Хемореактомный скрининг воздействия фармакологических препаратов на SARS-CoV-2 и виром человека как информационная основа для принятия решений по фармакотерапии COVID-19

Актуальность. Поиск эффективных и безопасных фармакологических подходов к лечению COVID-19 существенно затруднен в рамках так называемого рационального дизайна лекарств. Поэтому перспективно перепрофилирование лекарственных препаратов, зарегистрированных в анатомо-терапевтическо-химической классификации лекарств (АТХ).

Материал и методы. Перепрофилирование около 2700 препаратов из АТХ проводилось методом хемореактомного скрининга, моделирующего результаты ингибирования роста вирусов в культуре клеток, воздействия препаратов на виром человека и оценки их побочных эффектов. Информационная технология хемореактомного анализа основана на топологической теории распознавания, развиваемой в Институте фармакоинформатики при Федеральном исследовательском центре «Информатика и управление» Российской академии наук.

Результаты. Установлены 62 препарата и 20 микронутриентов, которые характеризуются выраженным противовирусным действием в сочетании с минимальными побочными эффектами. Сопоставление полученных результатов с данными фундаментальных и клинических исследований показало, что для 31 из 62 препаратов имеются независимые подтверждения целесообразности их использования для лечения COVID-19. Установленные препараты являются ингибиторами коронавирусных белков и/или молекулами- адаптогенами, улучшающими функционирование клеток в условиях стресса при вирусной инфекции. Среди изученных «антикоронавирусных» микронутриентов наилучшим профилем безопасности, в т.ч. минимальным воздействием на виром здоровых людей, обладал глюкозамина сульфат.

Заключение. Перепрофилирование лекарственных препаратов, зарегистрированных в АТХ, может существенно ускорить нахождение более эффективных и безопасных подходов к фармакотерапии COVID-19. Перспективно применение ряда микронутриентов в программах долговременной профилактики коронавирусной инфекции, особенно у пожилых.

1. Торшин И.Ю., Громова О.А. Микронутриенты против коронавирусов. М.: ГЭОТАР-Медиа; 2020.

2. Riva L., Yuan S., Yin X., et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature. 2020; 586 (7827): 113–9. https://doi.org/10.1038/s41586-020-2577-1.

3. Шендеров Б.А. Медицинская микробная экология и функциональное питание. Т. 3. Пробиотики и функциональное питание. М.: ГРАНТЪ; 2001.

4. Scarpellini E., Fagoonee S., Rinninella E., et al. Gut microbiota and liver interaction through immune system cross-talk: a comprehensive review at the time of the SARS-CoV-2 pandemic. J Clin Med. 2020; 9 (8): 2488. https://doi.org/10.3390/jcm9082488.

5. Громова О.А., Торшин И.Ю., Наумов А.В., Максимов В.А. Хемомикробиомный анализ глюкозамина сульфата, пребиотиков и нестероидных противовоспалительных препаратов. ФАРМАКО- ЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология. 2020; 13 (3): 270–82. https://doi.org/10.17749/2070-4909/farmakoekonomika.2020.049.

6. Kumata R., Ito J., Takahashi K., et al. A tissue level atlas of the healthy human virome. BMC Biol. 2020; 18 (1): 55. https://doi.org/10.1186/s12915-020-00785-5.

7. Xiang J., Wünschmann S., Diekema D.J., et al. Effect of coinfection with GB virus C on survival among patients with HIV infection. N Engl J Med. 2001; 345 (10): 707–14. https://doi.org/10.1056/NEJMoa003364.

8. Barton E.S., White D.W., Cathelyn J.S., et al. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature. 2007; 447 (7142): 326–9. https://doi.org/10.1038/nature05762.

9. Wang L., Candia J., Ma L., et al. Serological responses to human virome define clinical outcomes of italian patients infected with SARSCoV- 2.medRxiv. Version 1. medRxiv. Preprint. 2020 Sep 7. https://doi.org/10.1101/2020.09.04.20187088.

10. Torshin I.Yu., Rudakov K.V. On the application of the combinatorial theory of solvability to the analysis of chemographs. Part 1: Fundamentals of modern chemical bonding theory and the concept of the chemograph. Pattern Recognit Image Anal. 2014; 24: 11–23. https://doi.org/10.1134/S1054661814010209.

11. Torshin I.Yu., Rudakov K.V. On the application of the combinatorial theory of solvability to the analysis of chemographs: Part 2. Local completeness of invariants of chemographs in view of the combinatorial theory of solvability. Pattern Recognit Image Anal. 2014; 24: 196–208. https://doi.org/10.1134/S1054661814020151.

12. Bolton E., Wang Y., Thiessen P.A., Bryant S.H. PubChem: Integrated platform of small molecules and biological activities. Chapter 12. Ann Rep Comput Chem. 2008; 4: 217–41. https://doi.org/10.1016/S1574-1400(08)00012-1.

13. Wishart D.S., Tzur D., Knox C., et al. HMDB: the Human Metabolome Database. Nucleic Acids Res. 2007; 35 (Database issue): D521–6. https://doi.org/10.1093/nar/gkl923.

14. Mering C., Jensen L., Snel B., et al. STRING: known and predicted protein–protein associations, integrated and transferred across organisms. Nucleic Acids Res. 2005; 33 (Database issue): D433–7. https://doi.org/10.1093/nar/gki005.

15. . Torshin I.Yu, Rudakov K.V. On the procedures of generation of numerical features over partitions of sets of objects in the problem of predicting numerical target variables. Pattern Recognit Image Anal. 2019; 29 (4): 654–67. https://doi.org/10.1134/S1054661819040175.

16. Kuhn M., Letunic I., Jensen L.J., Bork P. The SIDER database of drugs and side effects. Nucleic Acids Res. 2016; 44 (D1): D1075–9. https://doi.org/10.1093/nar/gkv1075.

17. Balakrishnan V., Lakshminarayanan K. Screening of FDA approved drugs against SARS-CoV-2 main protease: coronavirus disease. Int J Pept Res Thers. 2020; Sep 28: 1–8. https://doi.org/10.1007/s10989-020-10115-6.

18. Kneller D.W., Galanie S., Phillips G., et al. Malleability of the SARSCoV- 2 3CL Mpro active-site cavity facilitates binding of clinical antivirals. Structure. 2020; 28 (12): 1313–20e3. https://doi.org/10.1016/j.str.2020.10.007.

19. Bollo L., Guerra T., Bavaro D.F., et al. Seroconversion and indolent course of COVID-19 in patients with multiple sclerosis treated with fingolimod and teriflunomide. J Neurol Sci. 2020; 416: 117011. https://doi.org/10.1016/j.jns.2020.117011.

20. Mallucci G., Zito A., Fabbro B.D., Bergamaschi R. Asymptomatic SARS-CoV-2 infection in two patients with multiple sclerosis treated with fingolimod. Mult Scler Relat Disord. 2020; 45: 102414. https://doi.org/10.1016/j.msard.2020.102414.

21. Gomez-Mayordomo V., Montero-Escribano P., Matías-Guiu J.A., et al. Clinical exacerbation of SARS-CoV2 infection after fingolimod withdrawal. J Med Virol. 2021: 93 (1): 546–9. https://doi.org/10.1002/jmv.26279.

22. Ciardi M.R., Zingaropoli M.A., Pasculli P., et al. The peripheral blood immune cell profile in a teriflunomide-treated multiple sclerosis patient with COVID-19 pneumonia. J Neuroimmunol. 2020; 346: 577323. https://doi.org/10.1016/j.jneuroim.2020.577323.

23. Ortega J.T., Serrano M.L., Jastrzebska B. Class A G protein-coupled receptor antagonist famotidine as a therapeutic alternative against SARS-CoV2: an in silico analysis. Biomolecules. 2020; 10 (6): 954. https://doi.org/10.3390/biom10060954.

24. Hogan Ii RB, Hogan Iii RB, Cannon T, et al. Dual-histamine receptor blockade with cetirizine – famotidine reduces pulmonary symptoms in COVID-19 patients. Pulm Pharmacol Ther. 2020; 63: 101942. https://doi.org/10.1016/j.pupt.2020.101942.

25. Freedberg D.E., Conigliaro J., Wang T.C., et al. Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: a propensity score matched retrospective cohort study. Gastroenterology. 2020; 159 (3): 1129–31.e3. https://doi.org/10.1053/j.gastro.2020.05.053.

26. Patel M., Dominguez E., Sacher D., et al. Etoposide as salvage therapy for cytokine storm due to coronavirus disease 2019. Chest. 2021; 159 (1): e7–11. https://doi.org/10.1016/j.chest.2020.09.077.

27. Takami A. Possible role of low-dose etoposide therapy for hemophagocytic lymphohistiocytosis by COVID-19. Int J Hematol. 2020; 112 (1): 122–4. https://doi.org/10.1007/s12185-020-02888-9.

28. Smetana K. Jr., Rosel D., BrÁbek J. Raloxifene and Bazedoxifene could be promising candidates for preventing the COVID-19 related cytokine storm, ARDS and mortality. In Vivo. 2020; 34 (5): 3027–8. https://doi.org/10.21873/invivo.12135.

29. Olagnier D., Farahani E., Thyrsted J., et al. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and antiinflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat Commun. 2020; 11 (1): 4938. https://doi.org/10.1038/s41467-020-18764-3.

30. Fatima S.A., Asif M., Khan K.A., et al. Comparison of efficacy of dexamethasone and methylprednisolone in moderate to severe covid 19 disease. Ann Med Surg (Lond). 2020; 60: 413–6. https://doi.org/10.1016/j.amsu.2020.11.027.

31. Rana M.A., Hashmi M., Qayyum A., et al. Comparison of efficacy of dexamethasone and methylprednisolone in improving PaO2/FiO2 ratio among COVID-19 patients. Cureus. 2020; 12 (10): e10918. https://doi.org/10.7759/cureus.10918.

32. Badawy A.A. Immunotherapy of COVID-19 with poly (ADP-ribose) polymerase inhibitors: starting with nicotinamide. Biosci Rep. 2020; 40 (10): BSR20202856. https://doi.org/10.1042/BSR20202856.

33. Kim J., Ochoa M.T., Krutzik S.R., et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol. 2002; 169 (3): 1535–41. https://doi.org/10.4049/jimmunol.169.3.1535.

34. Ten Hove A.S., Brinkman D.J., Li Yim A.Y., et al. The role of nicotinic receptors in SARS-CoV-2 receptor ACE2 expression in intestinal epithelia. Bioelectron Med. 2020; 6: 20. https://doi.org/10.1186/s42234-020-00057-1.

35. Oliveira A.S., Ibarra A.A., Bermudez I., et al. Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors. Version 3. bioRxiv. Preprint. NaN NaN [revised 2020 Sep 14]. https://doi.org/10.1101/2020.07.16.206680.

36. Blasco H., Bessy C., Plantier L., et al. The specific metabolome profiling of patients infected by SARS-COV-2 supports the key role of tryptophan-nicotinamide pathway and cytosine metabolism. Sci Rep. 2020; 10 (1): 16824. https://doi.org/10.1038/s41598-020-73966-5.

37. Farsalinos K., Eliopoulos E., Leonidas D.D., et al. Nicotinic cholinergic system and COVID-19: in silico identification of an interaction between SARS-CoV-2 and nicotinic receptors with potential therapeutic targeting implications. Int J Mol Sci. 2020; 21 (16): 5807. https://doi.org/10.3390/ijms21165807.

38. Ghiasvand F., Ghadimi M., Sadr S., et al. COVID-19 treatment success after repeat courses of azithromycin: a report of three cases. Infect Disord Drug Targets. 2020; Nov 26. https://doi.org/10.2174/1871526520999201126203510.

39. Du X., Zuo X., Meng F., et al. Direct inhibitory effect on viral entry of influenza A and SARS-CoV-2 viruses by azithromycin. Cell Prolif. 2021; 54 (1): e12953. https://doi.org/10.1111/cpr.12953.

40. Renteria A.E., Mfuna Endam L., Adam D., et al. Azithromycin downregulates gene expression of IL-1β and pathways involving TMPRSS2 and TMPRSS11D required by SARS-CoV-2. Am J Respir Cell Mol Biol. 2020; 63 (5): 707–9. https://doi.org/10.1165/rcmb.2020-0285LE.

41. Ulrich H., Pillat M.M. CD147 as a target for COVID-19 treatment: suggested effects of azithromycin and stem cell engagement. Stem Cell Rev Rep. 2020; 16 (3): 434–40. https://doi.org/10.1007/s12015-020-09976-7.

42. Scherrmann J.M. Possible role of ABCB1 in lysosomal accumulation of azithromycin in COVID-19 therapy. Clin Pharmacol Ther. 2020; 108: 201–11. https://doi.org/10.1002/cpt.2020.

43. Maggio R., Corsini G.U. Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection. Pharmacol Res. 2020; 157: 104837. https://doi.org/10.1016/j.phrs.2020.104837.

44. Ansarin K., Tolouian R., Ardalan M., et al. Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: a randomized clinical trial. Bioimpacts. 2020; 10 (4): 209–15. https://doi.org/10.34172/bi.2020.27.

45. Bradfute S.B., Ye C., Clarke E.C., et al. Ambroxol and ciprofloxacin show activity against SARS-CoV2 in Vero E6 cells at clinically-relevant concentrations. Version 1. bioRxiv. Preprint. 2020 Aug 11. https://doi.org/10.1101/2020.08.11.245100.

46. Olaleye O.A., Kaur M., Onyenaka C.C. Ambroxol hydrochloride inhibits the interaction between severe acute respiratory syndrome coronavirus 2 spike protein's receptor binding domain and recombinant human ACE2. bioRxiv. Preprint. 2020 Sep 14:2020.09.13.295691. https://doi.org/10.1101/2020.09.13.295691.

47. Kumar P. Co-aerosolized pulmonary surfactant and ambroxol for COVID-19 ARDS intervention: what are we waiting for? Front Bioeng Biotechnol. 2020; 8: 577172. https://doi.org/10.3389/fbioe.2020.577172.

48. Brenner S.R. The potential of memantine and related adamantanes such as amantadine, to reduce the neurotoxic effects of COVID-19, including ARDS and to reduce viral replication through lysosomal effects. J Med Virol. 2020; 92 (1): 2341–2. https://doi.org/10.1002/jmv.26030.

49. Jiménez-Jiménez F.J., Alonso-Navarro H., García-Martín E., Agúndez J.A. Anti-inflammatory effects of amantadine and memantine: possible therapeutics for the treatment of COVID-19? J Pers Med. 2020; 10 (4): 217. https://doi.org/10.3390/jpm10040217.

50. Aranda-Abreu G.E., Aranda-Martínez J.D., Araújo R., et al. Observational study of people infected with SARS-Cov-2, treated with amantadine. Pharmacol Rep. 2020; 72 (6): 1538–41. https://doi.org/10.1007/s43440-020-00168-1.

51. Singh Tomar P.P., Arkin I.T. SARS-CoV-2 E protein is a potential ion channel that can be inhibited by Gliclazide and Memantine. Biochem Biophys Res Commun. 2020; 530 (1): 10–4. https://doi.org/10.1016/j.bbrc.2020.05.206.

52. Hasanagic S., Serdarevic F. Potential role of memantine in the prevention and treatment of COVID-19: its antagonism of nicotinic acetylcholine receptors and beyond. Eur Respir J. 2020; 56 (2): 2001610. https://doi.org/10.1183/13993003.01610-2020.

53. Risner K.H., Tieu K.V., Wang Y., et al. Maraviroc inhibits SARSCoV- 2 multiplication and s-protein mediated cell fusion in cell culture. bioRxiv. Preprint. 2020 Aug 13:2020.08.12.246389. https://doi.org/10.1101/2020.08.12.246389.

54. Shamsi A., Mohammad T., Anwar S., et al. Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: possible implication in COVID-19 therapy. Biosci Rep. 2020; 40 (6): BSR20201256. https://doi.org/10.1042/BSR20201256.

55. Tariq A., Mateen R.M., Afzal M.S., Saleem M. Paromomycin: a potential dual targeted drug effectively inhibits both spike (S1) and main protease of COVID-19. Int J Infect Dis. 2020; 98: 166–75. https://doi.org/10.1016/j.ijid.2020.06.063.

56. Bolelli K., Ertan-Bolelli T., Unsalan O., Altunayar-Unsalan C. Fenoterol and dobutamine as COVID-19 main protease inhibitors: a virtual screening study. J Mol Struct. 2021; 1228: 129449. https://doi.org/10.1016/j.molstruc.2020.129449.

57. Bagheri M., Niavarani A. Molecular dynamics analysis predicts ritonavir and naloxegol strongly block the SARS-CoV-2 spike proteinhACE2 binding. J Biomol Struct Dyn. 2020; Oct 8: 1–10. https://doi.org/10.1080/07391102.2020.1830854.

58. Scalise M, Indiveri C. Repurposing nimesulide, a potent inhibitor of the B0AT1 subunit of the SARS-CoV-2 receptor, as a therapeutic adjuvant of COVID-19. SLAS Discov. 2020; 25 (10): 1171–3. https://doi.org/10.1177/2472555220934421.

59. Peng H., Chen Z., Wang Y., et al. Systematic review and pharmacological considerations for chloroquine and its analogs in the treatment for COVID-19. Front Pharmacol. 2020; 11: 554172. https://doi.org/10.3389/fphar.2020.554172.

60. Li G., Yuan M., Li H., et al. Safety and efficacy of artemisininpiperaquine for treatment of COVID-19: an open-label, non-randomised and controlled trial. Int J Antimicrob Agents. 2021; 57 (1): 106216. https://doi.org/10.1016/j.ijantimicag.2020.106216.

61. Fragoso-Saavedra S., Iruegas-Nunez D.A., Quintero-Villegas A., et al. A parallel-group, multicenter randomized, double-blinded, placebo-controlled, phase 2/3, clinical trial to test the efficacy of pyridostigmine bromide at low doses to reduce mortality or invasive mechanical ventilation in adults with severe SARS-CoV-2 infection: the pyridostigmine in severe COVID-19 (PISCO) trial protocol. BMC Infect Dis. 2020; 20 (1): 765. https://doi.org/10.1186/s12879-020-05485-7.

62. Aliter K.F., Al-Horani R.A. Thrombin inhibition by argatroban: potential therapeutic benefits in COVID-19. Cardiovasc Drugs Ther. 2021; 35: 195–203. https://doi.org/10.1007/s10557-020-07066-x.

63. Habibzadeh P., Mofatteh M., Ghavami S., Roozbeh J. The potential effectiveness of acetazolamide in the prevention of acute kidney injury in COVID-19: a hypothesis. Eur J Pharmacol. 2020; 888: 173487. https://doi.org/10.1016/j.ejphar.2020.173487.

64. Unal G., Turan B., Balcioglu Y.H. Immunopharmacological management of COVID-19: potential therapeutic role of valproic acid. Med Hypotheses. 2020; 143: 109891. https://doi.org/10.1016/j.mehy.2020.109891.

65. Revannasiddaiah S., Kumar Devadas S., Palassery R., et al. A potential role for cyclophosphamide in the mitigation of acute respiratory distress syndrome among patients with SARS-CoV-2. Med Hypotheses. 2020; 144: 109850. https://doi.org/10.1016/j.mehy.2020.109850.

66. Cure E., Cumhur Cure M. Can dapagliflozin have a protective effect against COVID-19 infection? A hypothesis. Diabetes Metab Syndr. 2020; 14 (4): 405–6. https://doi.org/10.1016/j.dsx.2020.04.024.

67. Lee D.Y., Lin T.E., Lee C.I., et al. MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases. Proc Natl Acad Sci USA. 2017; 114 (8): 2072–7. https://doi.org/10.1073/pnas.1621425114.

68. Uzzan M., Soudan D., Peoc'h K., et al. Patients with COVID-19 present with low plasma citrulline concentrations that associate with systemic inflammation and gastrointestinal symptoms. Dig Liver Dis. 2020; 52 (10): 1104–5. https://doi.org/10.1016/j.dld.2020.06.042.

69. Торшин И.Ю., Громова О.А., Федотова Л.Э., и др. Хемореактомный анализ молекул цитруллина и малата. Неврология, нейропсихиатрия, психосоматика. 2017; 9 (2): 30–5. https://doi.org/10.14412/2074-2711-2017-2-30-35.

70. Legendre F., Bauge C., Roche R., et al. Chondroitin sulfate modulation of matrix and inflammatory gene expression in IL-1betastimulated chondrocytes-study in hypoxic alginate bead cultures. Osteoarthritis Cartilage. 2008; 16: 105–14. https://doi.org/10.1016/j.joca.2007.05.020.

71. Campo G., Avenoso A., Campo S., et al. Glycosaminoglycans reduced inflammatory response by modulating toll-like receptor-4 in LPS-stimulated chondrocytes. Arch Biochem Biophys. 2009; 491: 7–15. https://doi.org/10.1016/j.abb.2009.09.017.

72. Kwon P.S., Oh H., Kwon SJ., et al. Sulfated polysaccharides effectively inhibit SARS-CoV-2 in vitro. Cell Discov. 2020; 6: 50. https://doi.org/10.1038/s41421-020-00192-8.

73. Ferreira A.O., Polonini H.C., Dijkers E.C. Postulated adjuvant therapeutic strategies for COVID-19. J Pers Med. 2020; 10 (3): 80. https://doi.org/10.3390/jpm10030080.

74. DiNicolantonio J., Barroso-Aranda J., McCarty M. Azithromycin and glucosamine may amplify the type 1 interferon response to RNA viruses in a complementary fashion. Immunology Letters. 2020; 228: 83–5. https://doi.org/10.1016/j.imlet.2020.09.008.

75. Громова О.А., Торшин И.Ю., Федотова Л.Э. Геронтоинформационный анализ свойств молекулы мексидола. Неврология, нейропсихиатрия, психосоматика. 2017; 9 (4): 46–54. http://doi.org/10.14412/2074-2711-2017-4-46-54.

76. Торшин И.Ю., Лила А.М., Лиманова О.А., Громова О.А. Перспективы применения хондроитина сульфата и глюкозамина сульфата при остеоартрите в сочетании с патологией почек и мочевыделительной системы. ФАРМАКОЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология. 2020; 13 (1): 23–34. https://doi.org/10.17749/2070-4909.2020.13.1.23-34.