Investigation of Antiviral Potential of Food Carotenoids and Apocarotenoids against RNA-dependent RNA Polymerase of Hepatitis C Virus

Abstract

Hepatitis C disease have been a global health threat and affects a significant portion of world population. Hepatitis C have also been a silent health threat for Turkiye, where there are around half million people infected with Hepatitis C Virus (HCV). Disease burden and mortality are expected to increase gradually in the next 20 years in Turkiye. Unavailability of enough data on the currently-available drugs in routine clinical practice, their side effects and interactions with other drugs, and their efficacies on the less common genotypes indicates the necessity of alternative treatment options. Natural products from herbal and medicinal plants can indeed provide an alternative as being drug-like dietary supplements. In particular, the carotenoids and apocarotenoids are underexplored in their antiviral potential, including anti-HCV activities. Therefore, we focused on the virtual screening of various carotenoids and apocarotenoids against the RNA-dependent RNA polymerase (RdRp) of HCV. Molecular docking experiments showed strong binding affinities of the ligands to both palm and thumb domains of RdRp of HCV. In fact, some of them such as neoxanthin, crocin, canthaxanthin and cryptoflavin bound quite strongly to both domains compared to native ligands and current antiviral drugs. MD simulation for neoxanthin-RdRp complex confirmed the stability of the ligand within the binding cavity of RdRp throughout 100 ns simulation. This clearly indicated the potential of carotenoids, specifically neoxanthin, as RdRp inhibitor in treating HCV. Thus, this study not only discovered anti-HCV drug candidates with the properties of easy-to-access and low cost, but also paved the way for the development of carotenoid or apocarotenoid based dietary supplement candidates for the prevention and treatment of HCV.

Keywords

• Carotenoids
• Apocarotenoids
• Hepatitis C Virus
• RNA-dependent RNA polymerase inhibitors
• Virtual Screening

Supporting Institution

The Scientific and Technological Research Council of Turkiye

Project Number

221Z280

References

1. V. A. Morozov and S. Lagaye, “Hepatitis C virus: Morphogenesis, infection and therapy,” World J Hepatol, vol. 10, pp. 186–212, 2018. https://doi.org/10.4254/WJH.V10.I2.186
2. E. Tang and L. Angeles, “Hepatitis C virus. A review.,” West J Med, vol. 155, pp. 164–168, 1991.
3. M. P. Manns, M. Buti, J-M. Pwalotsky, H. Razavi, N. Terrault, and Z. Younossi, “Hepatitis C virus infection,” Nat Rev Dis Prim, vol. 3, pp. 1–19, 2017. https://doi.org/10.1038/nrdp.2017.6
4. A. J. Millman, N. P. Nelson, and C. Vellozzi, “Hepatitis C: Review of the Epidemiology, Clinical Care, and Continued Challenges in the Direct Acting Antiviral Era,” Curr Epidemiol reports, vol. 4, pp. 174–185, 2017. https://doi.org/10.1007/S40471-017-0108-X
5. A. M. Hauri, G. L. Armstrong, and Y. J. F. Hutin, “The global burden of disease attributable to contaminated injections given in health care settings,” Int J STD AIDS, vol. 15, pp. 7–16, 2004. https://doi.org/10.1258/095646204322637182
6. C. W. Spearman, G. M. Dusheiko, M. Hellard, and M. Sonderup, “Hepatitis C,” Lancet, vol. 394, pp. 1451–1466, 2019. https://doi.org/10.1016/S0140-6736(19)32320-7
7. A. A. Rabaan, S. H. Al-Ahmed, A. M. Bazzi, W. A. Alfouzan, S. A, Alsuliman, F. A. Aldrazi, and S. Haque, “Overview of hepatitis C infection, molecular biology, and new treatment,” J Infect Public Health, vol. 13, pp. 773–783, 2020. https://doi.org/10.1016/J.JIPH.2019.11.015
8. N. Tozun, O. Ozdogan, Y. Cakaloglu, R. Idilman, Z. Karasu, U. Akarca, S. Kaymakoglu, and O. Ergonul, “Seroprevalence of hepatitis B and C virus infections and risk factors in Turkey: a fieldwork TURHEP study,” Clin Microbiol Infect, vol. 21, pp. 1020–1026, 2015. https://doi.org/10.1016/J.CMI.2015.06.028

9. “Türkiye Viral Hepatit Önleme ve Kontrol Programi”, Accessed: Aug. 01, 2022. [Online]. Available: https://hsgm.saglik.gov.tr/tr/bulasicihastaliklar-haberler/turkiye-viral-hepatit-onleme-ve-kontrol-programi.html
10. H. Razavi et al., “The present and future disease burden of hepatitis C virus (HCV) infection with today’s treatment paradigm,” J Viral Hepat, vol. 21, pp. 34–59, 2014. https://doi.org/10.1111/JVH.12248
11. E. Gower, C. Estes, S. Blach, K. Razavi-Shearer, and H. Razavi, “Global epidemiology and genotype distribution of the hepatitis C virus infection,” J Hepatol, vol. 61, pp. S45–S57, 2014. https://doi.org/10.1016/J.JHEP.2014.07.027
12. B. Henry, “Drug pricing and challenges to hepatitis c treatment access,” J Heal Biomed law, vol. 14, pp. 265–283, 2018.
13. J. H. Hoofnagle and L. B. Seeff, “Peginterferon and Ribavirin for Chronic Hepatitis C,” N Engl J Med, vol. 355, pp. 2444–2451, 2006. https://doi.org/10.1056/NEJMCT061675
14. M. Zając, I. Muszalska, A. Sobczak, A. Dadej, S. Tomczak, and A. Jelińska, “Hepatitis C – New drugs and treatment prospects,” Eur J Med Chem, vol. 165, pp. 225–249, 2019. https://doi.org/10.1016/J.EJMECH.2019.01.025
15. R. González-Grande, M. Jiménez-Pérez, C. G. Arjona, and J. M. Torres, “New approaches in the treatment of hepatitis C,” World J Gastroenterol, vol. 22, pp. 1421–1432, 2016. https://doi.org/10.3748/WJG.V22.I4.1421
16. J. Yabuzaki, “Carotenoids Database: structures, chemical fingerprints and distribution among organisms,” Database, vol. 2017, pp. 1–11, 2017 https://doi.org/10.1093/DATABASE/BAX004
17. O. Fidan and J. Zhan, “Discovery and engineering of an endophytic Pseudomonas strain from Taxus chinensis for efficient production of zeaxanthin diglucoside,” J Biol Eng, vol. 13, pp. 1–18, 2019. https://doi.org/10.1186/S13036-019-0196-X
18. J. Dzib-Cauich, R. Us-Camas, and R. Rivera-Madrid, “Natural Sources of Apocarotenoids and Their Applications,” in Biol Chem Appl Apocarotenoids, S. Ramamoorthy, R. R. Madrid, C, G. P. Doss, Eds. Boca Raton: CRC Press, pp. 11–39, 2020. https://doi.org/10.1201/9780429344206-2
19. C. Zhang, “Biosynthesis of Carotenoids and Apocarotenoids by Microorganisms and Their Industrial Potential,” in Prog Carotenoid Res, L. Q. Zepka, E. Jacob-Lopes and V. V. De Rosso, Eds. London: IntechOpen, pp. 85–105, 2018. https://doi.org/10.5772/INTECHOPEN.79061
20. R. W. Tuveson, R. A. Larson, and J. Kagan, “Role of cloned carotenoid genes expressed in Escherichia coli in protecting against inactivation by near-UV light and specific phototoxic molecules,” J Bacteriol, vol. 170, pp. 4675–4680, 1988. https://doi.org/10.1128/jb.170.10.4675-4680.1988
21. A. J. Simkin, “Carotenoids and Apocarotenoids in Planta: Their Role in Plant Development, Contribution to the Flavour and Aroma of Fruits and Flowers, and Their Nutraceutical Benefits,” Plants (Basel), vol. 10, pp. 2321, 2021. https://doi.org/10.3390/PLANTS10112321
22. Y. Sharoni et al., “Carotenoids and apocarotenoids in cellular signaling related to cancer: A review,” Mol Nutr Food Res, vol. 56, pp. 259–269, 2012. https://doi.org/10.1002/MNFR.201100311
23. S. Mujwar, L. Sun, and O. Fidan, “In silico evaluation of food-derived carotenoids against SARS-CoV-2 drug targets: Crocin is a promising dietary supplement candidate for COVID-19,” J Food Biochem, vol. 2022 May 11, pp. e14219, 2022. https://doi.org/10.1111/JFBC.14219
24. G. E. Hegazy, M. M. Abu-Serie, G. M. Agu-Elela, H. Ghozlan, S. A. Sabry, N. A. Soliman, and Y. R. Abdel-Fattah, “In vitro dual (anticancer and antiviral) activity of the carotenoids produced by haloalkaliphilic archaeon Natrialba sp. M6,” Sci Rep, vol. 10, pp. 5986, 2020. https://doi.org/10.1038/s41598-020-62663-y
25. S. Santoyo, L. Jaime, M. Plaza, M. Herrero, I.Rodriguez-Meizoso, E. Ibañez, and G. Reglero, “Antiviral compounds obtained from microalgae commonly used as carotenoid sources,” J Appl Phycol, vol. 24, pp. 731–741, 2011. https://doi.org/10.1007/s10811-011-9692-1
26. S. Fakhri, Z. Nouri, S. Z. Moradi, and M. H. Farzaei, “Astaxanthin, COVID‐19 and immune response: Focus on oxidative stress, apoptosis and autophagy,” Phyther Res, vol. 34, pp. 2790–2792, 2020. https://doi.org/10.1002/PTR.6797
27. D. J. Kaio, P. H. Rondo, J. M. Souza, A. V Firmino, L. A. Luzia, and A. A. Segurado, “Vitamin A and beta-carotene concentrations in adults with HIV/AIDS on highly active antiretroviral therapy,” J Nutr Sci Vitaminol, vol. 59, pp. 496–502, 2013. https://doi.org/10.3177/jnsv.59.496
28. S. Seren, M. Mutchnick, D. Hutchinson, O. Harmanci, Y. Bayraktar, S. Mutchnick, K. Sahin, and O. Kucuk, “Potential role of lycopene in the treatment of hepatitis C and prevention of hepatocellular carcinoma,” Nutr Cancer, vol. 60, pp. 729–735, 2008. https://doi.org/10.1080/01635580802419772
29. J. Talukdar, B. Bhadra, T. Dattaroy, V. Nagle, and S. Dasgupta, “Potential of natural astaxanthin in alleviating the risk of cytokine storm in COVID-19,” Biomed Pharmacother, vol. 132, pp. 110886, 2020. https://doi.org/10.1016/j.biopha.2020.110886
30. O. Fidan, S. Mujwar, and M. Kciuk, “Discovery of adapalene and dihydrotachysterol as antiviral agents for the Omicron variant of SARS-CoV-2 through computational drug repurposing,” Mol Divers, vol. 1, pp. 1–13, 2022. https://doi.org/10.1007/S11030-022-10440-6
31. S. Le Pogam, H. Kang, S. F. Harris, V. Leveque, A. M. Giannetti, S. Ali, W.-R. Jiang, S. Rajyaguru, G. Tavares, C. Oshiro, T. Hendricks, K, Klumpp, J. Symons, M. F. Browner, N. Cammack, I. Nájera, “Selection and Characterization of Replicon Variants Dually Resistant to Thumb- and Palm-Binding Nonnucleoside Polymerase Inhibitors of the Hepatitis C Virus,” J Virol, vol. 80, pp. 6146–6154, 2006. https://doi.org/10.1128/JVI.02628-05
32. O. Trott and A. J. Olson, “AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading,” J Comput Chem, vol. 31, pp. 455–461, 2010. https://doi.org/10.1002/jcc.21334
33. S. Mujwar and R. K. Harwansh, “In silico bioprospecting of taraxerol as a main protease inhibitor of SARS-CoV-2 to develop therapy against COVID-19,” Struct Chem, vol. 1, pp. 1–12, 2022. https://doi.org/10.1007/S11224-022-01943-X
34. M. E. O’Neill, Y. Carroll, B. Corridan, B. Olmedilla, F. Granado, I. Blanco, H. Van den Berg, I. Hininger, A. M. Rousell, M. Chopra, S. Southon, and D. I. Thurnham, “A European carotenoid database to assess carotenoid intakes and its use in a five-country comparative study,” Br J Nutr, vol. 85, pp. 499–507, 2001. https://doi.org/10.1079/BJN2000284
35. D. B. Rodriguez-Amaya, “Latin American food sources of carotenoids,” Arch Latinoam Nutr, vol. 49, , pp. 74S-84S, 1999.
36. J. M. Holden, A. L. Eldridge, G. R. Beecher, I. M. Buzzard, A. S. Bhagwat, C. S. Davis, L. W. Douglass, E. S. Gebhardt, D. Haytowitz, and S. Schakel, “Carotenoid Content of U.S. Foods: An Update of the Database,” J Food Compos Anal, vol. 12, pp. 169–196, 1999. https://doi.org/10.1006/JFCA.1999.0827
37. B. Setiawan, A. Sulaeman, D. W. Giraud, and J. A. Driskell, “Carotenoid Content of Selected Indonesian Fruits,” J Food Compos Anal, vol. 14, pp. 169–176, 2001. https://doi.org/10.1006/JFCA.2000.0969
38. A. J. Meléndez-Martínez, G. Britton, I. M. Vicario, and F. J. Heredia, “Does the carotenoid neoxanthin occur in orange juice?,” Food Chem, vol. 107, pp. 49–54, 2008. https://doi.org/10.1016/J.FOODCHEM.2007.07.022
39. T. Řezanka, L. Nedbalová, I. Kolouchová, and K. Sigler, “LC–MS/APCI identification of glucoside esters and diesters of astaxanthin from the snow alga Chlamydomonas nivalis including their optical stereoisomers,” Phytochemistry, vol. 88, pp. 34–42, 2013. https://doi.org/10.1016/J.PHYTOCHEM.2013.01.003
40. B. Tian and Y. Hua, “Carotenoid biosynthesis in extremophilic Deinococcus–Thermus bacteria,” Trends Microbiol, vol. 18, pp. 512–520, 2010. https://doi.org/10.1016/J.TIM.2010.07.007
41. N. J. C. Fong, M. L. Burgess, K. D. Barrow, and D. R. Glenn, “Carotenoid accumulation in the psychrotrophic bacterium Arthrobacter agilis in response to thermal and salt stress,” Appl Microbiol Biotechnol, vol. 56, pp. 750–756, 2001. https://doi.org/10.1007/S002530100739
42. M. H. Walter, D. S. Floss, and D. Strack, “Apocarotenoids: Hormones, mycorrhizal metabolites and aroma volatiles,” Planta, vol. 232, pp. 1–17, 2010. https://doi.org/10.1007/S00425-010-1156-3
43. E. H. Harrison and L. Quadro, “Apocarotenoids: Emerging Roles in Mammals,” Annu Rev Nutr, vol. 38, pp. 153–172, 2018. https://doi.org/10.1146/ANNUREV-NUTR-082117-051841
44. S. M. C, A. Treesa Mathew, S. Rekha, P. G. R, and C. Author, “Apocarotenoids: A Brief Review,” Int J Res Rev, vol. 7, pp. 252–256, 2020.
45. S. A. Cherrak, H. Merzouk, and N. Mokhtari-Soulimane, “Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: A molecular docking and simulation studies,” PLoS One, vol. 15, pp. e0240653, 2020. https://doi.org/10.1371/JOURNAL.PONE.0240653
46. S. I. Elshahawi, K. A. Shaaban, M. K. Kharel, and J. S. Thorson, “A comprehensive review of glycosylated bacterial natural products,” Chem Soc Rev, vol. 44, pp. 7591–7697, 2015. https://doi.org/10.1039/C4CS00426D
47. S. Fakhri, Z. Nouri, S. Z. Moradi, and M. H. Farzaei, “Astaxanthin, COVID-19 and immune response: Focus on oxidative stress, apoptosis and autophagy,” Phytother Res, vol. 34, pp. 2790–2792, 2020. https://doi.org/10.1002/ptr.6797
48. S. Fakhri, F. Abbaszadeh, L. Dargahi, and M. Jorjani, “Astaxanthin: A mechanistic review on its biological activities and health benefits,” Pharmacol Res, vol. 136, pp. 1–20, 2018. https://doi.org/10.1016/J.PHRS.2018.08.012
49. J. Talukdar, B. Bhadra, T. Dattaroy, V. Nagle, and S. Dasgupta, “Potential of natural astaxanthin in alleviating the risk of cytokine storm in COVID-19,” Biomed Pharmacother, vol. 132, pp. 110886, 2020. https://doi.org/10.1016/J.BIOPHA.2020.110886
50. A. A. Mentis, M. Dalamaga, C. Lu, and M. G. Polissiou, “Saffron for ‘toning down’ COVID-19-related cytokine storm: Hype or hope? A mini-review of current evidence,” Metab Open, vol. 11, pp. 100111, 2021. https://doi.org/10.1016/j.metop.2021.100111
51. S. K. Yim, I. Kim, B. Warren, J. Kim, K. Jung, and B. Ku, “Antiviral Activity of Two Marine Carotenoids against SARS-CoV-2 Virus Entry In Silico and In Vitro,” Int J Mol Sci, vol. 22, pp. 6481, 2021. https://doi.org/10.3390/ijms22126481
52. A. P. Rumengan, E. S. Mandiangan, W. A. Tanod, D. S. J. Paransa, C. P. Paruntu, and D. M. H. Mantiri, “Identification of pigment profiles and antioxidant activity of Rhizophora mucronata mangrove leaves origin Lembeh, North Sulawesi, Indonesia,” Biodiversitas J Biol Divers, vol. 22, pp. 2805–2816, 2021. https://doi.org/10.13057/BIODIV/D220730
53. C. Giossi, P. Cartaxana, and S. Cruz, “Photoprotective Role of Neoxanthin in Plants and Algae,” Molecules, vol. 25, pp. 4617, 2020. https://doi.org/10.3390/MOLECULES25204617
54. H. Ibrahim, M. Shaaban, A. A. M. Hanafi, and K. M. Abdulsalam, “Inhibition of bacteria isolated from human specimens by selected marine-origin extracts,” Egypt J Exp Biol (Bot), vol. 16, pp. 91–103, 2020. https://doi.org/10.5455/egyjebb.20200509032540
55. S. U. Kadam and P. Prabhasankar, “Marine foods as functional ingredients in bakery and pasta products,” Food Res Int, vol. 43, pp. 1975–1980, 2010. https://doi.org/110.1016/J.FOODRES.2010.06.007
56. T. M. Karpiński, M. Kwaśniewski, M. Ożarowski, and R. Alam, “In silico studies of selected xanthophylls as potential candidates against SARS-CoV-2 targeting main protease (Mpro) and papain-like protease (PLpro),” Herba Pol, vol. 67, pp. 1–8, 2021. https://doi.org/10.2478/hepo-2021-0009
57. S. Soleymani, R. Zabihollahi, S. Shahbazi, and A. Bolhassani, “Antiviral Effects of Saffron and its Major Ingredients,” Curr Drug Deliv, vol. 15, pp. 698–704, 2018. https://doi.org/10.2174/1567201814666171129210654