SARS-CoV-2 Proteases: Role and Potential as Drug Target

Authors

  • Chrecentia Hanna Swestikaputri Master Programme in Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
  • Tjahjani Mirawati Sudiro Department of Microbiology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

DOI:

https://doi.org/10.24036/eksakta/vol23-iss03/437

Keywords:

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

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.

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References

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.

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

Cascella, M., Rajnik, M., Aleem, A., Dulebohn, S. C., & Napoli, R. Di. (2023). Features, Evaluation, and Treatment of Coronavirus (COVID-19). StatPearls Publishing.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

Caroline Ritchie. (2013). Protease Inhibitors. Materials and Methods. https://doi.org/DOI:10.13070/mm.en.3.169

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

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

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

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

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

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

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,

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

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

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

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

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

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

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

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

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-

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

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

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

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Published

2023-09-30

How to Cite

1.
SARS-CoV-2 Proteases: Role and Potential as Drug Target. EKSAKTA [Internet]. 2023 Sep. 30 [cited 2026 Aug. 1];24(03):453-64. Available from: https://eksakta.ppj.unp.ac.id/index.php/eksakta/article/view/437