Assessing Antiviral Mechanisms of N-acetyl-D-glucosamine, N-acetylcysteine and Acetylsalicylic acid on SARS-CoV-2

Abstract

The potential antiviral activity of FDA-approved 3 compounds (N-acetyl-D-glucosamine; GlcNAc, N-acetylcysteine; NAC, and Acetylsalicylic acid; ASA) against SARS-CoV-2 was investigated. Molecular docking analysis of these compounds as ligands with the main 22 viral proteins was made to predict their possible interaction. All molecules showed interactions with the viral proteins; the mean binding scores for GlcNAc and ASA were very close (-6.81 kcal/mol and -6.31 kcal/mol, respectively), while NAC designated the lowest value (-4.69 kcal/mol). GlcNAc showed the highest binding energy of -8.80 kcal/mol against both the target proteins RdRp-RTP site (7BV2) and Helicase-ANP binding site (7NN0). Since these 22 proteins, including main protease (Mpro) and Papain-like protease (PLpro), are responsible for replication and various pathogenesis processes, it could be concluded that these FDA-approved commercially available compounds have antiviral properties against SARS-CoV-2, which should be confirmed with further in vivo and clinical trials.

Keywords

• bioinformatics
• ligand
• molecular docking
• nCoV
• repurposing
• SARS-CoV-2

N-asetil-D-glukozamin, N-asetilsistein ve Asetilsalisilik asidin SARS-CoV-2’ye Antiviral Mekanizmalarının Değerlendirilmesi

Abstract

FDA onaylı 3 bileşiğin (N-asetil-D-glukozamin; GlcNAc, N-asetilsistein; NAC ve Asetilsalisilik asit; ASA) SARS-CoV-2'ye karşı potansiyel antiviral aktivitesi araştırılmıştır. Bu bileşiklerin ligand olarak 22 belli başlı viral proteinle moleküler kenetlenme analizleri yapılarak olası etkileşimleri tahmin edilmiştir. Tüm moleküller viral proteinlerle etkileşim göstermiştir; GlcNAc ve ASA için ortalama bağlanma skorları birbirine çok yakın çıkmıştır (-6.81 kcal/mol ve -6.31 kcal/mol, sırasıyla), NAC ise en düşük değeri göstermiştir (-4.69 kcal/mol). GlcNAc, hedef proteinler olan hem RdRp-RTP bölgesine (7BV2) hem de Helikaz-ANP bağlanma bölgesine (7NN0) -8.80 kcal/mol ile en yüksek bağlanma enerjisini göstermiştir. Bu 22 protein arasında ana proteaz (Mpro) ve Papain-benzeri proteaz (PLpro) gibi replikasyon ve çeşitli patogenez süreçlerinden sorumlu proteinler yer aldığından, bu FDA onaylı ve ticari olarak mevcut bileşiklerin SARS-CoV-2'ye karşı antiviral özelliklere sahip olduğu, ancak bunun daha ileri in vivo ve klinik çalışmalarla doğrulanması gerektiği sonucuna varılmıştır.

Keywords

• Biyoenformatik
• ligand
• moleküler kenetlenme
• nCoV
• yeniden amaçlandırma
• SARS-CoV-2

References

1. Tay, M. Z., Poh, C. M., Rénia, L., MacAry, P. A., & Ng, L. F. P. (2020). The trinity of COVID-19: immunity, inflammation and intervention. Nature reviews. Immunology, 20(6), 363–374. https://doi.org/10.1038/s41577-020-0311-8
2. van Eijk, L. E., Binkhorst, M., Bourgonje, A. R., Offringa, A. K., Mulder, D. J., Bos, E. M., Kolundzic, N., Abdulle, A. E., van der Voort, P. H., Olde Rikkert, M. G., van der Hoeven, J. G., den Dunnen, W. F., Hillebrands, J. L., & van Goor, H. (2021). COVID-19: immunopathology, pathophysiological mechanisms, and treatment options. The Journal of pathology, 254(4), 307–331. https://doi.org/10.1002/path.5642
3. 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. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579(7798), 270–273. https://doi.org/10.1038/s41586-020-2012-7
4. Coronavirus disease (COVID-19) Fact sheets, https://www.who.int/news-room/fact-sheets/detail/coronavirus-disease-(covid-19), (August 2023).
5. Liang, Y., Wang, M. L., Chien, C. S., Yarmishyn, A. A., Yang, Y. P., Lai, W. Y., Luo, Y. H., Lin, Y. T., Chen, Y. J., Chang, P. C., & Chiou, S. H. (2020). Highlight of Immune Pathogenic Response and Hematopathologic Effect in SARS-CoV, MERS-CoV, and SARS-Cov-2 Infection. Frontiers in immunology, 11, 1022. https://doi.org/10.3389/fimmu.2020.01022
6. Malone, B., Urakova, N., Snijder, E. J., & Campbell, E. A. (2022). Structures and functions of coronavirus replication-transcription complexes and their relevance for SARS-CoV-2 drug design. Nature reviews. Molecular cell biology, 23(1), 21–39. https://doi.org/10.1038/s41580-021-00432-z
7. Hashimoto, T., Perlot, T., Rehman, A., Trichereau, J., Ishiguro, H., Paolino, M., Sigl, V., Hanada, T., Hanada, R., Lipinski, S., Wild, B., Camargo, S. M., Singer, D., Richter, A., Kuba, K., Fukamizu, A., Schreiber, S., Clevers, H., Verrey, F., Rosenstiel, P., & Penninger, J. M. (2012). ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature, 487(7408), 477–481. https://doi.org/10.1038/nature11228
8. Varga, Z., Flammer, A. J., Steiger, P., Haberecker, M., Andermatt, R., Zinkernagel, A. S., Mehra, M. R., Schuepbach, R. A., Ruschitzka, F., & Moch, H. (2020). Endothelial cell infection and endotheliitis in COVID-19. Lancet (London, England), 395(10234), 1417–1418. https://doi.org/10.1016/S0140-6736(20)30937-5

9. Bourgonje, A. R., Abdulle, A. E., Timens, W., Hillebrands, J. L., Navis, G. J., Gordijn, S. J., Bolling, M. C., Dijkstra, G., Voors, A. A., Osterhaus, A. D., van der Voort, P. H., Mulder, D. J., & van Goor, H. (2020). Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). The Journal of pathology, 251(3), 228–248. https://doi.org/10.1002/path.5471
10. Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y., & Zhou, Q. (2020). Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science (New York, N.Y.), 367(6485), 1444–1448. https://doi.org/10.1126/science.abb2762
11. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., Xiao, Y., Gao, H., Guo, L., Xie, J., Wang, G., Jiang, R., Gao, Z., Jin, Q., Wang, J., & Cao, B. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England), 395(10223), 497–506. https://doi.org/10.1016/S0140-6736(20)30183-5
12. Kim, J. S., Lee, J. Y., Yang, J. W., Lee, K. H., Effenberger, M., Szpirt, W., Kronbichler, A., & Shin, J. I. (2021). Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics, 11(1), 316–329. https://doi.org/10.7150/thno.49713
13. Schurink, B., Roos, E., Radonic, T., Barbe, E., Bouman, C. S. C., de Boer, H. H., de Bree, G. J., Bulle, E. B., Aronica, E. M., Florquin, S., Fronczek, J., Heunks, L. M. A., de Jong, M. D., Guo, L., du Long, R., Lutter, R., Molenaar, P. C. G., Neefjes-Borst, E. A., Niessen, H. W. M., van Noesel, C. J. M., Roelofs, J. J. T. H., Snijder, E. J., Soer, E. C., Verheij, J., Vlaar, A. P. J., Vos, W., van der Wel, N. N., van der Wal, A. C., van der Valk, P., & Bugiani, M. (2020). Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study. The Lancet Microbe, 1(7), e290–e299. https://doi.org/10.1016/S2666-5247(20)30144-0
14. Bettini, E., & Locci, M. (2021). SARS-CoV-2 mRNA Vaccines: Immunological Mechanism and Beyond. Vaccines, 9(2), 147. https://doi.org/10.3390/vaccines9020147
15. Yadav, T., Kumar, S., Mishra, G., & Saxena, S. K. (2023). Tracking the COVID-19 vaccines: The global landscape. Human vaccines & immunotherapeutics, 19(1), 2191577. https://doi.org/10.1080/21645515.2023.2191577
16. Yasmin, F., Najeeb, H., Naeem, U., Moeed, A., Atif, A. R., Asghar, M. S., Nimri, N., Saleem, M., Bandyopadhyay, D., Krittanawong, C., Fadelallah Eljack, M. M., Tahir, M. J., & Waqar, F. (2023). Adverse events following COVID-19 mRNA vaccines: A systematic review of cardiovascular complication, thrombosis, and thrombocytopenia. Immunity, inflammation and disease, 11(3), e807. https://doi.org/10.1002/iid3.807
17. Haider, S. M. S., Alvi, S. A., Khan, H., Majeed, R., Syed, T., Anwar, A., & Hashmi, A. A. (2023). Common side effects of Pfizer COVID-19 vaccine: An experience from Pakistan. Cureus, 15(6), e40878. https://doi.org/10.7759/cureus.40878
18. Abukhalil, A. D., Shatat, S. S., Abushehadeh, R. R., Al-Shami, N., Naseef, H. A., & Rabba, A. (2023). Side effects of Pfizer/BioNTech (BNT162b2) COVID-19 vaccine reported by the Birzeit University community. BMC infectious diseases, 23(1), 5. https://doi.org/10.1186/s12879-022-07974-3
19. Sha, A., Liu, Y., & Hao, H. (2023). Current state-of-the-art and potential future therapeutic drugs against COVID-19. Frontiers in cell and developmental biology, 11, 1238027. https://doi.org/10.3389/fcell.2023.1238027
20. Focosi, D., Sullivan, D. J., & Franchini, M. (2025). Development of antiviral drugs for COVID-19 in 2025: unmet needs and future challenges. Expert review of anti-infective therapy, 23(6), 351–358. https://doi.org/10.1080/14787210.2025.2473044
21. Hurt, A. C., & Wheatley, A. K. (2021). Neutralizing antibody therapeutics for COVID-19. Viruses, 13(4), 628. https://doi.org/10.3390/v13040628
22. Baysal, Ö., & Silme, R. S. (2021). Utilization from computational methods and omics data for antiviral drug discovery to control of SARS-CoV-2. IntechOpen. https://doi.org/10.5772/intechopen.98319
23. Rodrigues, L., Bento Cunha, R., Vassilevskaia, T., Viveiros, M., & Cunha, C. (2022). Drug repurposing for COVID-19: a review and a novel strategy to identify new targets and potential drug candidates. Molecules (Basel, Switzerland), 27(9), 2723. https://doi.org/10.3390/molecules27092723
24. Herrera-Rodulfo, A., Andrade-Medina, M., & Carrillo-Tripp, M. (2023). Repurposing drugs as potential therapeutics for the SARS-Cov-2 viral infection: automatizing a blind molecular docking high-throughput pipeline. IntechOpen. https://doi.org/10.5772/intechopen.105792
25. Liu, K., Lu, X., Shi, H., Xu, X., Kong, R., & Chang, S. (2023). nCoVDock2: a docking server to predict the binding modes between COVID-19 targets and its potential ligands. Nucleic acids research, 51(W1), W365–W371. https://doi.org/10.1093/nar/gkad414
26. Eberhardt, J., Santos-Martins, D., Tillack, A. F., & Forli, S. (2021). AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. Journal of chemical information and modeling, 61(8), 3891–3898. https://doi.org/10.1021/acs.jcim.1c00203
27. Trott, O., & Olson, A. J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of computational chemistry, 31(2), 455–461. https://doi.org/10.1002/jcc.21334
28. O'Boyle, N. M., Banck, M., James, C. A., Morley, C., Vandermeersch, T., & Hutchison, G. R. (2011). Open Babel: An open chemical toolbox. Journal of cheminformatics, 3, 33. https://doi.org/10.1186/1758-2946-3-33
29. NCBI-National Center for Biotechnology Information (2025). PubChem Compound Summary for a) CID 439174, N-Acetyl-D-Glucosamine, b) CID 12035, Acetylcysteine and c) CID 2244, Aspirin Retrieved March 23, 2025 from a) https://pubchem.ncbi.nlm.nih.gov/compound/N-Acetyl-D-Glucosamine, b) https://pubchem.ncbi.nlm.nih.gov/compound/Acetylcysteine, and c) https://pubchem.ncbi.nlm.nih.gov/compound/Aspirin
30. The PyMOL Molecular Graphics System, Version 3.1.3 Schrödinger, LLC. https://www.pymol.org
31. BIOVIA, Dassault Systèmes, BIOVIA Discovery Studio Visualizer, version 25.1.0.24284, San Diego, 2025
32. Wallace, A. C., Laskowski, R. A., & Thornton, J. M. (1996). LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein engineering, 8(2), 127–134. https://doi.org/10.1093/protein/8.2.127
33. Laskowski, R. A., & Swindells, M. B. (2011). LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. Journal of chemical information and modeling, 51(10), 2778–2786. https://doi.org/10.1021/ci200227u
34. Li, H., Leung, K. S., Wong, M. H., & Ballester, P. J. (2016). Correcting the impact of docking pose generation error on binding affinity prediction. BMC bioinformatics, 17(Suppl 11), 308. https://doi.org/10.1186/s12859-016-1169-4
35. Hu, Q., Xiong, Y., Zhu, G. H., Zhang, Y. N., Zhang, Y. W., Huang, P., & Ge, G. B. (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
36. Varghese, A., Liu, J., Liu, B., Guo, W., Dong, F., Patterson, T. A., & Hong, H. (2025). Analysis of structures of SARS-CoV-2 papain-like protease bound with ligands unveils structural features for inhibiting the enzyme. Molecules (Basel, Switzerland), 30(3), 491. https://doi.org/10.3390/molecules30030491
37. 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, 155–170. https://doi.org/10.1038/s41579-020-00468-6
38. Wang, Y., Grunewald, M., & Perlman, S. (2020). Coronaviruses: an updated overview of their replication and pathogenesis. In: Coronaviruses. Methods in Molecular Biology, Maier, H., Bickerton, E. (eds.), vol 2203, Humana, New York, NY, USA, pp. 1–29. https://doi.org/10.1007/978-1-0716-0900-2_1
39. Walsh, D., & Mohr, I. (2011). Viral subversion of the host protein synthesis machinery. Nature Reviews Microbiology, 9, 860–875. https://doi.org/10.1038/nrmicro2655
40. Minkoff, J. M., & tenOever, B. (2023). Innate immune evasion strategies of SARS-CoV-2. Nature reviews. Microbiology, 21(3), 178–194. https://doi.org/10.1038/s41579-022-00839-1
41. Wong, L. R., & Perlman, S. (2022). Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses - are we our own worst enemy? Nature reviews. Immunology, 22, 47–56. https://doi.org/10.1038/s41577-021-00656-2
42. Thiel, V., Ivanov, K. A., Putics, Á., Hertzig, T., Schelle, B., Bayer, S., Weißbrich, B., Snijder, E. J., Rabenau, H., Doerr, H. W., Gorbalenya, A. E., & Ziebuhr, J. (2003). Mechanisms and enzymes involved in SARS coronavirus genome expression. The Journal of general virology, 84(Pt 9), 2305–2315. https://doi.org/10.1099/vir.0.19424-0
43. Zhu, W., Xu, M., Chen, C. Z., Guo, H., Shen, M., Hu, X., Shinn, P., Klumpp-Thomas, C., Michael, S. G., & Zheng, W. (2020). Identification of SARS-CoV-2 3CL protease inhibitors by a quantitative high-throughput screening. ACS pharmacology & translational science, 3(5), 1008–1016. https://doi.org/10.1021/acsptsci.0c00108
44. Dai, W., Zhang, B., Jiang, X. M., Su, H., Li, J., Zhao, Y., Xie, X., Jin, Z., Peng, J., Liu, F., Li, C., Li, Y., Bai, F., Wang, H., Cheng, X., Cen, X., Hu, S., Yang, X., Wang, J., Liu, X., Xiao, G., Jiang, H., Rao, Z., Zhang, L.-K., Xu, Y., Yang, H., & Liu, H. (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
45. De Clercq, E. (2023). Hydrogen bonding (Base Pairing) in antiviral activity. Viruses, 15(5), 1145. https://doi.org/10.3390/v15051145
46. Baysal, Ö., Silme, R. S., Karaaslan, İ. Ç., & Ignatov, A. N. (2021a). Genetic uniformity of a specific region in SARS-CoV-2 genome and repurposing of N-acetyl-d-glucosamine. Fresenius Environmental Bulletin, 30(3), 2848-2857. https://doi.org/10.5281/zenodo.4621319
47. Baysal, Ö., Abdul Ghafoor, N., Silme, R. S., Ignatov, A. N., & Kniazeva, V. (2021b). Molecular dynamics analysis of N-acetyl-D-glucosamine against specific SARS-CoV-2’s pathogenicity factors. PloS One, 16(5), e0252571. https://doi.org/10.1371/journal.pone.0252571
48. De Clercq, E. (2021). Perspectives for antivirals to limit SARS-CoV-2 infection (COVID-19). Microbiology Australia, 42, 47–53.
49. Vishwakarma, K., Ravi, S., & Mittal S. (2024). Ab initio modeling of hydrogen bonding of Remdesivir and Adenosine with Uridine. ChemPhysChem, 25(3), e202300552. https://doi.org/10.1002/cphc.202300552
50. Nicholls, A., & Honig, B. (1995). Classical electrostatics in biology and chemistry. Science, 268(5214), 1144–1149. https://doi.org/10.1126/science.7761829
51. Shang, J., Ye, G., Shi, K., Wan, Y., Luo, C., Aihara, H., Geng, Q., Auerbach, A., & Li, F. (2020). Structural basis of receptor recognition by SARS-CoV-2. Nature, 581, 221–224. https://doi.org/10.1038/s41586-020-2179-y
52. Norel, R., Sheinerman, F., Petrey, D., & Honig, B. (2008). Electrostatic contributions to protein-protein interactions: fast energetic filters for docking and their physical basis. Protein Science, 10(11), 2147–2161. https://doi.org/10.1110/ps.12901
53. Sheinerman F. (2000). Electrostatic aspects of protein–protein interactions. Current Opinion in Structural Biology, 10(2), 153–159. https://doi.org/10.1016/S0959-440X(00)00065-8
54. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N. H., Nitsche, A., Müller, M. A., Drosten, C., & Pöhlmann, S. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181(2), 271–280.e8. https://doi.org/10.1016/j.cell.2020.02.052
55. Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y., & Zhou, Q. (2020). Structural basis for the recognition of SARSCoV-2 by full-length human ACE2. Science, 367(6485), 1444–1448. https://doi.org/10.1126/science.abb2762
56. Ali, F., Elserafy, M., Akordi, M.H., Amin, M. (2020). ACE2 coding variants in different populations and their potential impact on SARS-CoV-2 binding affinity. Biochemistry and Biophysics Reports, 24, 100798. https://doi.org/10.1016/j.bbrep.2020.100798
57. Amin, M., Sorour, M. K., & Kasry, A. (2020). Comparing the binding interactions in the receptor binding domains of SARS-CoV-2 and SARS-CoV. The journal of physical chemistry letters, 11(12), 4897–4900. https://doi.org/10.1021/acs.jpclett.0c01064
58. Sarkar, A., & Kellogg, G. E. (2010). Hydrophobicity--shake flasks, protein folding and drug discovery. Current topics in medicinal chemistry, 10(1), 67–83. https://doi.org/10.2174/156802610790232233
59. Simm, S., Einloft, J., Mirus, O., & Schleiff, E. (2016). 50 years of amino acid hydrophobicity scales: revisiting the capacity for peptide classification. Biological research, 49, 31. https://doi.org/10.1186/s40659-016-0092-5
60. Aydin, H., Al-Khooly, D., & Lee, J.E. (2014). Influence of hydrophobic and electrostatic residues on SARScoronavirus S2 protein stability: insights into mechanisms of general viral fusion and inhibitor design. Protein science, 23(5), 603–617. https://doi.org/10.1002/pro.2442
61. Nelson, D. L., & Cox, M. M. (2008). Lehninger Principles of Biochemistry. 5th Edition, 1-1294.
62. Wang, H.-J., Xi, X.-K., Kleinhammes, A., & Wu, Y. (2008). Temperature-induced hydrophobic-hydrophilic transition observed by water adsorption. Science, 322(5898), 80–83 https://doi.org/10.1126/science.1162412
63. Meyer, E. E., Rosenberg, K. J., & Israelachvili, J. (2006). Recent progress in understanding hydrophobic interactions. Proceedings of the National Academy of Sciences of the United States of America, 103(43), 15739–15746. https://doi.org/10.1073/pnas.0606422103
64. Kumar, S., Thambiraja, T. S., Karuppanan, K., & Subramaniam, G. (2022). Omicron and Delta variant of SARS-CoV-2: A comparative computational study of spike protein. Journal of medical virology, 94(4), 1641–1649. https://doi.org/10.1002/jmv.27526
65. Brogi, S., Ramalho, T. C., Kuca, K., Medina-Franco, J. L., & Valko, M. (2020). Editorial: In silico methods for drug design and discovery. Frontiers in chemistry, 8, 612. https://doi.org/10.3389/fchem.2020.00612
66. Hassan, A. E. (2021). An observational cohort study to assess N-acetylglucosamine for COVID-19 treatment in the inpatient setting. Annals of medicine and surgery, 68, 102574. https://doi.org/10.1016/j.amsu.2021.102574
67. Qi, Q., Chen, Q., Dong, Y., Wang, K., Wang, J., Jin, G., Zheng, A., Zhang, R., Deng, Y., Li, Y., Qin, C., & Duan, X. (2023). Oral administration of D-glucosamine confers broad-spectrum protection against human coronaviruses including SARS-CoV-2. Signal transduction and targeted therapy, 8, 250. https://doi.org/10.1038/s41392-023-01483-8
68. Geiger, N., König, E. M., Oberwinkler, H., Roll, V., Diesendorf, V., Fähr, S., Obernolte, H., Sewald, K., Wronski, S., Steinke, M., & Bodem, J. (2022). Acetylsalicylic acid and salicylic acid inhibit SARS-CoV-2 replication in precision-cut lung slices. Vaccines, 10(10), 1619. https://doi.org/10.3390/vaccines10101619
69. Bianconi, V., Violi, F., Fallarino, F., Pignatelli, P., Sahebkar, A., & Pirro, M. (2020). Is acetylsalicylic acid a safe and potentially useful choice for adult patients with COVID-19? Drugs, 80, 1383–1396. https://doi.org/10.1007/s40265-020-01365-1
70. Cacciapuoti, F., & Cacciapuoti, F. (2021). Could low doses acetylsalicylic acid prevent thrombotic complications in COVID-19 patients? Clinical and applied thrombosis/hemostasis: official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis, 27, 10760296211014592. https://doi.org/10.1177/10760296211014592
71. Mazik M. (2022). Promising therapeutic approach for SARS-CoV-2 infections by using a rutin-based combination therapy. ChemMedChem, 17(11), e202200157. https://doi.org/10.1002/cmdc.202200157
72. Rizk, J. G., Lavie, C. J., & Gupta, A. (2021). Low-dose aspirin for early COVID-19: does the early bird catch the worm? Expert opinion on investigational drugs, 30(8), 785–788. https://doi.org/10.1080/13543784.2021.1950687
73. Avdeev, S. N., Gaynitdinova, V. V., Merzhoeva, Z. M., & Berikkhanov, Z. G. (2022). N-acetylcysteine for the treatment of COVID-19 among hospitalized patients. The Journal of infection, 84(1), 94–118. https://doi.org/10.1016/j.jinf.2021.07.003
74. Faverio, P., Rebora, P., Rossi, E., Del Giudice, S., Montanelli, F., Garzillo, L., Busnelli, S., Luppi, F., Valsecchi, M. G., & Pesci, A. (2021). Impact of N-acetyl-l-cysteine on SARS-CoV-2 pneumonia and its sequelae: results from a large cohort study. ERJ open research, 8(1), 00542-2021. https://doi.org/10.1183/23120541.00542-2021
75. Izquierdo-Alonso, J. L., Pérez-Rial, S., Rivera, C. G., & Peces-Barba, G. (2022). N-acetylcysteine for prevention and treatment of COVID-19: Current state of evidence and future directions. Journal of infection and public health, 15(12), 1477–1483. https://doi.org/10.1016/j.jiph.2022.11.009
76. Wong, K. K., Lee, S. W. H., & Kua, K. P. (2021). N-Acetylcysteine as Adjuvant Therapy for COVID-19 - A perspective on the current state of the evidence. Journal of inflammation research, 14, 2993–3013. https://doi.org/10.2147/JIR.S306849
77. Werz, O., Stettler, H., Theurer, C., & Seibel, J. (2024). The 125th anniversary of Aspirin-the story continues. Pharmaceuticals (Basel, Switzerland), 17(4), 437. https://doi.org/10.3390/ph17040437
78. Tantry, U. S., Bliden, K. P., & Gurbel, P. A. (2022). Further evidence for the use of aspirin in COVID-19. International journal of cardiology, 346, 107–108. https://doi.org/10.1016/j.ijcard.2021.11.021
79. Ballering, A. V., van Zon, S. K. R., Olde Hartman, T. C., Rosmalen, J. G. M., & Lifelines Corona Research Initiative (2022). Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study. The Lancet (London, England), 400(10350), 452–461. https://doi.org/10.1016/S0140-6736(22)01214-4
80. O'Mahoney, L. L., Routen, A., Gillies, C., Ekezie, W., Welford, A., Zhang, A., Karamchandani, U., Simms-Williams, N., Cassambai, S., Ardavani, A., Wilkinson, T. J., Hawthorne, G., Curtis, F., Kingsnorth, A. P., Almaqhawi, A., Ward, T., Ayoubkhani, D., Banerjee, A., Calvert, M., Shafran, R., Stephenson, T., Sterne, J., Ward, H., Evans, R. A., Zaccardi, F., Wright, S., & Khunti, K. (2023). The prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: A systematic review and meta-analysis. eClinicalMedicine. 55, 101762. https://doi.org/10.1016/j.eclinm.2022.101762
81. Oronsky, B., Larson, C., Hammond, T. C., Oronsky, A., Kesari, S., Lybeck, M., & Reid, T. R. (2023). A review of persistent post-COVID syndrome (PPCS). Clinical reviews in allergy & immunology, 64(1), 66–74. https://doi.org/10.1007/s12016-021-08848-3
82. Bonilla, H., Peluso, M. J., Rodgers, K., Aberg, J. A., Patterson, T. F., Tamburro, R., Baizer, L., Goldman, J. D., Rouphael, N., Deitchman, A., Fine, J., Fontelo, P., Kim, A. Y., Shaw, G., Stratford, J., Ceger, P., Costantine, M. M., Fisher, L., O'Brien, L., Maughan, C., Quigley, J. G., Gabbay, V., Mohandas, S., Williams, D., & McComsey, G. A. (2023). Therapeutic trials for long COVID-19: A call to action from the interventions taskforce of the RECOVER initiative. Frontiers in immunology, 14, 1129459. https://doi.org/10.3389/fimmu.2023.1129459
83. Váncsa, S., Dembrovszky, F., Farkas, N., Szakó, L., Teutsch, B., Bunduc, S., Nagy, R., Párniczky, A., Erőss, B., Péterfi, Z., & Hegyi, P. (2021). Repeated SARS-CoV-2 positivity: analysis of 123 cases. Viruses, 13(3), 512. https://doi.org/10.3390/v13030512
84. Korber, B., Fischer, W. M., Gnanakaran, S., Yoon, H., Theiler, J., Abfalterer, W., Hengartner, N., Giorgi, E. E., Bhattacharya, T., Foley, B., Hastie, K. M., Parker, M. D., Partridge, D. G., Evans, C. M., Freeman, T. M., de Silva, T. I., Sheffield COVID-19 Genomics Group, McDanal, C., Perez, L. G., Tang, H., Moon-Walker, A., Whelan, S. P., LaBranche, C. C., Saphire, E. O., & Montefiori, D. C. (2020). Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell, 182(4), 812–827.e19. https://doi.org/10.1016/j.cell.2020.06.043
85. Kong, R., Yang, G. B., Xue, R., Liu, M., Wang, F., Hu, J. P., Guo, X. Q., & Chang, S. (2020). COVID-19 Docking server: a meta server for docking small molecules, peptides and antibodies against potential targets of COVID-19. Bioinformatics, 36(20), 5109–5111. https://doi.org/10.1093/bioinformatics/btaa645