1887
  1. Home
  2. A-Z Publications
  3. Avicenna
  4. Volume 2022, Issue 1
  5. Article
Volume 2022, Issue 1
  • EISSN: 2220-2749

Abstract

Cysteine cathepsins are defined as lysosomal enzymes that are members of the papain family. Cysteine cathepsins (Cts) prevalently exist in whole organisms, varying from prokaryotes to mammals, and possess greatly conserved cysteine residues in their active sites. Cts are engaged in the digestion of cellular proteins, activation of zymogens, and remodeling of the extracellular matrix (ECM). Host cells are entered by SARS-CoV-2 via endocytosis. Cathepsin L and phosphatidylinositol 3-phosphate 5-kinase are crucial in endocytosis by cleaving the spike protein, which permits viral membrane fusion with the endosomal membrane and succeeds in the release of the viral genome to the host cell. Therefore, inhibition of cathepsin L may be advantageous in terms of decreasing infection caused by SARS-CoV-2. Coordinate inhibition of multiple Cts and lysosomal function by different drugs and biological agents might be of value for some purposes, such as a parasite or viral infections and antineoplastic applications. Zn2+ deficiency or dysregulation leads to exaggerated cysteine cathepsin activity, increasing the autoimmune/inflammatory response. For this purpose, Zn2+ metal can be safely combined with a drug that increases the anti-proteolytic effect of endogenous Zn2+, lowering the excessive activity of some CysCts. Biguanide derivative complexes with Zn2+ have been found to be promising inhibitors of CysCts protease reactions. Molecular docking studies of cathepsin L inhibited by the metformin-Zn+2 complex have been performed, showing two strong key interactions (Cys-25&His-163) and an extra H-bond with Asp-163 compared to cocrystallized Zn+2 (PDB ID 4axl).

© 2021 The Author(s), licensee HBKU Press.
Loading

Article metrics loading...

/content/journals/10.5339/avi.2022.2
2021-11-22
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/avi/2022/1/avi.2022.2.html?itemId=/content/journals/10.5339/avi.2022.2&mimeType=html&fmt=ahah

References

  1. Rudzińska, M., et al.,. The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance. 2019. 20:(14): p. 3602.
     [Google Scholar]
  2. Madadlou, A.J.E.J.o.P., Food proteins are a potential resource for mining cathepsin L inhibitory drugs to combat SARS-CoV-2. 2020. 885: p. 173499.
     [Google Scholar]
  3. Pu, J., et al., Mechanisms and functions of lysosome positioning. J Cell Sci, 2016. 129:(23): p. 4329-4339.
     [Google Scholar]
  4. Fonović, M. and B. Turk, Cysteine cathepsins and extracellular matrix degradation. Biochim Biophys Acta, 2014. 1840:(8): p. 2560-70.
     [Google Scholar]
  5. Reiser, J., B. Adair, and T. Reinheckel, Specialized roles for cysteine cathepsins in health and disease. J Clin Invest, 2010. 120:(10): p. 3421-31.
     [Google Scholar]
  6. Sudhan, D.R. and D.W. Siemann, Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells. Clin Exp Metastasis, 2013. 30:(7): p. 891-902.
     [Google Scholar]
  7. Chen, S., et al., Cathepsins in digestive cancers. Oncotarget, 2017. 8:(25): p. 41690-41700.
     [Google Scholar]
  8. Turk, V., B. Turk, and D. Turk, Lysosomal cysteine proteases: facts and opportunities. Embo j, 2001. 20:(17): p. 4629-33.
     [Google Scholar]
  9. Brömme, D. and S. Wilson, Role of cysteine cathepsins in extracellular proteolysis, in Extracellular matrix degradation. 2011, Springer. p. 23-51.
     [Google Scholar]
  10. Verma, S., R. Dixit, and K.C. Pandey, Cysteine Proteases: Modes of Activation and Future Prospects as Pharmacological Targets. 2016. 7:(107).
     [Google Scholar]
  11. Hämälistö, S. and M. Jäättelä, Lysosomes in cancer—living on the edge (of the cell). Current Opinion in Cell Biology, 2016. 39: p. 69-76.
     [Google Scholar]
  12. Sui, H., et al., Overexpression of Cathepsin L is associated with chemoresistance and invasion of epithelial ovarian cancer. Oncotarget, 2016. 7:(29): p. 45995-46001.
     [Google Scholar]
  13. Zheng, X., et al., Senescence-initiated reversal of drug resistance: specific role of cathepsin L. Cancer Res, 2004. 64:(5): p. 1773-80.
     [Google Scholar]
  14. Han, M.L., et al., Cathepsin L upregulation-induced EMT phenotype is associated with the acquisition of cisplatin or paclitaxel resistance in A549 cells. Acta Pharmacol Sin, 2016. 37:(12): p. 1606-1622.
     [Google Scholar]
  15. Zheng, X., et al., Cathepsin L inhibition suppresses drug resistance in vitro and in vivo: a putative mechanism. Am J Physiol Cell Physiol, 2009. 296:(1): p. C65-74.
     [Google Scholar]
  16. Lindner, H.A., et al., The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme. 2005. 79:(24): p. 15199-15208.
     [Google Scholar]
  17. Schornberg, K., et al., Role of endosomal cathepsins in entry mediated by the Ebola virus glycoprotein. 2006. 80:(8): p. 4174-4178.
     [Google Scholar]
  18. Ou, X., et al., Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. 2020. 11:(1): p. 1-12.
     [Google Scholar]
  19. Buzon, M.J., et al., Inhibition of HIV-1 integration in ex vivo-infected CD4 T cells from elite controllers. Journal of virology, 2011. 85:(18): p. 9646-9650.
     [Google Scholar]
  20. Guicciardi, M.E., et al., Cathepsin B knockout mice are resistant to tumor necrosis factor-α-mediated hepatocyte apoptosis and liver injury: implications for therapeutic applications. 2001. 159:(6): p. 2045-2054.
     [Google Scholar]
  21. Hsing, L.C., et al., Roles for cathepsins S, L, and B in insulitis and diabetes in the NOD mouse. 2010. 34:(2): p. 96-104.
     [Google Scholar]
  22. Lockwood, T.D.J.B., Biguanide is a modifiable pharmacophore for recruitment of endogenous Zn 2+ to inhibit cysteinyl cathepsins: review and implications. 2019. 32:(4): p. 575-593.
     [Google Scholar]
  23. Perry, D.K., et al., Zinc is a potent inhibitor of the apoptotic protease, caspase-3: a novel target for zinc in the inhibition of apoptosis. 1997. 272:(30): p. 18530-18533.
     [Google Scholar]
  24. Eron, S.J., et al., Multiple mechanisms of zinc-mediated inhibition for the apoptotic caspases-3,-6,-7, and-8. 2018. 13:(5): p. 1279-1290.
     [Google Scholar]
  25. Parvez, M.K. and A.A.J.V.r. Khan, Molecular modeling and analysis of hepatitis E virus (HEV) papain-like cysteine protease. 2014. 179: p. 220-224.
     [Google Scholar]
  26. Nakajima, E., et al., Activation of the mitochondrial caspase pathway and subsequent calpain activation in monkey RPE cells cultured under zinc depletion. 2014. 28:(1): p. 85-92.
     [Google Scholar]
  27. Chouduri, A.U., et al., High affinity Zn2+ inhibitory site (s) for the trypsin-like peptidase of the 20S proteasome. 2008. 477:(1): p. 113-120.
     [Google Scholar]
  28. Kiss, P., et al., Zn2+-induced reversible dissociation of subunit Rpn10/p54 of the Drosophila 26 S proteasome. The Biochemical journal, 2005. 391:(Pt 2): p. 301-310.
     [Google Scholar]
  29. Sweeney, D., M.L. Raymer, and T.D.J.B.p. Lockwood, Antidiabetic and antimalarial biguanide drugs are metal-interactive antiproteolytic agents. 2003. 66:(4): p. 663-677.
     [Google Scholar]
  30. Bonaventura, P., et al., Zinc and its role in immunity and inflammation. 2015. 14:(4): p. 277-285.
     [Google Scholar]
  31. Bailey, C.J.J.D., Metformin: historical overview. 2017. 60:(9): p. 1566-1576.
     [Google Scholar]
  32. Pavan, R., S. Jain, and A. Kumar, Properties and therapeutic application of bromelain: a review. Biotechnology research international, 2012. 2012:.
     [Google Scholar]
  33. Sano, E., et al., Cysteine protease inhibitors in various milk preparations and its importance as a food. Food research international, 2005. 38:(4): p. 427-433.
     [Google Scholar]
  34. Bikle, D., Nonclassic Actions of Vitamin D. The Journal of Clinical Endocrinology & Metabolism, 2009. 94:(1): p. 26-34.
     [Google Scholar]
  35. Swami, S., et al., Vitamin D growth inhibition of breast cancer cells: gene expression patterns assessed by cDNA microarray. Breast cancer research and treatment, 2003. 80:(1): p. 49-62.
     [Google Scholar]
  36. Álvarez-Díaz, S., et al., Vitamin D: Proteases, protease inhibitors and cancer. Cell Cycle, 2010. 9:(1): p. 32-37.
     [Google Scholar]
  37. Mycroft-West, C., et al., Heparin inhibits cellular invasion by SARS-CoV-2: structural dependence of the interaction of the surface protein (spike) S1 receptor binding domain with heparin. BioRxiv, 2020.
     [Google Scholar]
  38. Kim, S.Y., et al., Glycosaminoglycan binding motif at S1/S2 proteolytic cleavage site on spike glycoprotein may facilitate novel coronavirus (SARS-CoV-2) host cell entry. BioRxiv, 2020.
     [Google Scholar]
  39. Huang, I.-C., et al., SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells. Journal of Biological Chemistry, 2006. 281:(6): p. 3198-3203.
     [Google Scholar]
  40. Wang, D., et al., Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. Jama, 2020. 323:(11): p. 1061-1069.
     [Google Scholar]
  41. Higgins, W.J., et al., Heparin enhances serpin inhibition of the cysteine protease cathepsin L. Journal of Biological Chemistry, 2010. 285:(6): p. 3722-3729.
     [Google Scholar]
  42. Gomes, C.P., et al., Cathepsin L in COVID-19: from pharmacological evidences to genetics. Frontiers in cellular and infection microbiology, 2020. 10.
     [Google Scholar]
  43. Hoffmann, M., et al., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. cell, 2020. 181:(2): p. 271-280. e8.
     [Google Scholar]
  44. Lehrer, S. and P.H. Rheinstein, Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. in vivo, 2020. 34:(5): p. 3023-3026.
     [Google Scholar]
  45. Glowacka, I., et al., Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. Journal of virology, 2011. 85:(9): p. 4122-4134.
     [Google Scholar]
  46. Caly, L., et al., The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral research, 2020. 178: p. 104787.
     [Google Scholar]
  47. Rowland, R.R., et al., Intracellular localization of the severe acute respiratory syndrome coronavirus nucleocapsid protein: absence of nucleolar accumulation during infection and after expression as a recombinant protein in vero cells. Journal of virology, 2005. 79:(17): p. 11507-11512.
     [Google Scholar]
  48. Tay, M., et al., Nuclear localization of dengue virus (DENV) 1–4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral research, 2013. 99:(3): p. 301-306.
     [Google Scholar]
  49. Wagstaff, K.M., et al., Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochemical Journal, 2012. 443:(3): p. 851-856.
     [Google Scholar]
  50. Yang, S.N., et al., The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral research, 2020. 177: p. 104760.
     [Google Scholar]
  51. Chen, J.-M., et al., Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase. Journal of Biological Chemistry, 1997. 272:(12): p. 8090-8098.
     [Google Scholar]
  52. Liu, C., et al., Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Cancer research, 2003. 63:(11): p. 2957-2964.
     [Google Scholar]
  53. Papaspyridonos, M., et al., Novel candidate genes in unstable areas of human atherosclerotic plaques. Arteriosclerosis, thrombosis, and vascular biology, 2006. 26:(8): p. 1837-1844.
     [Google Scholar]
  54. Shirahama-Noda, K., et al., Biosynthetic processing of cathepsins and lysosomal degradation are abolished in asparaginyl endopeptidase-deficient mice. Journal of Biological Chemistry, 2003. 278:(35): p. 33194-33199.
     [Google Scholar]
  55. Abisi, S., et al., Effect of statins on proteolytic activity in the wall of abdominal aortic aneurysms. British journal of surgery, 2008. 95:(3): p. 333-337.
     [Google Scholar]
  56. Wang, Z.h., et al., Pleiotropic effects of atorvastatin on monocytes in atherosclerotic patients. The Journal of Clinical Pharmacology, 2010. 50:(3): p. 311-319.
     [Google Scholar]
  57. Moheimani, F., et al., Inhibition of lysosomal function in macrophages incubated with elevated glucose concentrations: a potential contributory factor in diabetes-associated atherosclerosis. Atherosclerosis, 2012. 223:(1): p. 144-151.
     [Google Scholar]
  58. Nguyen-Ba, G., et al., Modulatory effect of dexamethasone on ornithine decarboxylase activity and gene Expression: a possible post-transcriptional regulation by a neutral metalloprotease. Cell Biochemistry and Function: Cellular biochemistry and its modulation by active agents or disease, 1994. 12:(2): p. 121-128.
     [Google Scholar]
  59. Group, R.C., Dexamethasone in hospitalized patients with Covid-19—preliminary report. New England Journal of Medicine, 2020.
     [Google Scholar]
  60. Lucas, J.M., et al., The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer discovery, 2014. 4:(11): p. 1310-1325.
     [Google Scholar]
  61. Zhou, N., et al., Glycopeptide antibiotics potently inhibit cathepsin l in the late endosome/lysosome and block the entry of ebola virus, middle east respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus (SARS-CoV). Journal of Biological Chemistry, 2016. 291:(17): p. 9218-9232.
     [Google Scholar]
  62. de Sousa LR, Wu H, Nebo L, Fernandes JB, da Silva MF, Kiefer W, Schirmeister T, Vieira PC. Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana. Exp Parasitol. 2015 Sep;156:42-8. doi: 10.1016/j.exppara.2015.05.016. Epub 2015 Jun 1. PMID: 26044356.
     [Google Scholar]
  63. Frlan R, Gobec S(2006) Inhibitors of cathepsin B. Curr Med Chem 13:2309–2327. https://doi.org/10.2174/09298 67067 77935 122
  64. Schrezenmeier E, Dorner T (2020) Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 16:(3): 155–166. https://doi.org/10.1038/s41584-020-0372-x (Epub 2020/02/09).
  65. Sainz RM, Mayo JC, Reiter RJ, Antolin I, Esteban MM, Rodriquez C. Melatonin regulates glucocorticoid receptor: an answer to its antiapoptotic action in thymus. Faseb J 1999; 13:1547–1557.
     [Google Scholar]
  66. Zeman M, Buyse J, Lamosova D, Herichova I, Decuypere E. Role of melatonin in the control of growth and growth hormone secretion in poultry. Domest Anim Endocrinol 1999; 17:199–209.
     [Google Scholar]
  67. Luboshitzky R, Shenorr Z, Shochat T, Herer P, Lavie P. Melatonin administered in the afternoon decreases next-day luteinizing hormone levels in men. Lack of antagonism by fl umazenil. J Mol Neurosci 1999;12:69–75.
     [Google Scholar]
  68. Maestroni GJM, Conti A, Covacci V. Melatonin-induced immunoopioids: fundamentals and clinical perspectives. Adv Pineal. Res 1994; 7:73–81.
     [Google Scholar]
  69. Van Dyke RW, Ervin LL, Lewis MR, Wang X. Effect of cholera toxin on rat liver lysosome acidification. Biochem Biophys Res. Commun 2000; 3: 717–721.
     [Google Scholar]
  70. Witek, B., Ochwanowska, E., Kolataj, A., Slewa, A. & Stanislawska, I. Effect of melatonin administration on activities of some lysosomal enzymes in the mouse. Neuroendocrinol. Lett. 22, 181–185 (2001).
     [Google Scholar]
  71. Miller B, Friedman AJ, Choi H, et al. The marine cyanobacterial metabolite gallinamide A is a potent and selective inhibitor of human cathepsin L. J Nat Prod. 2014; 77:(1): 92-99. doi:10.1021/np400727r.
     [Google Scholar]
  72. Morrissey, M.T., Hartley, P.S. and An, H. 1995. Proteolysis in pacific whiting and effect of surimi processing. Journal of Aquatic Food Product Technology 4:(4): 5-18.
     [Google Scholar]
  73. Hu, Y., Morioka, K. and Itoh, Y. 2007. Existence of cathepsin L and its characterization in Red Bulleye Surimi. Pakistan Journal of Biological Science 10:(1): 78-83.
     [Google Scholar]
  74. Ustadi, Kim, K.Y. and Kim, S.M. 2005. Purification and identification of a protease inhibitor from glassfish (Liparis tanakai) Eggs. Journal of Agricultural and Food Chemistry, 53:7667-7672.
     [Google Scholar]
  75. Olonen, A. 2004. High molecular weight cysteine proteinase inhibitors in Atlantic Salmon and other fish species. Helsinki, Finland. University of Helsinki, Ph.D dissertation.
     [Google Scholar]
  76. Li, D.K., Lin, H. and Kim, S.M. 2008. Purification and characterization of a cysteine protease inhibitor from chum salmon (Oncorhynchus keta) Plasma. Journal of Agricultural and Food Chemistry 56:106–111.
     [Google Scholar]
  77. Choi, J.H., Park, P.J. and Kim, S.K. 2002. Purification and characterization of a trypsin inhibitor from the egg of skipjack tuna Katsuwonus pelamis. Fisheries Science 68:1367-1373.
     [Google Scholar]
  78. Sentandreu, M.A., Coulis, G. and Ouali, A. 2002. Role of muscle endopeptidases and their inhibitors in meat tenderness. Trends in Food Science and Technology 13:(12): 400-421.
     [Google Scholar]
  79. Huang IC, Bosch BJ, Li F, et al. SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells. J Biol Chem. 2006; 281: 3198-203.
     [Google Scholar]
  80. Gerber A, Welte T, Ansorge S, Buhling F, Expression of cathepsin B and L in human lung epithelial cells is regulated by cytokines, Adv Exp Med Biol. 2000;477:287-92.
     [Google Scholar]
  81. Lockwood T. Biguanide is a modifiable pharmacophore for recruitment of endogenous Zn2+ to inhibit cysteinyl cathepsins: review and implications. BioMetals. 2019; 32:(4): 575-593. doi:10.1007/s10534-019-00197-1
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journals/10.5339/avi.2022.2
Loading
After one year of the COVID-19 pandemic and hundreds of suggested drugs, will cathepsin L inhibitors be the solution?
Avicenna 2022, 2 (2022); https://doi.org/10.5339/avi.2022.2
/content/journals/10.5339/avi.2022.2
/content/journals/10.5339/avi.2022.2
Loading

Data & Media loading...

  • Article Type: Research Article
Keyword(s): cathepsin L, COVID-19, metformin, moelcular docking, SARS-CoV-2 and viral fusion

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error