Melatonin inhibits Zika virus replication in Vero epithelial cells and SK-N-SH human neuroblastoma cells
Inhibitory effect of melatonin on Zika virus replication
Keywords:
Melatonin, Zika virus, flavivirus, viral replication, mechanisms of action, antiviral activity, Vero epithelial cells, SK-N-SH human neuroblastoma cells
Abstract
Zika virus (ZIKV) is an emerging flavivirus that is causing significant public health concerns worldwide because of its association with severe neurological disorders in both newborns and adults. At present, the search for effective antiviral drugs for ZIKV infection is intense. Melatonin is a molecule that influences a wide variety of physiological processes. Melatonin is a direct free radical scavenger, an indirect antioxidant due to its stimulation of antioxidant enzymes and an anti-inflammatory and immunoregulatory molecule; recent studies also have shown melatonin to have anti-viral activity. Here, we are the first to show that melatonin inhibits ZIKV replication in both Vero cells and SK-N-SH cells. The suppressive actions of melatonin pretreatment on ZIKV infection was found to be time- and dose-dependent. The inhibitory effect of melatonin was more pronounced in human SK-N-SH neural cells than in Vero cells. Molecular docking experiments showed that melatonin exhibited high binding affinity to ZIKV nonstructural 3 (NS3) protein, the possible underlying inhibitory mechanism of melatonin on ZIKV replication. The results suggest that melatonin may have potential prophylactic and treatment effects against ZIKV infection.
References
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.
2. Hancock WT, Marfel M, Bel M (2014) Zika virus, French Polynesia, South Pacific, 2013. Emerg. Infec.t Dis. 20 (11): 1960.
3. Li H, Saucedo-Cuevas L, Shresta S, Gleeson JG (2016) The neurobiology of Zika virus. Neuron 92 (5): 949-958.
4. Carod-Artal FJ (2018) Neurological complications of Zika virus infection. Expert Rev. Anti. Infect Ther. 16 (5): 399-410.
5. Oehler E, et al. (2014) Zika virus infection complicated by Guillain-Barre syndrome--case report, French Polynesia, December 2013. Euro. Surveill. 19 (9): 20720.
6. Weaver SC, et al. (2016) Zika virus: History, emergence, biology, and prospects for control. Antiviral Res. 130: 69-80.
7. Hamel R, et al. (2015) Biology of Zika virus infection in human skin cells. J. Virol. 89 (17): 8880-8896.
8. Saiz JC, et al. (2016) Zika virus: the latest newcomer. Front. Microbiol. 7: 496.
9. Paz-Bailey G, et al. (2018) Persistence of Zika virus in body fluids - Final report. N. Engl. J. Med. 379 (13): 1234-1243.
10. Dupont-Rouzeyrol M, Biron A, O'Connor O, Huguon E, Descloux E (2016) Infectious Zika viral particles in breastmilk. Lancet 387 (10023): 1051.
11. Reiter RJ, Tan DX, Kim SJ, Cruz MH (2014) Delivery of pineal melatonin to the brain and SCN: Role of canaliculi, cerebrospinal fluid, tanycytes and Virchow-Robin perivascular spaces. Brain Struct. Funct. 219 (6): 1873-1887.
12. Bitar RD, Torres-Gomez J, Reiter RJ, Phillips WT (2021) Neural glymphatic system: Clinical implications and potential importance of melatonin. Melatonin Res. 4 (4): 551-565.
13. von Gall C (2022) The effects of light and the circadian system on rhythmic brain function. Int. J. Mol. Sci. 23 (5): 2778.
14. Acuna-Castroviejo D, et al. (2014) Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol. Life Sci. 71 (16): 2997-3025.
15. Claustrat B, Leston J (2015) Melatonin: Physiological effects in humans. Neurochirurgie 61.(2-3): 77-84.
16. Galano A, Reiter RJ (2018) Melatonin and its metabolites vs oxidative stress: From individual actions to collective protection. J. Pineal Res. 65 (1): e12514.
17. Rommasi F, Nasiri MJ, Mirsaeidi M (2022) Immunomodulatory agents for COVID-19 treatment: Possible mechanism of action and immunopathology features. Mol. Cell. Biochem. 477 (3): 711-726.
18. El-Sokkary GH, Omar HM, Hassanein AF, Cuzzocrea S, Reiter RJ (2002) Melatonin reduces oxidative damage and increases survival of mice infected with Schistosoma mansoni. Free Radic. Biol. Med. 32 (4): 319-332.
19. Tekbas OF, Ogur R, Korkmaz A, Kilic A, Reiter RJ (2008) Melatonin as an antibiotic: new insights into the actions of this ubiquitous molecule. J. Pineal Res. 44 (2): 222-226.
20. Vielma JR, et al. (2014) Effects of melatonin on oxidative stress, and resistance to bacterial, parasitic, and viral infections: a review. Acta Trop. 137: 31-38.
21. Srinivasan V, Mohamed M, Kato H (2012) Melatonin in bacterial and viral infections with focus on sepsis: A review. Rec. Pat. Endoc.r Metab. Immune Drug Discov. 6 (1): 30-39.
22. Bonilla E, Valero N, Chacin-Bonilla L, Medina-Leendertz S (2004) Melatonin and viral infections. J. Pineal Res. 36 (2): 73-79.
23. Huang S-H, et al. (2019) Melatonin possesses an anti-influenza potential through its immune modulatory effect. J. Funct. Foods 58: 189-198.
24. Wongchitrat P, Shukla M, Sharma R, Govitrapong P, Reiter RJ (2021) Role of melatonin on virus-induced neuropathogenesis-A concomitant therapeutic strategy to understand SARS-CoV-2 infection. Antioxidants (Basel) 10 (1): 47.
25. Zhai X, et al. (2021) Melatonin and other indoles show antiviral activities against swine coronaviruses in vitro at pharmacological concentrations. J. Pineal Res. 71 (2): e 12754.
26. Silvestri M, Rossi GA (2013) Melatonin: its possible role in the management of viral infections--a brief review. Ital. J. Pediatr. 39: 61.
27. Reiter RJ, et al. (2022) Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection. Cell. Mol. Life Sci. 79 (3): 143.
28. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31 (2):455-461.
29. Boutin JA (2016) Quinone reductase 2 as a promising target of melatonin therapeutic actions. Expert Opin. Ther. Targets 20 (3): 303-317.
30. Liu L, Labani N, Cecon E, Jockers R (2019) Melatonin target proteins: Too many or not enough? Front. Endocrinol.) 10: 791.
31. Wallace AC, Laskowski RA, Thornton JM (1995) LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Protein Eng. 8 (2):127-134.
32. Calamini B, Santarsiero BD, Boutin JA, Mesecar AD (2008) Kinetic, thermodynamic and X-ray structural insights into the interaction of melatonin and analogues with quinone reductase 2. Biochem. J. 413 (1): 81-91.
33. Ferreira AC, et al. (2017) Sofosbuvir protects Zika virus-infected mice from mortality, preventing short- and long-term sequelae. Sci. Rep. 7 (1): 9409.
34. Chan JF, et al. (2017) Novel antiviral activity and mechanism of bromocriptine as a Zika virus NS2B-NS3 protease inhibitor. Antiviral Res. 141: 29-37.
35. Vicenti I, et al. (2018) Comparative analysis of different cell systems for Zika virus (ZIKV) propagation and evaluation of anti-ZIKV compounds in vitro. Virus Res. 244: 64-70.
36. Mounce BC, Cesaro T, Carrau L, Vallet T, Vignuzzi M (2017) Curcumin inhibits Zika and chikungunya virus infection by inhibiting cell binding. Antiviral Res. 142: 148-157.
37. Sharma N, Murali A, Singh SK, Giri R (2017) Epigallocatechin gallate, an active green tea compound inhibits the Zika virus entry into host cells via binding the envelope protein. Int. J. Biol. Macromol. 104 (Pt A): 1046-1054.
38. Oo A, Teoh BT, Sam SS, Bakar SA, Zandi K (2019) Baicalein and baicalin as Zika virus inhibitors. Arch. Virol. 164 (2): 585-593.
39. Valero N, Espina LM, Mosquera J (2006) Melatonin decreases nitric oxide production, inducible nitric oxide synthase expression and lipid peroxidation induced by Venezuelan encephalitis equine virus in neuroblastoma cell cultures. Neurochem. Res. 31 (7): 925-932.
40. Montiel M, et al. (2015) Melatonin decreases brain apoptosis, oxidative stress, and CD200 expression and increased survival rate in mice infected by Venezuelan equine encephalitis virus. Antivir. Chem. Chemother. 24 (3-4): 99-108.
41. Rabbani MAG, Barik S (2017) 5-Hydroxytryptophan, a major product of tryptophan degradation, is essential for optimal replication of human parainfluenza virus. Virology 503: 46-51.
42. Morchang A, et al. (2021) Melatonin inhibits dengue virus infection via the sirtuin 1-mediated interferon pathway. Viruses 13 (4): 659.
43. Jain R, Coloma J, Garcia-Sastre A, Aggarwal AK (2016) Structure of the NS3 helicase from Zika virus. Nat. Struct. Mol. Biol. 23 (8): 752-754.
44. Tay MYF, Vasudevan SG (2018) The transactions of NS3 and NS5 in flaviviral RNA replication. Adv. Exp. Med. Biol. 1062: 147-163.
45. Pathak N, et al. (2020) Zika virus NS3 protease pharmacophore anchor model and drug discovery. Sci. Rep. 10 (1): 8929.
46. Xu S, et al. (2019) Zika virus NS3 is a canonical RNA helicase stimulated by NS5 RNA polymerase. Nucleic Acids Res. 47 (16):8693-8707.
47. Faizan MI, et al. (2019) Structure based identification of potential inhibitors of NS3 protein of Zika virus. Lett. Drug Des. Discov. 16 (7): 761-774.
48. Kumar D, Sharma N, Aarthy M, Singh SK, Giri R (2020) Mechanistic insights into Zika virus NS3 helicase inhibition by epigallocatechin-3-gallate. ACS Omega 5 (19): 11217-11226.
49. Sahoo M, Jena L, Daf S, Kumar S (2016) Virtual screening for potential inhibitors of NS3 protein of Zika virus. Genomics Inform. 14 (3): 104-111.
50. Tan CW, Sam IC, Chong WL, Lee VS, Chan YF (2017) Polysulfonate suramin inhibits Zika virus infection. Antiviral Res. 143: 186-194.
51. Valero N, et al. (2015) Melatonin, minocycline and ascorbic acid reduce oxidative stress and viral titers and increase survival rate in experimental Venezuelan equine encephalitis. Brain Res. 1622: 368-376.
52. Ben-Nathan D, Maestroni GJ, Lustig S, Conti A (1995) Protective effects of melatonin in mice infected with encephalitis viruses. Arch. Virol. 140 (2): 223-230.
53. Crespo I, et al. (2016) Melatonin inhibits the sphingosine kinase 1/sphingosine-1-phosphate signaling pathway in rabbits with fulminant hepatitis of viral origin. J. Pineal Res. 61 (2):168-176.
54. San-Miguel B, et al. (2014) Melatonin modulates the autophagic response in acute liver failure induced by the rabbit hemorrhagic disease virus. J. Pineal Res. 56 (3): 313-321.
55. Valero N, et al. (2005) In vitro, melatonin treatment decreases nitric oxide levels in murine splenocytes cultured with the venezuelan equine encephalomyelitis virus. Neurochem. Res. 30 (11): 1439-1442.
56. Huang SH, Cao XJ, Liu W, Shi XY, Wei W (2010) Inhibitory effect of melatonin on lung oxidative stress induced by respiratory syncytial virus infection in mice. J. Pineal Res. 48 (2): 109-116.
57. Sang Y, et al. (2018) Melatonin ameliorates coxsackievirus B3-induced myocarditis by regulating apoptosis and autophagy. Front. Pharmacol. 9: 1384.
58. Bonilla E, et al. (2003) Melatonin increases interleukin-1beta and decreases tumor necrosis factor alpha in the brain of mice infected with the Venezuelan equine encephalomyelitis virus. Neurochem. Res. 28 (5): 681-686.
59. Acuna-Castroviejo D, et al. (2020) Clinical trial to test the efficacy of melatonin in COVID-19. J Pineal Res. 69 (3): e12683.
60. Rodriguez-Rubio M, et al. (2020) A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in patients with COVID-19 admitted to the intensive care unit (MelCOVID study): A structured summary of a study protocol for a randomized controlled trial. Trials 21 (1): 699.
61. Brusco LI, Cruz P, Cangas AV, Gonzalez-Rojas C, Vigo DE, Cardinali DP (2021) Efficacy of melatonin in non-intensive care unit patients with COVID-19 pneumonia and sleep dysregulation. Melatonin Res. 4: 173-188.
62. Garcez PP, et al. (2016) Zika virus impairs growth in human neurospheres and brain organoids. Science 352 (6287): 816-818.
63. Tang H, et al. (2016) Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 18 (5): 587-590.
64. Russo FB, Beltrao-Braga PCB (2017) The impact of Zika virus in the brain. Biochem. Biophys. Res. Commun. 492 (4):603-607.
65. Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT (2012) Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol. Cell Endocrinol. 351 (2): 152-166.
66. Hevia D, et al. (2015) Melatonin uptake through glucose transporters: A new target for melatonin inhibition of cancer. J. Pineal Res. 58 (2): 234-250.
67. Huo X, et al. (2017) Human transporters, PEPT1/2, facilitate melatonin transportation into mitochondria of cancer cells: An implication of the therapeutic potential. J. Pineal Res. 62 (4): e12390.
68. Moravcik R, Okuliarova M, Kovacova E, Zeman M (2014) Diquat-induced cytotoxicity on Vero and HeLa cell lines: effect of melatonin and dihydromelatonin. Interdiscip. Toxicol. 7 (4): 184-188.
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Published
2022-06-30
How to Cite
[1]
Wongchitrat, P., Yasawong, M., Jumpathong, W., Chanmanee, T., Samutpong, A., Dangsakul, W., Govitrapong, P., Reiter, R.J. and Puthavathana, P. 2022. Melatonin inhibits Zika virus replication in Vero epithelial cells and SK-N-SH human neuroblastoma cells. Melatonin Research. 5, 2 (Jun. 2022), 171-185. DOI:https://doi.org/https://doi.org/10.32794/mr112500127.
Section
Research Articles
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