Важность противовирусных препаратов, содержащих H₂S, в протоколах лечения COVID-19
https://doi.org/10.18093/0869-0189-2021-31-5-636-644
Аннотация
Целью исследования явилось предложение нового типа противовирусной терапии для больных COVID-19 в ожидании выведения на рынок разработанных вакцин в обход устойчивости к вакцинам новых мутаций вируса. Поиск средств для профилактики и ранней терапии был сосредоточен на низкомолекулярных препаратах или перепрофилировании безопасных пероральных недорогих препаратов, подходящих для применения в т. ч. в странах с низким уровнем доходов.
Материалы и методы. При поиске публикаций в рецензируемых журналах рассматривались работы о механизмах защиты от вируса, описанных у животных. Для дальнейшего подробного клинического анализа обнаружены 2 клинических исследования на следующие темы: 1) успешное применение высоких доз N-ацетилцистеина (NAC) при очень тяжелой пневмонии COVID-19; 2) подтверждение прогностической роли сывороточного уровня H2S (сероводорода) в организме хозяина.
Результаты. После объединения результатов указанных исследований поэтапно описаны 3 основных аспекта – как H2S работает при вирусных респираторных заболеваниях; как H2S воздействует на уязвимости вируса SARS-CoV-2 по крайней мере 3 типов; как и под действием каких лекарств вырабатывается H2S. Обнаружено более 3 десятков успешных примеров применения этого механизма с подробными клиническими данными.
Заключение. При использовании NAC в качестве донора H2S эндогенный противовирусный H2S реактивирует врожденный иммунитет, который противодействует COVID-19. С учетом того, что противовирусный H2S может быть включен в некоторые основные протоколы клинических испытаний, необходимы дальнейшие рандомизированные контролируемые исследования.
При поддержке: Автор благодарит компанию Van der Hallen & Sons за консультации и пристрастную вычитку этого документа.
Об авторе
Ed. J. van Hezik
Некоммерческая рабочая группа Waterfront at Sea
Нидерланды
Конфликт интересов:
Нидерланды
van Hezik E.J. – доктор медицины, старший внештатный пульмонолог
2235TD-10, Валкенбург
тел.: +3 (161) 829-92-09
Конфликт интересов:
В отношении этого исследования и рукописи конфликт интересов автором не заявлен.
Список литературы
1. RECOVERY Collaborative Group, Horby P., Lim W.S. et al. Dexamethasone in hospitalized patients with Covid-19. N. Engl. J. Med. 2021; 384 (8): 693–704. DOI: 10.1056/NEJMoa2021436.
2. Kuy S. et al. Retraction: cardiovascular disease, drug therapy, and mortality in Covid-19. N. Engl. J. Med. 2020; 382 (26): 2582 https://doi.org/10.1056/NEJMc2021225.
3. Moynihan R., Macdonald H., Bero L., Godlee F. Commercial influence and COVID-19. BMJ. 2020; 369: m2456. DOI: 10.1136/bmj.m2456.
4. Boulware D.R., Pullen M.F., Bangdiwala A.S. et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. N. Engl. J. Med. 2020; 383 (6): 517–525. DOI: 10.1056/NEJMoa2016638.
5. Korber B., Fischer W.M., Gnanakaran S. et al. Tracking changes in SARS-CoV-2 spike: Evidence that D614G increases infectivity of the COVID-19 virus. Cell. 2020; 182 (4): 812–827e19. DOI: 10.1016/j.cell.2020.06.043.
6. Fedson D.S. Treating the host response to emerging virus diseases: Lessons learned from sepsis, pneumonia, influenza and Ebola. Ann. Transl. Med. 2016; 4 (21): 421. DOI: 10.21037/atm.2016.11.03.
7. Renieris G., Katrini K., Damoulari C. et al. Serum hydrogen sulfide and outcome association in pneumonia by the SARSCoV- 2 coronavirus. Shock. 2020; 54 (5): 633–637. DOI: 10.1097/SHK.0000000000001562.
8. Wang R. Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J. 2002: 16 (13): 1792–1798. DOI: 10.1096/fj.02-0211hyp.
9. Marutani E., Ichinose F. Emerging pharmacological tools to control hydrogen sulfide signaling in critical illness. Intensive Care Med. Exp. 2020; 8 (1): 5. DOI: https://doi.org/10.1186/s40635-020-0296-4.
10. Li H., Ma Y., Escaffre O. et al. Role of hydrogen sulfide in paramyxovirus infections. J. Virol. 2015: 89 (10): 5557–5568. DOI: 10.1128/jvi.00264-15.
11. Bazhanov N., Escaffre O., Freiberg A. N. et al. Broad-range antiviral activity of hydrogen sulfide against highly pathogenic RNA viruses. Sci. Rep. 2017: 7: 41029. DOI: 10.1038/srep41029.
12. Bazhanov N., Ansar M., Ivanciuc T. et al. Hydrogen sulfide: A novel player in airway development, pathophysiology of respiratory diseases, and antiviral defenses. Am. J. Respir. Cell Mol. Biol. 2017; 57 (4): 403–410. DOI: 10.1165/rcmb.2017-0114TR.
13. Ivanciuc T., Sbrana E., Ansar M. et al. Hydrogen sulfide is an antiviral and antiinflammatory endogenous gasotransmitter in the airways. Role in respiratory syncytial virus infection. Am. J. Respir. Cell Mol. Biol. 2016; 55 (5): 684–696. DOI: 10.1165/rcmb.2015-0385OC.
14. Yang G. H2S as a potential defense against COVID-19? Am. J. Physiol. Cell Physiol. 2020; 319 (2): C244–249. DOI: 10.1152/ajpcell.00187.2020.
15. Evgen'ev M.B., Frenkel A. Possible application of H2S-producing compounds in therapy of coronavirus (COVID-19) infection and pneumonia. Cell Stress Chaperones. 2020; 25 (5): 713–715. DOI: 10.1007/s12192-020-01120-1.
16. Citi V., Martelli A., Brancaleone V. et al. Anti‐inflammatory and antiviral roles of hydrogen sulfide: Rationale for considering H2S donors in COVID‐19 therapy. Br. J. Pharmacol. 2020; 177 (21): 4931–4941. DOI: 10.1111/bph.15230.
17. Zanardo R. C., Brancaleone V., Distrutti E. et al. Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation. FASEB J. 2006; 20 (12): 2118–2120. DOI: 10.1096/fj.06-6270fje.
18. Ezerina D., Takano Y., Hanaoka K. et al. N-acetyl cysteine functions as a fast-acting antioxidant by triggering intracellular H2S and sulfane sulfur production. Cell Chem. Biol. 2018; 25 (4): 447–459e4. DOI: 10.1016/j.chembiol.2018.01.011.
19. Cerda M. M., Pluth M.D. S marks the spot: linking the antioxidant activity of N-acetyl cysteine to H2S and sulfane sulfur species. Cell Chem. Biol. 2018: 25 (4): 353–355. DOI: 10.1016/j.chembiol.2018.04.001.
20. Zhao H., Qu J., Li Q. et al. Taurine supplementation reduces neuroinflammation and protects against white matter injury after intracerebral hemorrhage in rats. Amino Acids. 2018; 50 (3-4): 439–451. DOI: 10.1007/s00726-0172529-8.
21. Di Nicolantonio J.J., O,Keefe J.H., McCarty M.F. Boosting endogenous production of vasoprotective hydrogen sulfide via supplementation with taurine and N-acetylcysteine: a novel way to promote cardiovascular health. Open Heart. 2017; 4 (1): e000600. DOI: 10.1136/openhrt-2017-000600.
22. Zuhra K., Tomé C.S., Masi L. et al. N-acetylcysteine serves as substrate of 3-Mercaptopyruvate sulfurtransferase and stimulates sulfide metabolism in colon cancer cells. Cells. 2019; 8 (8): 828. DOI: 10.3390/cells8080828.
23. Yadav P.K., Vitvitsky V., Carballal S. et al. Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically-relevant concentrations. J. Biol. Chem. 2020; 295 (19): 6299–6311. DOI: 10.1074/jbc.RA120.012616.
24. Sun Q., Wang B., Li Y. et al. Taurine supplementation lowers blood pressure and improves vascular function in prehypertension: randomized, double-blind, placebo-controlled study. Hypertension. 2016; 67 (3): 541–549. DOI: 10.1161/HYPERTENSIONAHA.115.06624.
25. Zaorska E., Tomasova L., Koszelewski D. et al. Hydrogen sulfide in pharmacotherapy, beyond the hydrogen sulfide-donors. Biomolecules. 2020; 10 (2): 323. DOI: 10.3390/biom10020323.
26. Kikkert M. Innate immune evasion by human respiratory RNA viruses. J. Innate Immun. 2020; 12 (1): 4–20. DOI: 10.1159/000503030.
27. Blanco-Melo D., Nilsson-Payant B.E., Liu W.C. et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020; 181 (5): 1036–1045.e9. DOI: 10.1016/j.cell.2020.04.026
28. Vardhana S.A., Wolchok J.D. The many faces of the anti-COVID immune response. J. Exp. Med. 2020; 217 (6): e20200678. DOI: 10.1084/jem.20200678.
29. Yang L., Liu S., Liu J. et al. COVID-19: immunopathogenesis and immunotherapeutics. Signal Transduct. Target. Ther. 2020; 5 (1): 128. DOI: 10.1038/s41392-020-00243-2.
30. Miller T.W., Wang E.A., Gould S. et al. Hydrogen sulfide is an endogenous potentiator of T cell activation. J. Biol. Chem. 2012; 287 (6): 4211–4221. DOI: 10.1074/jbc.M111.307819.
31. Thomas T., Stefanoni D., Reisz J.A. et al. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight. 2020; 5 (14): e140327. DOI: 10.1172/jci.insight.140327.
32. De Rosa S.C., Zaretsky M.D., Dubs J.G. et al. N-acetylcysteine replenishes glutathione in HIV infection. Eur. J. Clin. Invest. 2000; 30 (10): 915–929. DOI: 10.1046/j.1365-2362.2000.00736.x.
33. Dröge W. Cysteine and glutathione deficiency in AIDS patients: a rationale for the treatment with N-acetylcysteine. Pharmacology. 1993; 46 (2): 61–65. DOI: 10.1159/000139029.
34. Stipanuk M.H., Ueki I., Dominy J.E. et al. Cysteine dioxygenase: a robust system for regulation of cellular cysteine levels. Amino Acids. 2009; 37 (1): 55–63. DOI: 10.1007/s00726-008-0202-y.
35. da Costa L.S., Outlioua A., Anginot A. et al. RNA viruses promote activation of the NLRP3 inflammasome through cytopathogenic effect-induced potassium efflux. Cell Death Dis. 2019; 10 (5): 346. DOI: 10.1038/s41419-019-1579-0.
36. Castelblanco M., Lugrin J., Ehirchiou D. et al. Hydrogen sulfide inhibits NLRP3 inflammasome activation and reduces cytokine production both in vitro and in a mouse model of inflammation. J. Biol. Chem. 2018; 293 (7): 2546–2557. DOI: 10.1074/jbc.m117.806869.
37. Gattinoni L., Chiumello D., Rossi S. COVID-19 pneumonia: ARDS or not? Crit. Care. 2020; 24 (1): 154. DOI: 10.1186/s13054-020-02880-z.
38. Klok F.A., Kruip M.J.H.A., van der Meer N.J.M. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb. Res. 2020; 191: 145–147. DOI: 10.1016/j.thromres.2020.04.013.
39. Wang B., Yee Aw. T., Stokes K.Y. N-acetylcysteine attenuates systemic platelet activation and cerebral vessel thrombosis in diabetes. Redox Biology. 2018, 14, 218–228. DOI: 10.1016/j.redox.2017.09.005.
40. Hamming I., Timens W., Bulthuis M. et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol. 2004; 203 (2): 631–637. DOI: 10.1002/path.1570.
41. Lin Y., Zeng H., Gao L. et al. Hydrogen sulfide attenuates atherosclerosis in a partially ligated carotid artery mouse model via regulating angiotensin converting enzyme 2 expression. Front. Physiol. 2017; 8: 782. DOI: 10.3389/fphys.2017.00782.
42. van Goor H., van den Born J.C., Hillebrands J.L., Joles, J.A. Hydrogen sulfide in hypertension. Curr. Opin. Nephrol. Hypertens. 2016. 25 (2): 107–113. DOI: 10.1097/MNH.0000000000000206.
43. De Flora S., Balansky R., La Maestra S. Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19. FASEB J. 2020; 34 (10): 13185–13193. DOI: 10.1096/fj.202001807.
44. Madu I.G., Belouzard S., Whittaker G.R. SARS-coronavirus spike S2 domain flanked by cysteine residues C822 and C833 is important for activation of membrane fusion. Virology. 2009; 393 (2): 265–271. DOI: 10.1016/j.virol.2009.07.038.
45. Lai A.L., Millet J.K., Daniel S. et al. The SARS-CoV fusion peptide forms an extended bipartite fusion platform that perturbs membrane order in a calcium-dependent manner. J. Mol. Biol. 2017; 429 (24): 3875–3892. DOI: 10.1016/j.jmb.2017.10.017.
46. Gao Y., Yan L., Huang Y. et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science. 2020; 368 (6492): 779–782. DOI: 10.1126/science.abb7498.
47. Siddiqi H.K., Mehra M.R. COVID-19 Illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J. Heart Lung Transplantat. 2020; 39 (5): 405–407. DOI: 10.1016/j.healun.2020.03.012.
48. de Alencar J.C.G., Moreira C.L., Müller A.D. et al. Double-blind, randomized, placebo-controlled trial with N-acetylcysteine for treatment of severe acute respiratory syndrome caused by coronavirus disease 2019 (COVID-19). Clin. Infect. Dis. 2020; 72 (11): e736–741. DOI: 10.1093/cid/ciaa1443.
49. Li H., Mani S., Wu L. et al. The interaction of estrogen and CSE/ H2S pathway in the development of atherosclerosis. Am. J. Physiol. Heart Circ. Physiol. 2017; 312 (3): H406–414. DOI: 10.1152/ajpheart.00245.2016.
50. Jain M., Chandel N.S. Rethinking antioxidants in the intensive care unit. Am. J. Respir. Crit. Care Med. 2013; 188 (11): 1283–1285. DOI: 10.1164/rccm.201307-1380CP.
51. Whiteman M., Gooding K.M., Whatmore J.L. et al. Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide. Diabetologia. 2010; 53 (8): 1722–1726. DOI: 10.1007/s00125-010-1761-5.
52. Sekhar R.V., Patel S.G., Guthikonda A.P. et al. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am. J. Clin. Nutr. 2011; 94 (3): 847–853. DOI: 10.3945/ajcn.110.003483.
53. Dattilo M. The role of host defences in Covid 19 and treatments thereof. Mol. Med. 2020; 26 (1): 90. DOI: 10.1186/s10020-020-00216-9.
54. Ibrahim H., Perl A., Smith D. et al. Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine. Clin. Immunol. 2020; 219: 108544. DOI: 10.1016/j.clim.2020.108544.
55. Barbaro R.P., MacLaren G., Boonstra P.S. et al. Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the extracorporeal life support organization registry. Lancet. 2020; 396 (10257): 1071–1078. DOI: 10.1016/S0140-6736(20)32008-0.
56. Гайнитдинова В.В., Авдеев С.Н., Мержоева З.М. и др. Опыт применения N-ацетилцистеина в комплексном лечении среднетяжелой COVID-ассоциированной пневмонии. Пульмонология. 2021; 31 (1): 21–29. DOI: 10.18093/0869-0189-2021-31-1-21-29.
57. Horowitz R.I., Freeman P.R., Bruzzese J.J. Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases. Respir. Med. Case Rep. 2020; 30: 101063. DOI: 101063.doi:10.1016/j.rmcr.2020.101063.
58. Amatore D., Celestino I., Brundu S. et al. Glutathione increase by the n-butanoyl glutathione derivative (GSH-C4) inhibits viral replication and induces a predominant Th1 immune profile in old mice infected with influenza virus. FASEB Bioadv. 2019; 1 (5): 296–305. DOI: 10.1096/fba.2018-00066.
59. Puyo C., Kreig D., Saddi V. et al. Case Report: Use of hydroxychloroquine and N-acetylcysteine for treatment of a COVID-19 positive patient. F1000Research. 2020; 9: 491. DOI: 10.12688/f1000research.23995.1.
60. De Flora S., Grassi C., Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur. Respir. J. 1997; 10 (7): 1535–1541. DOI: 10.1183/09031936.97.10071535.
61. Lai K.Y., Ng W.Y., Osburga Chan P.K. High-dose N-acetylcysteine therapy for novel H1N1 influenza pneumonia. Ann. Intern. Med. 2010; 152 (10): 687–688. DOI: 10.7326/0003-4819-152-10-201005180-00017.
62. Garigliany M.M., Desmecht D.J. N-acetylcysteine lacks universal inhibitory activity against influenza A viruses. J. Negat. Results Biomed. 2011; 10: 5. DOI: 10.1186/1477-5751-10-5.
63. Hortin G.L., Landt M., Powderly W.G. Changes in plasma amino acid concentrations in response to HIV-1 infection. Clin. Chem. 1994; 40 (5): 785–789. DOI: 10.1093/clinchem/40.5.785.
64. de Quay B., Malinverni R., Lauterburg B.H. Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine. AIDS. 1992; 6 (8): 815–820. Available at: https://journals.lww.com/aidsonline/Abstract/1992/08000/Glutathione_depletion_in_HIV_infected_patients_.8.aspx
65. Poe F.L., Corn J. N-Acetylcysteine: A potential therapeutic agent for SARS-CoV-2. Med. Hypotheses. 2020; 143: 109862. DOI: 10.1016/j.mehy.2020.109862.
66. Olson K.R. Reactive oxygen species or reactive sulfur species: why we should consider the latter. J. Exp. Biol. 2020; 223 (Pt 4): jeb196352. DOI: 10.1242/jeb.196352.
67. van Hezik E.J. Adapted incremental treatment plan in COVID-19 - version nov 2020: poster. DOI: 10.13140/RG.2.2.19955.04643.
68. Innsamlingskontrollen. Drugs for Neglected Diseases initiative (DNDi). Available at: https://www.innsamlingskontrollen.no/organisasjoner/drugs-for-neglegted-diseases-initiative-dndi/
Рецензия
Для цитирования:
van Hezik E. Важность противовирусных препаратов, содержащих H₂S, в протоколах лечения COVID-19. Пульмонология. 2021;31(5):636-644. https://doi.org/10.18093/0869-0189-2021-31-5-636-644
For citation:
van Hezik E. Importance of antiviral H₂S in treatment protocols for COVID-19. PULMONOLOGIYA. 2021;31(5):636-644. (In Russ.) https://doi.org/10.18093/0869-0189-2021-31-5-636-644
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