhao P, Qi ZT. Entry inhibitors: New advances in HCV treatment. Emerg Microbes Infect. 2016;5:e3. https://doi.org/10.1038/emi.2016.3
  • [26] McGivern DR, Masaki T, Lovell W, Hamlett C, Saalau-Bethell S, Graham B. Protease inhibitors block multiple functions of the NS3/4A Protease-Helicase during the Hepatitis C virus life cycle. J Virol. 2015;89(10):5362-5370. https://doi.org/10.1128/jvi.03188-14
  • [27] Yin C, Goonawardane N, Stewart H, Harris M. A role for domain I of the hepatitis C virus NS5A protein in virus assembly. PLoS Pathog. 2018;14(1):e1006834. https://doi.org/10.1371/journal.ppat.1006834

Yıl 2023, Cilt: 27 Sayı: 3, 1301 - 1312, 28.06.2025

Aty Widyawaruyanti Lidya Tumewu Achmad F. Hafid Tutik S. Wahyun Adita A. Permanasari Myrna Adianti Maria I. Lusida Soetjipto Soetjipto Hiroyuki Fuchino Nobuo Kawahara Chie Aoki-utsubo Tri Widiandani Hak Hotta

Öz

Kaynakça

  • [1] Lindenbach BD, Evans MJ, Syder AJ, Wölk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, Rice CM. Complete replication of hepatitis C virus in cell culture. Science. 2005;309(5734):623-626. https://doi.org/10.1126/science.1114016.
  • [2] Ireton RC, Gale M Jr. Pushing to a cure by harnessing innate immunity against hepatitis C virus. Antiviral Res. 2014;108:156-164. https://doi.org/10.1016/j.antiviral.2014.05.012
  • [3] Gonzalez-Grande R, Jimenez-Perez M, Gonzalez Arjona C, Mostazo Torres J. New approaches in the treatment of hepatitis C. World J Gastroenterol. 2016;22(4):1421-1432. https://doi.org/10.3748/wjg.v22.i4.1421
  • [4] Kiser JJ, Flexner C. Direct-acting antiviral agents for hepatitis C virus infection. Annu Rev Pharmacol Toxicol. 2013;53:427-449. https://doi.org/10.1146%2Fannurev-pharmtox-011112-140254
  • [5] Hussein G, Miyashiro H, Nakamura N, Hattori M, Kakiuchi N, Shimotohno K. Inhibitory effects of Sudanese medicinal plant extracts on hepatitis C virus (HCV) protease. Phytother Res. 2000;14(7):510-516. https://doi.org/10.1002/1099-1573(200011)14:7<510::AID-PTR646>3.0.CO;2-B
  • [6] Calland N, Dubuisson J, Rouille Y, Seron K. Hepatitis C virus and natural compounds: A new antiviral approach? Viruses. 2012;4(10):2197-2217. https://doi.org/10.3390%2Fv4102197
  • [7] Ashfaq UA, Idrees S. Medicinal plants against hepatitis C virus. World J Gastroenterol. 2014;20(11):2941-2947. https://doi.org/10.3748/wjg.v20.i11.2941
  • [8] Khachatoorian R, Arumugaswami V, Raychaudhuri S, Yeh GK, Maloney EM, Wang J, Dasgupta A, French SW. Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle. Virology. 2012;433(2):346-355. https://doi.org/10.1016/j.virol.2012.08.029
  • [9] Shibata C, Ohno M, Otsuka M, Kishikawa T, Goto K, Muroyama R, Kato N, Yoshikawa T, Takata A, Koike K. The flavonoid apigenin inhibits hepatitis C virus replication by decreasing mature microRNA122 levels. Virology. 2014;462-463:42-48. https://doi.org/10.1016/j.virol.2014.05.024
  • [10] Nahmias Y, Goldwasser J, Casali M, van Poll D, Wakita T, Chung RT, Yarmush ML. Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology. 2008;47(5):1437-45. https://doi.org/10.1002/hep.22197
  • [11] Bachmetov L, Gal-Tanamy M, Shapira A, Vorobeychik M, Giterman-Galam T, Sathiyamoorthy P, Golan-Goldhirsh A, Benhar I, Tur-Kaspa R, Zemel R. Suppression of hepatitis C virus by the flavonoid quercetin is mediated by inhibition of NS3 protease activity. J Viral Hepat. 2012;19(2):e81-88. https://doi.org/10.1111/j.1365-2893.2011.01507.x
  • [12] Adianti M, Aoki C, Komoto M, Deng L, Shoji I, Wahyuni TS, Lusida MI, Soetjipto, Fuchino H, Kawahara N, Hotta H. Anti-hepatitis C virus compounds obtained from Glycyrrhiza uralensis and other Glycyrrhiza species. Microbiol Immunol. 2014;58(3):180-187. https://doi.org/10.1111/1348-0421.12127
  • [13] Ratnoglik SL, Aoki C, Sudarmono P, Komoto M, Deng L, Shoji I, Fuchino H, Kawahara N, Hotta H. Antiviral activity of extracts from Morinda citrifolia leaves and chlorophyll catabolites, pheophorbide a and pyropheophorbide a, against hepatitis C virus. Microbiol Immunol. 2014;58(3):188-194. https://doi.org/10.1111/1348-0421.12133
  • [14] Wahyuni TS, Tumewu L, Permanasari AA, Apriani E, Adianti M, Rahman A, Widyawaruyanti A, Lusida MI, Fuad A, Soetjipto, Nasronudin, Fuchino H, Kawahara N, Shoji I, Deng L, Aoki C, Hotta H. Antiviral activities of Indonesian medicinal plants in the East Java region against hepatitis C virus. Virol J. 2013;10:259. https://doi.org/10.1186/1743-422X-10-259
  • [15] Lange CM, Jacobson IM, Rice CM, Zeuzem S. Emerging therapies for the treatment of hepatitis C. EMBO Mol Med. 2014;6(1):4-15. https://doi.org/10.1002/emmm.201303131
  • [16] Keyvani H, Fazlalipour M, Monavari SH, Mollaie HR. Hepatitis C virus--proteins, diagnosis, treatment and new approaches for vaccine development. Asian Pac J Cancer Prev. 2012;13(12):5931-5949. https://doi.org/10.7314/APJCP.2012.13.12.5917
  • [17] Sagir A, Avci A, Erhardt A, Lorke J, Heintges T, Haussinger D. New approaches in the treatment of hepatitis B. Dtsch Med Wochenschr. 2004;129(21):1203-1208. https://doi.org/10.3390%2Fjcm9103187
  • [18] Abe H, Hayes CN, Hiraga N, Imamura M, Tsuge M, Miki D, Takahashi S, Ochi H, Chayama K. A translational study of resistance emergence using sequential direct-acting antiviral agents for hepatitis C using ultra-deep sequencing. Am J Gastroenterol. 2013;108(9):1464-1472. https://doi.org/10.1038/ajg.2013.205
  • [19] Ahsan M, Amstrong JA, Gibbons S, Gray AI, Waterman PG. Novel O-Prenylated flavonoid from two varieties of Boronia coerulescens. Phytochemistry. 1994;37(1):259-266. https://doi.org/10.1016/0031-9422(94)85037-2
  • [20] Wollenweber E, Fischer R, Dörr M, Irvine K, Pereira C, Stevens J. Chemodiversity of exudate flavonoids in Cassinia and Ozothamnus (Asteraceae, Gnaphalieae). Z Naturforsch C. 2008;63(9-10):731-739. https://doi.org/10.1515/znc-2008-9-1019
  • [21] Li S, Lo C-Y, Ho C-T. Hydroxylated polymethoxyflavones and methylated flavonoids in sweet orange (Citrus sinensis) peel. J Agric Food Chem. 2006;54(12):4176-4185. https://doi.org/10.1021/jf060234n
  • [22] George S, Ajikumaran Nair S, Johnson AJ, Venkataraman R, Baby S. O-prenylated flavonoid, an antidiabetes constituent in Melicope lunuankenda. J Ethnopharmacol. 2015;168:158-163. https://doi.org/10.1016/j.jep.2015.03.060
  • [23] Yang X, Yang J, Jiang Y, Yang H, Yun Z, Rong W, Yang B. Regiospecific synthesis of prenylated flavonoids by a prenyltransferase cloned from Fusarium oxysporum. Sci Rep. 2016;6:24819. https://doi.org/10.1038/srep24819
  • [24] Chen X, Mukwaya E, Wong MS, Zhang Y. A systematic review on biological activities of prenylated flavonoids. Pharm Biol. 2014;52(5):655-660. https://doi.org/10.3109/13880209.2013.853809
  • [25] Qian XJ, Zhu YZ, Zhao P, Qi ZT. Entry inhibitors: New advances in HCV treatment. Emerg Microbes Infect. 2016;5:e3. https://doi.org/10.1038/emi.2016.3
  • [26] McGivern DR, Masaki T, Lovell W, Hamlett C, Saalau-Bethell S, Graham B. Protease inhibitors block multiple functions of the NS3/4A Protease-Helicase during the Hepatitis C virus life cycle. J Virol. 2015;89(10):5362-5370. https://doi.org/10.1128/jvi.03188-14
  • [27] Yin C, Goonawardane N, Stewart H, Harris M. A role for domain I of the hepatitis C virus NS5A protein in virus assembly. PLoS Pathog. 2018;14(1):e1006834. https://doi.org/10.1371/journal.ppat.1006834
Toplam 27 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Eczacılık ve İlaç Bilimleri (Diğer)
Bölüm Articles
Yazarlar

Aty Widyawaruyanti

Lidya Tumewu

Achmad F. Hafid

Tutik S. Wahyun

Adita A. Permanasari

Myrna Adianti

Maria I. Lusida

Soetjipto Soetjipto

Hiroyuki Fuchino

Nobuo Kawahara

Chie Aoki-utsubo

Tri Widiandani

Hak Hotta

Yayımlanma Tarihi 28 Haziran 2025
Yayımlandığı Sayı Yıl 2023 Cilt: 27 Sayı: 3

Kaynak Göster

APA Widyawaruyanti, A., Tumewu, L., Hafid, A. F., Wahyun, T. S., vd. (2025). Antiviral and molecular docking analysis of methoxyflavones isolated from Melicope latifolia leaves against HCV. Journal of Research in Pharmacy, 27(3), 1301-1312.
AMA Widyawaruyanti A, Tumewu L, Hafid AF, Wahyun TS, Permanasari AA, Adianti M, Lusida MI, Soetjipto S, Fuchino H, Kawahara N, Aoki-utsubo C, Widiandani T, Hotta H. Antiviral and molecular docking analysis of methoxyflavones isolated from Melicope latifolia leaves against HCV. J. Res. Pharm. Haziran 2025;27(3):1301-1312.
Chicago Widyawaruyanti, Aty, Lidya Tumewu, Achmad F. Hafid, Tutik S. Wahyun, Adita A. Permanasari, Myrna Adianti, Maria I. Lusida, Soetjipto Soetjipto, Hiroyuki Fuchino, Nobuo Kawahara, Chie Aoki-utsubo, Tri Widiandani, ve Hak Hotta. “Antiviral and Molecular Docking Analysis of Methoxyflavones Isolated from Melicope Latifolia Leaves Against HCV”. Journal of Research in Pharmacy 27, sy. 3 (Haziran 2025): 1301-12.
EndNote Widyawaruyanti A, Tumewu L, Hafid AF, Wahyun TS, Permanasari AA, Adianti M, Lusida MI, Soetjipto S, Fuchino H, Kawahara N, Aoki-utsubo C, Widiandani T, Hotta H (01 Haziran 2025) Antiviral and molecular docking analysis of methoxyflavones isolated from Melicope latifolia leaves against HCV. Journal of Research in Pharmacy 27 3 1301–1312.
IEEE A. Widyawaruyanti, “Antiviral and molecular docking analysis of methoxyflavones isolated from Melicope latifolia leaves against HCV”, J. Res. Pharm., c. 27, sy. 3, ss. 1301–1312, 2025.
ISNAD Widyawaruyanti, Aty vd. “Antiviral and Molecular Docking Analysis of Methoxyflavones Isolated from Melicope Latifolia Leaves Against HCV”. Journal of Research in Pharmacy 27/3 (Haziran 2025), 1301-1312.
JAMA Widyawaruyanti A, Tumewu L, Hafid AF, Wahyun TS, Permanasari AA, Adianti M, Lusida MI, Soetjipto S, Fuchino H, Kawahara N, Aoki-utsubo C, Widiandani T, Hotta H. Antiviral and molecular docking analysis of methoxyflavones isolated from Melicope latifolia leaves against HCV. J. Res. Pharm. 2025;27:1301–1312.
MLA Widyawaruyanti, Aty vd. “Antiviral and Molecular Docking Analysis of Methoxyflavones Isolated from Melicope Latifolia Leaves Against HCV”. Journal of Research in Pharmacy, c. 27, sy. 3, 2025, ss. 1301-12.
Vancouver Widyawaruyanti A, Tumewu L, Hafid AF, Wahyun TS, Permanasari AA, Adianti M, Lusida MI, Soetjipto S, Fuchino H, Kawahara N, Aoki-utsubo C, Widiandani T, Hotta H. Antiviral and molecular docking analysis of methoxyflavones isolated from Melicope latifolia leaves against HCV. J. Res. Pharm. 2025;27(3):1301-12.