Main Article Content

Abstract

The coronavirus disease of 2019 (COVID-19) has become a long global pandemic caused by a transmitted and pathogenic virus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Even though WHO has retracted the global emergency status of COVID-19, it remains a threat. Various antiviral treatments are being devised and developed due to the coronavirus's high rate of mutation and need to create more effective treatments for infections. Protease is an important part of the life cycle of SARS CoV-2 hence it is intended as an antiviral target. Several protease inhibitor candidates have been identified, but there is still much to learn, including the structure and mechanism by which these inhibitors inhibit protease. This article investigates the function of proteases in the SARS CoV-2 life cycle and the mechanism of protease inhibition. Past and present research on the protease inhibitor mechanism of action was evaluated in order to generate this literature review. Here we found that the main protease (Mpro), one of SARS-CoV's proteases, is highly conserved among coronaviruses and has no human homolog. As a result, numerous Mpro inhibitors have been developed in an effort to treat COVID-19. PAXLOVID, an Mpro inhibitor, is already approved by FDA for emergency use.

Keywords

Antivirus, Mpro, Protease, Protease Inhibitor, SARS-CoV-2

Article Details

How to Cite
1.
Swestikaputri CH, Sudiro TM. SARS-CoV-2 Proteases: Role and Potential as Drug Target. EKSAKTA [Internet]. 2023Sep.30 [cited 2024Nov.21];23(03):453-64. Available from: https://eksakta.ppj.unp.ac.id/index.php/eksakta/article/view/437

References

  1. Satuan Tugas Penanganan COVID-19. (2023). Situasi COVID-19 di Indonesia (Update per 16 Mei 2023). Retrieve from https://covid19.go.id/artikel/2023/05/16/situasi-covid-19-di-indonesia-update-16-mei-2023. Diakses pada tanggal 16 Mei 2023.
  2. Chen, T., Wu, D., Chen, H., Yan, W., Yang, D., et al. (2020). Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. https://doi.org/10.1136/bmj.m1091
  3. Albrecht, D. (2022). Vaccination, politics and COVID-19 impacts. BMC Public Health, 22(1), 1–12. https://doi.org/10.1186/S12889-021-12432-X/FIGURES/3
  4. Abavisani, M., Rahimian, K., Mahdavi, B., Tokhanbigli, S., Mollapour Siasakht, M., et al. (2022). Mutations in SARS-CoV-2 structural proteins: a global analysis. Virology Journal, 19(1), 1–19. https://doi.org/10.1186/S12985-022-01951-7/FIGURES/12
  5. Pillaiyar, T., Manickam, M., Namasivayam, V., Hayashi, Y., & Jung, S. H. (2016). An overview of severe acute respiratory syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: Peptidomimetics and small molecule chemotherapy. Journal of Medicinal Chemistry, 59(14), 6595–6628. https://doi.org/10.1021/acs.jmedchem.5b01461
  6. Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., et al. (2020). Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 582(7811), 289–293. https://doi.org/10.1038/s41586-020-2223-y
  7. Kumar, S., Zhi, K., Mukherji, A., & Gerth, K. (2020). Repurposing antiviral protease inhibitors using extracellular vesicles for potential therapy of COVID-19. Viruses, 12(5). https://doi.org/10.3390/v12050486
  8. Hu, Q., Xiong, Y., Zhu, G. H., Zhang, Y. N., Zhang, Y. W., et al. (2022). The SARS-CoV-2 main protease (Mpro): Structure, function, and emerging therapies for COVID-19. MedComm, 3(3), e151. https://doi.org/10.1002/MCO2.151
  9. Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., et al. (2020). Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors. Science, 368(6489), 409–412. https://doi.org/10.1126/science.abb3405
  10. Zhu, G., Zhu, C., Zhu, Y., & Sun, F. (2020). Minireview of progress in the structural study of SARS-CoV-2 proteins. Current Research in Microbial Sciences, 1(June), 53–61. https://doi.org/10.1016/j.crmicr.2020.06.003
  11. Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M.,et al. (2020). Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 582(7811), 289–293. https://doi.org/10.1038/s41586-020-2223-y
  12. Cho, E., Rosa, M., Anjum, R., Mehmood, S., Soban, M.,et al. (2021). Dynamic Profiling of β-Coronavirus 3CL MproProtease Ligand-Binding Sites. Journal of Chemical Information and Modeling, 61(6), 3058–3073. https://doi.org/10.1021/acs.jcim.1c00449
  13. Antonopoulou, I., Sapountzaki, E., Rova, U., & Christakopoulos, P. (2022). Inhibition of the main protease of SARS-CoV-2 (Mpro) by repurposing/designing drug-like substances and utilizing nature’s toolbox of bioactive compounds. Computational and Structural Biotechnology Journal, 20, 1306–1344. https://doi.org/10.1016/j.csbj.2022.03.009
  14. FDA. (n.d.). Emergency Use Authorization (EUA) for PAXLOVID Center for Drug Evaluation and Research Review Memorandum. Retrieved from https://www.fda.gov/media/159724/download. Diakses pada tanggal 21 May 2023.
  15. Greasley, S. E., Noell, S., Plotnikova, O., Ferre, R. A., Liu, W., et al. (2022). Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants. Journal of Biological Chemistry, 298(6), 1–7. https://doi.org/10.1016/j.jbc.2022.101972
  16. Naqvi, A. A. T., Fatima, K., Mohammad, T., Fatima, U., Singh, I. K., et al. (2020). Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1866(10), 165878. https://doi.org/10.1016/j.bbadis.2020.165878
  17. Kumar, P., Sobhanan, J., Takano, Y., & Biju, V. (2021). Molecular recognition in the infection, replication, and transmission of COVID-19-causing SARS-CoV-2: an emerging interface of infectious disease, biological chemistry, and nanoscience. NPG Asia Materials, 13(1). https://doi.org/10.1038/s41427-020-00275-8
  18. Cascella, M., Rajnik, M., Aleem, A., Dulebohn, S. C., & Napoli, R. Di. (2023). Features, Evaluation, and Treatment of Coronavirus (COVID-19). StatPearls Publishing.
  19. Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., et al. (2020). Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature, 581(7807), 215–220. https://doi.org/10.1038/s41586-020-2180-5
  20. Haque, S. K. M., Ashwaq, O., Sarief, A., & Azad John Mohamed, A. K. (2020). A comprehensive review about SARS-CoV-2. Future Virology, 15(9), 625–648. https://doi.org/10.2217/fvl-2020-0124
  21. Yuan, Y., Cao, D., Zhang, Y., Ma, J., Qi, J., et al. (2017). Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal the dynamic receptor binding domains. Nature Communications, 8(China CDC), 1–9. https://doi.org/10.1038/ncomms15092
  22. Guo, Y.-R., Cao, Q.-D., Hong3, Z.-S., Tan, Y.-Y., Chen, S.-D., et al. (2020). The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Military Medical Research, 7(1), 2124–2125. https://doi.org/https://doi.org/10.1186/s40779-020-00240-0
  23. Dagotto, G., Yu, J., & Barouch, D. H. (2020). Approaches and Challenges in SARS-CoV-2 Vaccine Development. Cell Host and Microbe, 28(September), 19–21. https://doi.org/https://doi.org/10.1016/j.chom.2020.08.002
  24. Sternberg, A., & Naujokat, C. (2020). Structural features of coronavirus SARS-CoV-2 spike protein: Targets for vaccination. Life Sciences, 257(July), 118056. https://doi.org/10.1016/j.lfs.2020.118056
  25. Jackson, C. B., Farzan, M., Chen, B., & Choe, H. (2022). Mechanisms of SARS-CoV-2 entry into cells. Nature Reviews Molecular Cell Biology, 23(1), 3–20. https://doi.org/10.1038/s41580-021-00418-x
  26. Forni, D., Sironi, M., & Cagliani, R. (2022). Evolutionary history of type II transmembrane serine proteases involved in viral priming. Human Genetics 2022 141:11, 141(11), 1705–1722. https://doi.org/10.1007/S00439-022-02435-Y
  27. Koch, J., Uckeley, Z. M., Doldan, P., Stanifer, M., Boulant, S., & Lozach, P.-Y. (2021). TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells. The EMBO Journal, 40. https://doi.org/https://doi.org/10.15252/embj.2021107821
  28. Bayati, A., Kumar, R., Francis, V., & McPherson, P. S. (2021). SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis. Journal of Biological Chemistry, 296, 100306. https://doi.org/10.1016/j.jbc.2021.100306
  29. V’kovski, P., Kratzel, A., Steiner, S., Stalder, H., & Thiel, V. (2021). Coronavirus biology and replication: implications for SARS-CoV-2. Nature Reviews Microbiology, 19(3), 155–170. https://doi.org/10.1038/s41579-020-00468-6
  30. Mishchenko, E. L., & Ivanisenko, V. A. (2022). Replication-transcription complex of coronaviruses: functions of individual viral non-structural subunits, properties and architecture of their complexes. Vavilov Journal of Genetics and Breeding, 26(2), 121. https://doi.org/10.18699/VJGB-22-15
  31. Pizzato, M., Baraldi, C., Boscato Sopetto, G., Finozzi, D., Gentile, C., et al. (2022). SARS-CoV-2 and the Host Cell: A Tale of Interactions. Frontiers in Virology, 1. https://doi.org/10.3389/FVIRO.2021.815388
  32. Agbowuro, A. A., Huston, W. M., Gamble, A. B., & Tyndall, J. D. A. (2018). Proteases and protease inhibitors in infectious diseases. Medicinal Research Reviews, 38(4), 1295–1331. https://doi.org/10.1002/med.21475
  33. Bond, J. S. (2019). Proteases: History, discovery, and roles in health and disease. Journal of Biological Chemistry, 294(5), 1643–1651. https://doi.org/10.1074/jbc.TM118.004156
  34. Sharma, A., & Gupta, S. P. (2017). Fundamentals of viruses and their proteases. Viral Proteases and Their Inhibitors, 1, 1–24. https://doi.org/10.1016/B978-0-12-809712-0.00001-0
  35. Noreen, S., Siddiqa, A., Fatima, R., Anwar, F., Adnan, M., & Raza, A. (2017). Protease Production and Purification from Agro Industrial Waste by Utilizing Penicillium digitatum. 1(4), 119–129.
  36. Rawlings, N. D., Barrett, A. J., Thomas, P. D., Huang, X., Bateman, A., & Finn, R. D. (2018). The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. Nucleic Acids Research, 46(D1), D624–D632. https://doi.org/10.1093/NAR/GKX1134
  37. Boon, L., Ugarte-Berzal, E., Vandooren, J., & Opdenakker, G. (2020). Critical reviews in biochemistry and molecular, 55(2), 111–165. https://doi.org/10.1080/10409238.2020.1742090
  38. Helm, K. von der, Korant, B. D., & Cheroni, J. C. (Eds.). (2000). Handbook of Experimental Pharmacology (Vol. 140). ProduServ GmbH Ver!agsservice. https://doi.org/10.1007/978-3-642-57092-6
  39. Osipiuk, J., Azizi, S. A., Dvorkin, S., Endres, M., Jedrzejczak, R., et al. (2021). Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nature Communications, 12(1), 1–9. https://doi.org/10.1038/s41467-021-21060-3
  40. Amin, Sk. A., Banerjee, S., Ghosh, K., Gayen, S., & Jha, T. (2021). Protease targeted COVID-19 drug discovery and its challenges: Insight into viral main protease (Mpro) and papain-like protease (PLpro) inhibitors. Bioorganic & Medicinal Chemistry, 29, 115860. https://doi.org/https://doi.org/10.1016/j.bmc.2020.115860
  41. Caroline Ritchie. (2013). Protease Inhibitors. Materials and Methods. https://doi.org/DOI:10.13070/mm.en.3.169
  42. Hong, T. T., Dat, T. T. H., Cuc, N. T. K., & Cuong, P. V. (2018). Mini-Review PROTEASE INHIBITOR (PI) AND PIs FROM SPONGE-ASSOCIATED MICROORGANISMS. Vietnam Journal of Science and Technology, 56(4), 405. https://doi.org/10.15625/2525-2518/56/4/10911
  43. Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K., & Hilgenfeld, R. (2020). Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science (New York, N.Y.), 368(6489), 409–412. https://doi.org/10.1126/SCIENCE.ABB3405
  44. Zhang, L. C., Zhao, H. L., Liu, J., He, L., Yu, R. L., & Kang, C. M. (2022). Design of SARS-CoV-2 Mpro, PLpro dual-target inhibitors based on deep reinforcement learning and virtual screening. Future Medicinal Chemistry, 14(6), 393–405. https://doi.org/10.4155/FMC-2021-0269/ASSET/IMAGES/LARGE/FIGURE9.JPEG
  45. Shen, Z., Ratia, K., Cooper, L., Kong, D., Lee, H., et al. (2022). Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity | Enhanced Reader. J Med Chem, 65(4), 2940–2955. https://doi.org/doi: 10.1021/acs.jmedchem.1c01307
  46. Ma, C., Sacco, M. D., Hurst, B., Townsend, J. A., Hu, Y., et al. (2020). Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease. Cell Research 2020 30:8, 30(8), 678–692. https://doi.org/10.1038/s41422-020-0356-z
  47. Mukherjee, R., & Dikic, I. (2023). Proteases of SARS Coronaviruses. Encyclopedia of Cell Biology, 941. https://doi.org/10.1016/B978-0-12-821618-7.00111-5
  48. PAXLOVIDTM (nirmatrelvir tablets; ritonavir tablets) | Pfizer Medical Information - US. (n.d.). Retrieved from https://www.pfizermedicalinformation.com/en-us/paxlovid. Diakses pada 21 May 2023,
  49. Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., et al. (2020). A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. The New England Journal of Medicine, 382(19), 1787–1799. https://doi.org/10.1056/NEJMOA2001282
  50. Foo, C. S., Abdelnabi, R., Kaptein, S. J. F., Zhang, X., ter Horst, S., et al. (2022). HIV protease inhibitors Nelfinavir and Lopinavir/Ritonavir markedly improve lung pathology in SARS-CoV-2-infected Syrian hamsters despite lack of an antiviral effect. Antiviral Research, 202. https://doi.org/10.1016/J.ANTIVIRAL.2022.105311
  51. Chavda, V. P., Gajjar, N., Shah, N., & Dave, D. J. (2021). Darunavir ethanolate: Repurposing an anti-HIV drug in COVID-19 treatment. European Journal of Medicinal Chemistry Reports, 3, 100013. https://doi.org/10.1016/J.EJMCR.2021.100013
  52. Mahdi, M., Mótyán, J. A., Szojka, Z. I., Golda, M., Miczi, M., & Tőzsér, J. (2020). Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2′s main protease. Virology Journal, 17(1), 1–8. https://doi.org/10.1186/S12985-020-01457-0/FIGURES/4
  53. Dai, W., Zhang, B., Jiang, X. M., Su, H., Li, J., et al. (2020). Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science (New York, N.Y.), 368(6497), 1331–1335. https://doi.org/10.1126/SCIENCE.ABB4489
  54. Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., et al. (2020). Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science (New York, N.Y.), 368(6489), 409–412. https://doi.org/10.1126/SCIENCE.ABB3405
  55. Macchiagodena, M., Pagliai, M., & Procacci, P. (2022). Characterization of the non-covalent interaction between the PF-07321332 inhibitor and the SARS-CoV-2 main protease. Journal of Molecular Graphics & Modelling, 110. https://doi.org/10.1016/J.JMGM.2021.108042
  56. De Meyer, S., Bojkova, D., Cinatl, J., Van Damme, E., Buyck, C., et al. (2020). Lack of antiviral activity of darunavir against SARS-CoV-2. International Journal of Infectious Diseases, 97, 7–10. https://doi.org/10.1016/J.IJID.2020.05.085
  57. FDA. (n.d.). Fact Sheet For Healthcare Providers: Emergency Use Authorization For Paxlovid Tm Highlights Of Emergency Use Authorization (EUA). https://www.cdc.gov/coronavirus/2019-
  58. Hammond, J., Leister-Tebbe, H., Gardner, A., Abreu, P., Bao, W., et al. (2022). Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. New England Journal of Medicine, 386(15), 1397–1408. https://doi.org/10.1056/NEJMOA2118542/SUPPL_FILE/NEJMOA2118542_DATA-SHARING.PDF
  59. Pedoman Tatalaksana COVID-19 edisi 4 - Protokol | Covid19.go.id. (n.d.). Retrieved June 1, 2023, from https://covid19.go.id/p/protokol/pedoman-tatalaksana-covid-19-edisi-4
  60. Owen, D. R., Allerton, C. M. N., Anderson, A. S., Aschenbrenner, L., Avery, M., et al. (2021). An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science, 374(6575), 1586–1593. https://doi.org/10.1126/SCIENCE.ABL4784