Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Perspective

Perspectives for the Use of N-acetylcysteine as a Candidate Drug to Treat COVID-19

Author(s): Pan Luo, Yi Liu, Dong Liu* and Juan Li*

Volume 21, Issue 3, 2021

Published on: 27 October, 2020

Page: [268 - 272] Pages: 5

DOI: 10.2174/1389557520666201027160833

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndromerelated coronavirus-2 (SARS-CoV-2), has become an ongoing pandemic worldwide. However, there are no vaccines or antiviral drugs with proven clinical efficacy. Therefore, a remedial measure is urgently needed to combat the devastating COVID-19. The pharmacological activities of Nacetylcysteine (NAC) and its potential functions in inhibiting the progression of COVID-19 make it a promising therapeutic agent for the infection. In this mini-review, we discussed the therapeutic potential of NAC in COVID-19 from the perspective of its multisite pharmacological actions.

Keywords: COVID-19, SARS-COV-2, N-acetylcysteine, oxidative stress, inflammation, thrombosis, nitric oxide, mental disorders.

[1]
Hadi, A.G.; Kadhom, M.; Hairunisa, N.; Yousif, E.; Mohammed, S.A. A Review on COVID-19: Origin, Spread, Symptoms, Treatment, and Prevention. Biointerface Res. Appl. Chem., 2020, 10, 7234-7242.
[http://dx.doi.org/10.33263/BRIAC106.72347242]
[2]
Aldini, G.; Altomare, A.; Baron, G.; Vistoli, G.; Carini, M.; Borsani, L.; Sergio, F. N-Acetylcysteine as an antioxidant and disulphide breaking agent: The reasons why. Free Radic. Res., 2018, 52(7), 751-762.
[http://dx.doi.org/10.1080/10715762.2018.1468564] [PMID: 29742938]
[3]
Tse, H.N.; Tseng, C.Z. Update on the pathological processes, molecular biology, and clinical utility of N-acetylcysteine in chronic obstructive pulmonary disease. Int. J. Chron. Obstruct. Pulmon. Dis., 2014, 9, 825-836.
[http://dx.doi.org/10.2147/COPD.S51057] [PMID: 25125976]
[4]
Vardhana, S.A.; Wolchok, J.D. The many faces of the anti-COVID immune response. J. Exp. Med., 2020, 217(6), 217.
[http://dx.doi.org/10.1084/jem.20200678] [PMID: 32353870]
[5]
Jaiswal, N.; Bhatnagar, M.; Shah, H. N-acetycysteine: A potential therapeutic agent in COVID-19 infection. Med. Hypotheses, 2020.144110133
[http://dx.doi.org/10.1016/j.mehy.2020.110133] [PMID: 32758904]
[6]
Silvagno, F.; Vernone, A.; Pescarmona, G.P. The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19. Antioxidants, 2020, 9(7), 9.
[http://dx.doi.org/10.3390/antiox9070624] [PMID: 32708578]
[7]
Wang, J.Z.; Zhang, R.Y.; Bai, J. An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients. Int. J. Cardiol., 2020, 312, 137-138.
[http://dx.doi.org/10.1016/j.ijcard.2020.04.009] [PMID: 32321655]
[8]
Duflo, F.; Debon, R.; Goudable, J.; Chassard, D.; Allaouchiche, B. Alveolar and serum oxidative stress in ventilator-associated pneumonia. Br. J. Anaesth., 2002, 89(2), 231-236.
[http://dx.doi.org/10.1093/bja/aef169] [PMID: 12378658]
[9]
Conner, E.M.; Grisham, M.B. Inflammation, free radicals, and antioxidants. Nutrition, 1996, 12(4), 274-277.
[http://dx.doi.org/10.1016/S0899-9007(96)00000-8] [PMID: 8862535]
[10]
Chiappelli, F.; Khakshooy, A.; Greenberg, G. COVID-19 Immunopathology and immunotherapy. Bioinformation, 2020, 16(3), 219-222.
[http://dx.doi.org/10.6026/97320630016219] [PMID: 32308263]
[11]
Mata, M.; Morcillo, E.; Gimeno, C.; Cortijo, J. N-acetyl-L-cysteine (NAC) inhibit mucin synthesis and pro-inflammatory mediators in alveolar type II epithelial cells infected with influenza virus A and B and with respiratory syncytial virus (RSV). Biochem. Pharmacol., 2011, 82(5), 548-555.
[http://dx.doi.org/10.1016/j.bcp.2011.05.014] [PMID: 21635874]
[12]
Ibrahim, H.; Perl, A.; Smith, D.; Lewis, T.; Kon, Z.; Goldenberg, R.; Yarta, K.; Staniloae, C.; Williams, M. Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine. Clin. Immunol., 2020.219108544
[http://dx.doi.org/10.1016/j.clim.2020.108544] [PMID: 32707089]
[13]
Michaelis, M.; Geiler, J.; Naczk, P.; Sithisarn, P.; Leutz, A.; Doerr, H.W.; Cinatl, J. Jr Glycyrrhizin exerts antioxidative effects in H5N1 influenza A virus-infected cells and inhibits virus replication and pro-inflammatory gene expression. PLoS One, 2011, 6(5)e19705
[http://dx.doi.org/10.1371/journal.pone.0019705] [PMID: 21611183]
[14]
Geiler, J.; Michaelis, M.; Naczk, P.; Leutz, A.; Langer, K.; Doerr, H.W.; Cinatl, J. Jr N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus. Biochem. Pharmacol., 2010, 79(3), 413-420.
[http://dx.doi.org/10.1016/j.bcp.2009.08.025] [PMID: 19732754]
[15]
Mata, M.; Sarrion, I.; Armengot, M.; Carda, C.; Martinez, I.; Melero, J.A.; Cortijo, J. Respiratory syncytial virus inhibits ciliagenesis in differentiated normal human bronchial epithelial cells: Effectiveness of N-acetylcysteine. PLoS One, 2012, 7(10)e48037
[http://dx.doi.org/10.1371/journal.pone.0048037] [PMID: 23118923]
[16]
Guerrero, C.A.; Murillo, A.; Acosta, O. Inhibition of rotavirus infection in cultured cells by N-acetyl-cysteine, PPARγ agonists and NSAIDs. Antiviral Res., 2012, 96(1), 1-12.
[http://dx.doi.org/10.1016/j.antiviral.2012.06.011] [PMID: 22842004]
[17]
Cecere, T.E.; Todd, S.M.; Leroith, T. Regulatory T cells in arterivirus and coronavirus infections: Do they protect against disease or enhance it? Viruses, 2012, 4(5), 833-846.
[http://dx.doi.org/10.3390/v4050833] [PMID: 22754651]
[18]
Chen, J.; Lau, Y.F.; Lamirande, E.W.; Paddock, C.D.; Bartlett, J.H.; Zaki, S.R.; Subbarao, K. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J. Virol., 2010, 84(3), 1289-1301.
[http://dx.doi.org/10.1128/JVI.01281-09] [PMID: 19906920]
[19]
Zhou, Y.; Zhang, Z.; Tian, J.; Xiong, S. Risk factors associated with disease progression in a cohort of patients infected with the 2019 novel coronavirus. Ann. Palliat. Med., 2020, 9(2), 428-436.
[http://dx.doi.org/10.21037/apm.2020.03.26] [PMID: 32233642]
[20]
Chen, J.; Qi, T.; Liu, L.; Ling, Y.; Qian, Z.; Li, T.; Li, F.; Xu, Q.; Zhang, Y.; Xu, S.; Song, Z.; Zeng, Y.; Shen, Y.; Shi, Y.; Zhu, T.; Lu, H. Clinical progression of patients with COVID-19 in Shanghai, China. J. Infect., 2020, 80(5), e1-e6.
[http://dx.doi.org/10.1016/j.jinf.2020.03.004] [PMID: 32171869]
[21]
Dagenais-Lussier, X.; Aounallah, M.; Mehraj, V.; El-Far, M.; Tremblay, C.; Sekaly, R.P.; Routy, J.P.; van Grevenynghe, J. Kynurenine reduces memory CD4 T-cell survival by interfering with interleukin-2 signaling early during HIV-1 infection. J. Virol., 2016, 90(17), 7967-7979.
[http://dx.doi.org/10.1128/JVI.00994-16] [PMID: 27356894]
[22]
Boesgaard, S.; Aldershvile, J.; Poulsen, H.E.; Christensen, S.; Dige-Petersen, H.; Giese, J. N-acetylcysteine inhibits angiotensin converting enzyme in vivo. J. Pharmacol. Exp. Ther., 1993, 265(3), 1239-1244.
[PMID: 8389858]
[23]
De Flora, S.; Balansky, R.; La Maestra, S. Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19. FASEB J., 2020.
[http://dx.doi.org/10.1096/fj.202001807] [PMID: 32780893]
[24]
Jorge-Aaron, R.M.; Rosa-Ester, M.P. N-acetylcysteine as a potential treatment for novel coronavirus disease 2019. Future Microbiol., 2020.
[25]
Wang, Y.X.; Liu, H.B.; Li, P.S.; Yuan, W.X.; Liu, B.; Liu, S.T.; Qin, K.R. ROS and NO dynamics in endothelial cells exposed to exercise-induced wall shear stress. Cell. Mol. Bioeng., 2018, 12(1), 107-120.
[http://dx.doi.org/10.1007/s12195-018-00557-w] [PMID: 31719902]
[26]
Nogueira, G.B.; Punaro, G.R.; Oliveira, C.S.; Maciel, F.R.; Fernandes, T.O.; Lima, D.Y.; Rodrigues, A.M.; Mouro, M.G.; Araujo, S.R.R.; Higa, E.M.S. N-acetylcysteine protects against diabetic nephropathy through control of oxidative and nitrosative stress by recovery of nitric oxide in rats. Nitric Oxide, 2018, 78, 22-31.
[http://dx.doi.org/10.1016/j.niox.2018.05.003] [PMID: 29778909]
[27]
Xiong, T.; Zhang, Z.; Zheng, R.; Huang, J.; Guo, L. N-acetyl cysteine inhibits lipopolysaccharide-induced apoptosis of human umbilical vein endothelial cells via the p38MAPK signaling pathway. Mol. Med. Rep., 2019, 20(3), 2945-2953.
[http://dx.doi.org/10.3892/mmr.2019.10526] [PMID: 31524245]
[28]
Keyaerts, E.; Vijgen, L.; Chen, L.; Maes, P.; Hedenstierna, G.; Van Ranst, M. Inhibition of SARS-coronavirus infection in vitro by S-nitroso-N-acetylpenicillamine, a nitric oxide donor compound. Int. J. Infect. Dis., 2004, 8(4), 223-226.
[http://dx.doi.org/10.1016/j.ijid.2004.04.012] [PMID: 15234326]
[29]
Zhou, P.; Yang, X.L.; Wang, X.G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.R.; Zhu, Y.; Li, B.; Huang, C.L.; Chen, H.D.; Chen, J.; Luo, Y.; Guo, H.; Jiang, R.D.; Liu, M.Q.; Chen, Y.; Shen, X.R.; Wang, X.; Zheng, X.S.; Zhao, K.; Chen, Q.J.; Deng, F.; Liu, L.L.; Yan, B.; Zhan, F.X.; Wang, Y.Y.; Xiao, G.F.; Shi, Z.L. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 2020, 579(7798), 270-273.
[http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID: 32015507]
[30]
Colasanti, M.; Persichini, T.; Venturini, G.; Ascenzi, P. S-nitrosylation of viral proteins: Molecular bases for antiviral effect of nitric oxide. IUBMB Life, 1999, 48(1), 25-31.
[http://dx.doi.org/10.1080/713803459] [PMID: 10791912]
[31]
Ignarro, L.J. Inhaled nitric oxide and COVID-19. Br. J. Pharmacol., 2020.
[http://dx.doi.org/10.1111/bph.15085]
[32]
Chen, L.; Liu, P.; Gao, H.; Sun, B.; Chao, D.; Wang, F.; Zhu, Y.; Hedenstierna, G.; Wang, C.G. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: A rescue trial in Beijing. Clin. Infect. Dis., 2004, 39(10), 1531-1535.
[http://dx.doi.org/10.1086/425357] [PMID: 15546092]
[33]
Blasi, F.; Page, C.; Rossolini, G.M.; Pallecchi, L.; Matera, M.G.; Rogliani, P.; Cazzola, M. The effect of N-acetylcysteine on biofilms: Implications for the treatment of respiratory tract infections. Respir. Med., 2016, 117, 190-197.
[http://dx.doi.org/10.1016/j.rmed.2016.06.015] [PMID: 27492531]
[34]
Helms, J.; Tacquard, C.; Severac, F.; Leonard-Lorant, I.; Ohana, M.; Delabranche, X.; Merdji, H.; Clere-Jehl, R.; Schenck, M.; Fagot Gandet, F.; Fafi-Kremer, S.; Castelain, V.; Schneider, F.; Grunebaum, L.; Anglés-Cano, E.; Sattler, L.; Mertes, P.M.; Meziani, F. CRICS TRIGGERSEP Group. (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: A multicenter prospective cohort study. Intensive Care Med., 2020, 46(6), 1089-1098.
[http://dx.doi.org/10.1007/s00134-020-06062-x] [PMID: 32367170]
[35]
Middeldorp, S.; Coppens, M.; van Haaps, T.F.; Foppen, M.; Vlaar, A.P.; Müller, M.C.A.; Bouman, C.C.S.; Beenen, L.F.M.; Kootte, R.S.; Heijmans, J.; Smits, L.P.; Bonta, P.I.; van Es, N. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J. Thromb. Haemost., 2020, 18(8), 1995-2002.
[http://dx.doi.org/10.1111/jth.14888] [PMID: 32369666]
[36]
Spiezia, L.; Boscolo, A.; Poletto, F.; Cerruti, L.; Tiberio, I.; Campello, E.; Navalesi, P.; Simioni, P. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thromb. Haemost., 2020, 120(6), 998-1000.
[http://dx.doi.org/10.1055/s-0040-1710018] [PMID: 32316063]
[37]
Klok, F.A.; Kruip, M.; van der Meer, N.J.M. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb. Res., 2020.
[http://dx.doi.org/10.1016/j.thromres.2020.04.013]
[38]
Craver, B.M.; Ramanathan, G.; Hoang, S.; Chang, X.; Mendez Luque, L.F.; Brooks, S.; Lai, H.Y.; Fleischman, A.G. N-acetylcysteine inhibits thrombosis in a murine model of myeloproliferative neoplasm. Blood Adv., 2020, 4(2), 312-321.
[http://dx.doi.org/10.1182/bloodadvances.2019000967] [PMID: 31978215]
[39]
Martinez de Lizarrondo, S.; Gakuba, C.; Herbig, B.A.; Repessé, Y.; Ali, C.; Denis, C.V.; Lenting, P.J.; Touzé, E.; Diamond, S.L.; Vivien, D.; Gauberti, M. Potent Thrombolytic Effect of N-Acetylcysteine on Arterial Thrombi. Circulation, 2017, 136(7), 646-660.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.027290] [PMID: 28487393]
[40]
Meshkini, A.; Tahmasbi, M. Antiplatelet aggregation activity of walnut hull extract via suppression of reactive oxygen species generation and Caspase activation. J. Acupunct. Meridian Stud., 2017, 10(3), 193-203.
[http://dx.doi.org/10.1016/j.jams.2017.02.007] [PMID: 28712479]
[41]
Monteiro, P.F.; Morganti, R.P.; Delbin, M.A.; Calixto, M.C.; Lopes-Pires, M.E.; Marcondes, S.; Zanesco, A.; Antunes, E. Platelet hyperaggregability in high-fat fed rats: A role for intraplatelet reactive-oxygen species production. Cardiovasc. Diabetol., 2012, 11, 5.
[http://dx.doi.org/10.1186/1475-2840-11-5] [PMID: 22248260]
[42]
Al-mashhadani, M.H.; Alsayed, R.; Hussain, Z.; Salih, N.; Yousif, E. An overview of possible therapeutic approaches against novel coronavirus Disease 2019 pandemic; Al-Nahrain J. Sci, 2020, pp. 6-11.
[43]
Fan, Z.; Chen, L.; Li, J. Clinical features of COVID-19-Related liver damage. Clin. Gastroenterol. Hepatol., 2020.
[http://dx.doi.org/10.1016/j.cgh.2020.04.002]
[44]
Cai, Q.; Huang, D.; Yu, H.; Zhu, Z.; Xia, Z.; Su, Y.; Li, Z.; Zhou, G.; Gou, J.; Qu, J.; Sun, Y.; Liu, Y.; He, Q.; Chen, J.; Liu, L.; Xu, L. COVID-19: Abnormal liver function tests. J. Hepatol., 2020, 73(3), 566-574.
[http://dx.doi.org/10.1016/j.jhep.2020.04.006] [PMID: 32298767]
[45]
Eroglu, N.; Erduran, E.; Reis, G.P.; Bahadır, A. Therapeutic effect of N-acetylcysteine on chemotherapy-induced liver injury. Iran. J. Med. Sci., 2020.
[http://dx.doi.org/10.1007/s11845-020-02219-1] [PMID: 32239424]
[46]
Patel, T.; Tarun, T.; Hudhud, D.; Krvavac, A. Novel use of N-Acetylcysteine in management of tyrosine kinase inhibitor induced acute liver injury. Cureus, 2019, 11(11)e6251
[http://dx.doi.org/10.7759/cureus.6251] [PMID: 31890447]
[47]
Jaeschke, H.; Akakpo, J.Y.; Umbaugh, D.S.; Ramachandran, A. Novel therapeutic Approaches Against Acetaminophen-induced Liver Injury and acute Liver Failure. Toxicol. Sci., 2020, 174(2), 159-167.
[http://dx.doi.org/10.1093/toxsci/kfaa002] [PMID: 31926003]
[48]
Mao, L; Jin, H; Wang, M . Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol.,.
[49]
Liu, Y.; Cao, L.; Li, X.; Jia, Y.; Xia, H. Awareness of mental health problems in patients with coronavirus disease 19 (COVID-19): A lesson from an adult man attempting suicide; Asian J. Psychiat, 2020, p. 51102106.
[http://dx.doi.org/10.1016/j.ajp.2020.102106]] [PMID: 32334411]
[50]
Zhang, K.; Zhou, X.; Liu, H.; Hashimoto, K. Treatment concerns for psychiatric symptoms in patients with COVID-19 with or without psychiatric disorders. Br. J. Psychiatry, 2020, 217(1), 351.
[http://dx.doi.org/10.1192/bjp.2020.84] [PMID: 32270760]
[51]
Shneider, A.; Kudriavtsev, A.; Vakhrusheva, A. Can melatonin reduce the severity of COVID-19 pandemic? Int. Rev. Immunol., 2020, 39(4), 153-162.
[http://dx.doi.org/10.1080/08830185.2020.1756284] [PMID: 32347747]
[52]
Ng, F.; Berk, M.; Dean, O.; Bush, A.I. Oxidative stress in psychiatric disorders: Evidence base and therapeutic implications. Int. J. Neuropsychopharmacol., 2008, 11(6), 851-876.
[http://dx.doi.org/10.1017/S1461145707008401] [PMID: 18205981]
[53]
Atrooz, F.; Liu, H.; Salim, S. Stress, psychiatric disorders, molecular targets, and more. Prog. Mol. Biol. Transl. Sci., 2019, 167, 77-105.
[http://dx.doi.org/10.1016/bs.pmbts.2019.06.006] [PMID: 31601407]
[54]
Dean, O.; Giorlando, F.; Berk, M. N-acetylcysteine in psychiatry: Current therapeutic evidence and potential mechanisms of action. J. Psychiatry Neurosci., 2011, 36(2), 78-86.
[http://dx.doi.org/10.1503/jpn.100057] [PMID: 21118657]
[55]
Berk, M.; Malhi, G.S.; Gray, L.J.; Dean, O.M. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol. Sci., 2013, 34(3), 167-177.
[http://dx.doi.org/10.1016/j.tips.2013.01.001] [PMID: 23369637]
[56]
Minarini, A.; Ferrari, S.; Galletti, M.; Giambalvo, N.; Perrone, D.; Rioli, G.; Galeazzi, G.M. N-acetylcysteine in the treatment of psychiatric disorders: Current status and future prospects. Expert Opin. Drug Metab. Toxicol., 2017, 13(3), 279-292.
[http://dx.doi.org/10.1080/17425255.2017.1251580] [PMID: 27766914]
[57]
Deepmala, S.J.; Slattery, J.; Kumar, N.; Delhey, L.; Berk, M.; Dean, O.; Spielholz, C.; Frye, R. Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci. Biobehav. Rev., 2015, 55, 294-321.
[http://dx.doi.org/10.1016/j.neubiorev.2015.04.015] [PMID: 25957927]

© 2022 Bentham Science Publishers | Privacy Policy