2,529
Views
28
CrossRef citations to date
0
Altmetric
Review

Therapeutic potential of chelerythrine as a multi-purpose adjuvant for the treatment of COVID-19

ORCID Icon, , & ORCID Icon
Pages 2321-2336 | Received 07 May 2021, Accepted 14 Sep 2021, Published online: 29 Sep 2021

References

  • Sanders JM, Monogue ML, Jodlowski TZ, et al. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. Jama. 2020;323(18):1824–1836.
  • Wink M, Roberts MF. Alkaloids: biochemistry, ecology, and medicinal applications. New York: Plenum Press; 1998.
  • Marschall M, Stein-Gerlach M, Freitag M, et al. Direct targeting of human cytomegalovirus protein kinase pUL97 by kinase inhibitors is a novel principle for antiviral therapy. J Gen Virol. 2002;83(5):1013–1023.
  • Chen W-C, Simanjuntak Y, Chu L-W, et al. Benzenesulfonamide derivatives as calcium/calmodulin-dependent protein kinase inhibitors and antiviral agents against dengue and zika virus infections. J Med Chem. 2020;63(3):1313–1327.
  • Garcia JG, Sharma A, Ramaiah A, et al. Antiviral drug screen of kinase inhibitors identifies cellular signaling pathways critical for SARS-CoV-2 replication. Available at SSRN 3682004. 2020.
  • Perwitasari O, Yan X, O’Donnell J, et al. Repurposing kinase inhibitors as antiviral agents to control influenza A virus replication. Assay Drug Dev Technol. 2015;13(10):638–649.
  • Hoffmann -H-H, Palese P, Shaw ML. Modulation of influenza virus replication by alteration of sodium ion transport and protein kinase C activity. Antiviral Res. 2008;80(2):124–134.
  • Mondal A, Dawson AR, Potts GK, et al. Influenza virus recruits host protein kinase C to control assembly and activity of its replication machinery. Elife. 2017;6:e26910.
  • McKernan LN, Momjian D, Kulkosky J. Protein kinase C: one pathway towards the eradication of latent HIV-1 reservoirs. Adv Virol. 2012;2012:8.  https://doi.org/10.1155/2012/805347
  • Weisberg E, Parent A, Yang PL, et al. Repurposing of kinase inhibitors for treatment of COVID-19. Pharm Res. 2020;37(9):1–29.
  • Herbert J, Augereau J, Gleye J, et al. Chelerythrine is a potent and specific inhibitor of protein kinase C. Biochem Biophys Res Commun. 1990;172(3):993–999.
  • Chmura SJ, Dolan ME, Cha A, et al. In vitro and in vivo activity of protein kinase C inhibitor chelerythrine chloride induces tumor cell toxicity and growth delay in vivo. Clin Cancer Res. 2000;6(2):737–742.
  • Davies SP, Reddy H, Caivano M, et al. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000;351(1):95–105.
  • Anastassiadis T, Deacon SW, Devarajan K, et al. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol. 2011;29(11):1039–1045.
  • Lee SK, Qing WG, Mar W, et al. Angoline and chelerythrine, benzophenanthridine alkaloids that do not inhibit protein kinase C. J Biol Chem. 1998;273(31):19829–19833.
  • Ghashghaeinia M, Dreischer P, Wieder T, et al. Coronavirus disease 2019 (COVID-19), human erythrocytes and the PKC-alpha/-beta inhibitor chelerythrine–possible therapeutic implication. Cell Cycle. 2020;19(24):3399–3405.
  • Dvořák Z, Vrzal R, Maurel P, et al. Differential effects of selected natural compounds with anti-inflammatory activity on the glucocorticoid receptor and NF-κB in HeLa cells. Chem Biol Interact. 2006;159(2):117–128.
  • Zhang J, Liang Y, Ren L, et al. In vitro anti-inflammatory potency of sanguinarine and chelerythrine via interaction with glucocorticoid receptor. eFood. 2021;1(6):392–398. 10.2991/efood.k.210118.001.
  • Niu X-F, Zhou P, Li W-F, et al. Effects of chelerythrine, a specific inhibitor of cyclooxygenase-2, on acute inflammation in mice. Fitoterapia. 2011;82(4):620–625.
  • Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002;298(5600):1911–1912.
  • Banerjee S, Narayanan K, Mizutani T, et al. Murine coronavirus replication-induced p38 mitogen-activated protein kinase activation promotes interleukin-6 production and virus replication in cultured cells. J Virol. 2002;76(12):5937–5948.
  • Kopecky-Bromberg SA, Martinez-Sobrido L, Palese P. 7a protein of severe acute respiratory syndrome coronavirus inhibits cellular protein synthesis and activates p38 mitogen-activated protein kinase. J Virol. 2006;80(2):785–793.
  • Kono M, Tatsumi K, Imai AM, et al. Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK. Antiviral Res. 2008;77(2):150–152.
  • Saccani S, Pantano S, Natoli G. p38-dependent marking of inflammatory genes for increased NF-κB recruitment. Nat Immunol. 2002;3(1):69–75.
  • Grimes JM, Grimes KV. p38 MAPK inhibition: a promising therapeutic approach for COVID-19. J Mol Cell Cardiol. 2020;144:63–65.
  • Yu R, Mandlekar S, Tan T-H, et al. Activation of p38 and c-Jun N-terminal kinase pathways and induction of apoptosis by chelerythrine do not require inhibition of protein kinase C. J Biol Chem. 2000;275(13):9612–9619.
  • Li W, Fan T, Zhang Y, et al. Effect of chelerythrine against endotoxic shock in mice and its modulation of inflammatory mediators in peritoneal macrophages through the modulation of mitogen-activated protein kinase (MAPK) pathway. Inflammation. 2012;35(6):1814–1824.
  • DiDonato JA, Hayakawa M, Rothwarf DM, et al. A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature. 1997;388(6642):548–554.
  • Santoro MG, Rossi A, Amici C. NF‐κB and virus infection: who controls whom. EMBO J. 2003;22(11):2552–2560.
  • DeDiego ML, Nieto-Torres JL, Regla-Nava JA, et al. Inhibition of NF-κB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival. J Virol. 2014;88(2):913–924.
  • Qj LIAO, Lb YE, Timani KA, et al. Activation of NF‐κB by the full‐length nucleocapsid protein of the SARS coronavirus. Acta Biochim Biophys Sin (Shanghai). 2005;37(9):607–612.
  • Kircheis R, Haasbach E, Lueftenegger D, et al. NF-κB pathway as a potential target for treatment of critical stage COVID-19 patients. Front Immunol. 2020;11:598444.
  • Hariharan A, Hakeem AR, Radhakrishnan S, et al. The role and therapeutic potential of NF-kappa-B pathway in severe COVID-19 patients. Inflammopharmacology. 2020; 29(1), 91–100.
  • Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284(20):13291–13295.
  • Ramezani A, Nahad MP, Faghihloo E. The role of Nrf2 transcription factor in viral infection. J Cell Biochem. 2018;119(8):6366–6382.
  • Huang H, Falgout B, Takeda K, et al. Nrf2-dependent induction of innate host defense via heme oxygenase-1 inhibits Zika virus replication. Virology. 2017;503:1–5.
  • Loboda A, Damulewicz M, Pyza E, et al. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci. 2016;73(17):3221–3247.
  • Ahmed SMU, Luo L, Namani A, et al. Nrf2 signaling pathway: pivotal roles in inflammation. Biochim Biophys Acta Mol Basis Dis. 2017;1863(2):585–597.
  • Buelna-Chontal M, Zazueta C. Redox activation of Nrf2 & NF-κB: a double end sword? Cell Signal. 2013;25(12):2548–2557.
  • Ren J, Li L, Wang Y, et al. Gambogic acid induces heme oxygenase-1 through Nrf2 signaling pathway and inhibits NF-κB and MAPK activation to reduce inflammation in LPS-activated RAW264. 7 cells. Biomed Pharmacother. 2019;109:555–562.
  • Cuadrado A, Pajares M, Benito C, et al. Can activation of NRF2 be a strategy against COVID-19? Trends in pharmacological sciences. 2020;41(9):598–610.
  • Zinovkin R, Grebenchikov O. Transcription factor Nrf2 as a potential therapeutic target for prevention of cytokine storm in COVID-19 patients. Biochemistry (Moscow). 2020;85(7):833–837.
  • McCord JM, Hybertson BM, Cota-Gomez A, et al. Nrf2 activator PB125® as a potential therapeutic agent against COVID-19. Antioxidants. 2020;9(6):518.
  • Ooi BK, Chan K-G, Goh BH, et al. The role of natural products in targeting cardiovascular diseases via Nrf2 pathway: novel molecular mechanisms and therapeutic approaches. Front Pharmacol. 2018;9:1308.
  • Kumar H, Kim I-S, More SV, et al. Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases. Nat Prod Rep. 2014;31(1):109–139.
  • Fan L, Fan Y, Liu L, et al. Chelerythrine attenuates the inflammation of lipopolysaccharide-induced acute lung inflammation through NF-κB signaling pathway mediated by Nrf2. Front Pharmacol. 2018;9:1047.
  • Peng L, Wen L, Shi Q, et al. Chelerythrine ameliorates pulmonary fibrosis via activating the Nrf2/ARE signaling pathway. Cell Biochem Biophys. 2021;79(2):337–347.
  • Liu L, Huang Y, Zhang K, et al. Hepatitis B core antigen regulates dendritic cell proliferation and apoptosis through regulation of PKC/NF‑κB signaling pathway. Mol Med Rep. 2018;18(6):5726–5732.
  • San-Juan-Vergara H, Peeples ME, Lockey RF, et al. Protein kinase C-α activity is required for respiratory syncytial virus fusion to human bronchial epithelial cells. J Virol. 2004;78(24):13717.
  • Blázquez AB, Á V-C, Martín-Acebes MA, et al. Pharmacological inhibition of protein kinase C reduces West Nile virus replication. Viruses. 2018;10(2):91.
  • Guo W, Lu X, Liu B, et al. Anti‐TMV activity and mode of action of three alkaloids isolated from Chelidonium majus. Pest Manag Sci. 2021;77(1):510–517.
  • Papi F, Ferraroni M, Rigo R, et al. Role of the benzodioxole group in the interactions between the natural alkaloids chelerythrine and coptisine and the human telomeric G-quadruplex DNA. A multiapproach investigation. J Nat Prod. 2017;80(12):3128–3135.
  • Bessi I, Bazzicalupi C, Richter C, et al. Spectroscopic, molecular modeling, and NMR-spectroscopic investigation of the binding mode of the natural alkaloids berberine and sanguinarine to human telomeric G-quadruplex DNA. ACS Chem Biol. 2012;7(6):1109–1119.
  • Wink M. Potential of DNA intercalating alkaloids and other plant secondary metabolites against SARS-CoV-2 causing COVID-19. Diversity. 2020;12(5):175.
  • Martinez-Rojas MA, Vega-Vega O, Bobadilla NA. Is the kidney a target of SARS-CoV-2? Am J Physiol Renal Physiol. 2020;318(6):F1454–F1462.
  • Delsante M, Rossi GM, Gandolfini I, et al. Kidney involvement in COVID-19: need for better definitions. J Am Soc Nephrol. 2020;31(9):2224–2225.
  • Kirton CA, Loutzenhiser R. Alterations in basal protein kinase C activity modulate renal afferent arteriolar myogenic reactivity. Am J Physiol Heart Circ Physiol. 1998;275(2):H467–H475.
  • Song J, Eyster KM, Kost JCK, et al. Involvement of protein kinase C-CPI-17 in androgen modulation of angiotensin II-renal vasoconstriction. Cardiovasc Res. 2010;85(3):614–621.
  • Ruan X, Arendshorst WJ. Role of protein kinase C in angiotensin II-induced renal vasoconstriction in genetically hypertensive rats. Am J Physiol Renal Physiol. 1996;270(6):F945–F952.
  • Nagahama T, Hayashi K, Ozawa Y, et al. Role of protein kinase C in angiotensin II-induced constriction of renal microvessels. Kidney Int. 2000;57(1):215–223.
  • Yu X, Cui L, Hou F, et al. Angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis prevents pancreatic acinar cell inflammatory response via inhibition of the p38 mitogen-activated protein kinase/nuclear factor-κB pathway. Int J Mol Med. 2018;41(1):409–420.
  • Park J-K, Fischer R, Dechend R, et al. p38 Mitogen-activated protein kinase inhibition ameliorates angiotensin II–Induced Target Organ Damage. Hypertension. 2007;49(3):481–489.
  • Ahmad I, Rathore FA. Neurological manifestations and complications of COVID-19: a literature review. J Clin Neurosci. 2020;77:8–12.
  • Bridwell R, Long B, Gottlieb M. Neurologic complications of COVID-19. Am J Emerg Med. 2020;38(7):1549.e3.
  • Li B, Yang J, Zhao F, et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol. 2020;109(5):531–538.
  • Hernández-Fernández F, Sandoval VH, Barbella-Aponte RA, et al. Cerebrovascular disease in patients with COVID-19: neuroimaging, histological and clinical description. Brain. 2020;143(10):3089–3103.
  • Xie J, Covassin N, Fan Z, et al., editors. Association between hypoxemia and mortality in patients with COVID-19. Mayo Clinic Proceedings; 2020;95(6):1138–1147.
  • Coen M, Allali G, Adler D, et al. Hypoxemia in COVID‐19; Comment on:“The neuroinvasive potential of SARS‐CoV2 may play a role in the respiratory failure of COVID‐19 patients”. J Med Virol. 2020;92(10):1705–1706.
  • Laher I, Zhang JH. Protein kinase C and cerebral vasospasm. J Cereb Blood Flow Metab. 2001;21(8):887–906.
  • Nishizawa S, Obara K, Koide M, et al. Attenuation of canine cerebral vasospasm after subarachnoid hemorrhage by protein kinase C inhibitors despite augmented phosphorylation of myosin light chain. J Vasc Res. 2003;40(2):169–178.
  • Aladağ M, Yıldız A, Türköz Y, et al. The ınhibition of cerebral vasospasm by using chelerythrine after experimental subarachnoidal haemorrhage in rats. 2017;6(1):18–22.
  • Boukhris M, Hillani A, Moroni F, et al. Cardiovascular implications of the COVID-19 pandemic: a global perspective. Can J Cardiol. 2020;36(7):1068–1080.
  • Wang H, Endoh M. Chelerythrine and genistein inhibit the endothelin-1-induced increase in myofilament Ca2+ sensitivity in rabbit ventricular myocytes. Eur J Pharmacol. 2001;424(2):91–96.
  • Piacentini L, Gray M, Honbo NY, et al. Endothelin-1 stimulates cardiac fibroblast proliferation through activation of protein kinase C. J Mol Cell Cardiol. 2000;32(4):565–576.
  • Wang S, Xu D-J, Cai J-B, et al. Rapid component IKr of cardiac delayed rectifier potassium currents in Guinea-pig is inhibited by α1-adrenoreceptor activation via protein kinase A and protein kinase C-dependent pathways. Eur J Pharmacol. 2009;608(1–3):1–6.
  • Voutilainen-Myllylä S, Tavi P, Weckström M. Chelerythrine and bisindolylmaleimide I prolong cardiac action potentials by protein kinase C-independent mechanism. Eur J Pharmacol. 2003;466(1–2):41–51.
  • Lundmark JL, Ramasamy R, Vulliet PR, et al. Chelerythrine increases Na-K-ATPase activity and limits ischemic injury in isolated rat hearts. Am J Physiol Heart Circ Physiol. 1999;277(3):H999–H1006.
  • Hu B, Xu G, Zheng Y, et al. Chelerythrine attenuates renal ischemia/reperfusion-induced myocardial injury by activating CSE/H2S via PKC/NF-κB pathway in diabetic rats. Kidney Blood Pressure Res. 2017;42(2):379–388.
  • George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med. 2020;8(8):807–815.
  • Ojo AS, Balogun SA, Williams OT, et al. Pulmonary fibrosis in COVID-19 survivors: predictive factors and risk reduction strategies. Pulm Med. 2020;2020. Article ID 6175964.
  • Dalvi R. Sanguinarine: its potential, as a liver toxic alkaloid present in the seeds of Argemone mexicana. Experientia. 1985;41(1):77–78.
  • Becci PJ, Schwartz H, Barnes HH, et al. Short‐term toxicity studies of sanguinarine and of two alkaloid extracts of sanguinaria canadensis L. Journal of Toxicology and Environmental Health, Part A Current Issues. 1987;20(1–2):199–208.
  • Ulrichová J, Walterová D, Vavrečková C, et al. Cytotoxicity of benzo [c] phenanthridinium alkaloids in isolated rat hepatocytes. Phytother Res. 1996;10(3):220–223.
  • Kosina P, Walterova D, Ulrichová J, et al. Sanguinarine and chelerythrine: assessment of safety on pigs in ninety days feeding experiment. Food Chem Toxicol. 2004;42(1):85–91.
  • Williams M, Dalvi S, Dalvi R. Influence of 3-methylcholanthrene pretreatment on sanguinarine toxicity in mice. Veterinary and human toxicology. 2000;42(4):196–198.
  • Vrba J, Kosina P, Ulrichová J, et al. Involvement of cytochrome P450 1A in sanguinarine detoxication. Toxicol Lett. 2004;151(2):375–387.
  • Zdařilová A, Vrzal R, Rypka M, et al. Investigation of sanguinarine and chelerythrine effects on CYP1A1 expression and activity in human hepatoma cells. Food Chem Toxicol. 2006;44(2):242–249.
  • Vieira SM, de Oliveira VH, do Carmo Valente R, et al. Chelerythrine inhibits the sarco/endoplasmic reticulum Ca2+-ATPase and results in cell Ca2+ imbalance. Arch Biochem Biophys. 2015;570:58–65.
  • Gao L, Schmitz H-J, Merz K-H, et al. Characterization of the cytotoxicity of selected Chelidonium alkaloids in rat hepatocytes. Toxicol Lett. 2019;311:91–97.
  • Zhao N-J, Wang -L-L, Liu Z-Y, et al. Pharmacokinetics of chelerythrine and its metabolite after oral and intramuscular administrations in pigs. Xenobiotica. 2021:1–24. 10.1080/00498254.2021.1882714.
  • Basu P, Bhowmik D, Kumar GS. The benzophenanthridine alkaloid chelerythrine binds to DNA by intercalation: photophysical aspects and thermodynamic results of iminium versus alkanolamine interaction. J Photochem Photobiol B Biol. 2013;129:57–68.
  • Dostál J, Táborská E, Slavík J, et al. Structure of chelerythrine base. J Nat Prod. 1995;58(5):723–729.
  • Maiti M, Das S, Sen A, et al. Influence of DNA structures on the conversion of sanguinarine alkanolamine form to iminium form. J Biomol Struct Dyn. 2002;20(3):455–464.
  • Bhuiya S, Pradhan AB, Haque L, et al. Molecular aspects of the interaction of iminium and alkanolamine forms of the anticancer alkaloid chelerythrine with plasma protein bovine serum albumin. J Phys Chem A. 2016;120(1):5–17.
  • Warowicka A, Nawrot R, Goździcka-Józefiak A. Antiviral activity of berberine. Arch Virol. 2020;165(9):1935–1945.
  • Sinha R, Kumar GS. Interaction of isoquinoline alkaloids with an RNA triplex: structural and thermodynamic studies of berberine, palmatine, and coralyne binding to poly (U). poly (A)* poly (U). J Phys Chem A. 2009;113(40):13410–13420.
  • Parra-Medina R, Sarmiento-Monroy JC, Rojas-Villarraga A, et al. Colchicine as a possible therapeutic option in COVID-19 infection. Clin Rheumatol. 2020;39(8):2485–2486.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.