Вопросы вирусологии. 2022; 67: 126-132
Бромгексин как потенциальный препарат против COVID-19: от гипотезы к клиническим исследованиям
https://doi.org/10.36233/0507-4088-106Аннотация
Новая коронавирусная инфекция (COVID-19), вызываемая вирусом SARS-CoV-2, имеет различные клинические проявления и несколько механизмов патогенеза. Хотя для борьбы с COVID-19 используется целый ряд терапевтических подходов, ни один из препаратов не является эффективным лекарством. Трансмембранная сериновая протеаза 2 (TMPRSS2) является протеазой, играющей ключевую роль в проникновении SARS-CoV-2 в клетку. После присоединения спайкового (S) белка вируса к рецептору на поверхности клетки – ангиотензинпревращающему ферменту 2 (ACE2), TMPRSS2 процессирует и активирует S-белок на поверхности эпителиальной клетки. В результате происходит слияние мембран клетки и вирусной оболочки. Бромгексин является специфичным ингибитором TMPRSS2, потенциально способным подавлять жизненный цикл SARS-CoV-2. В настоящее время в нескольких клинических исследованиях проводится оценка эффективности бромгексина у пациентов с COVID-19. Результаты этих исследований показывают, что бромгексин позволяет улучшать клинические исходы COVID-19 и обладает профилактическим действием, ингибируя TMPRSS2 и проникновение вируса в клетку. Бромгексин в качестве монотерапии не позволяет лечить все симптомы инфекции, вызванной SARS-CoV-2. Однако он может выступать как эффективное дополнение для профилактики и терапии прогрессирования заболевания в сочетании с другими препаратами, используемыми для лечения COVID-19. Необходимы дальнейшие исследования для оценки эффективности бромгексина при COVID-19.
Список литературы
1. De Wit E., van Doremalen N., Falzarano D., Munster V.J. SARS and MERS: recent insights into emerging coronaviruses. Nat. Rev. Microbiol. 2016; 14(8): 523–34. https://doi.org/10.1038/nrmicro.2016.81
2. Harrison A.G., Lin T., Wang P. Mechanisms of SARS-CoV-2 transmission and pathogenesis. Trends Immunol. 2020; 41(12): 1100–15. https://doi.org/10.1016/j.it.2020.10.004
3. Cameroni E., Bowen J.E., Rosen L.E., Saliba C., Zepeda S.K., Culap K., et al. Broadly neutralizing antibodies overcome SARSCoV-2 Omicron antigenic shift. Nature. 2022; 602(7898): 664–70. https://doi.org/10.1038/s41586-021-04386-2
4. Depfenhart M., de Villiers D., Lemperle G., Meyer M., Di Somma S. Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy? Intern. Emerg. Med. 2020; 15(5): 801–12. https://doi.org/10.1007/s11739-020-02383-3
5. To K.K., Tsang O.T., Leung W.S., Tam A.R., Wu T.C., Lung D.C., et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARSCoV-2: an observational cohort study. Lancet Infect. Dis. 2020; 20(5): 565–74. https://doi.org/10.1016/s1473-3099(20)30196-1
6. Niknam Z., Jafari A., Golchin A., Danesh Pouya F., Nemati M., Rezaei-Tavirani M., et al. Potential therapeutic options for COVID-19: an update on current evidence. Eur. J. Med. Res. 2022; 27(1): 6. https://doi.org/10.1186/s40001-021-00626-3
7. Grove J., Marsh M. The cell biology of receptor-mediated virus entry. J. Cell Biol. 2011; 195(7): 1071–82. https://doi.org/10.1083/jcb.201108131
8. Weiss S.R., Navas-Martin S. Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol. Mol. Biol. Rev. 2005; 69(4): 635–64. https://doi.org/10.1128/mmbr.69.4.635-664.2005
9. Huang Y., Yang C., Xu X.F., Xu W., Liu S.W. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol. Sin. 2020; 41(9): 1141–9. https://doi.org/10.1038/s41401-020-0485-4
10. Astuti I., Ysrafil. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response. Diabetes Metab. Syndr. 2020; 14(4): 407–12. https://doi.org/10.1016/j.dsx.2020.04.020
11. Zhang H., Penninger J.M., Li Y., Zhong N., Slutsky A.S. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020; 46(4): 586–90. https://doi.org/10.1007/s00134-020-05985-9
12. Gheblawi M., Wang K., Viveiros A., Nguyen Q., Zhong J.C., Turner A.J., et al. Angiotensin-converting enzyme 2: SARSCoV-2 receptor and regulator of the renin-angiotensin system: Celebrating the 20th anniversary of the discovery of ACE2. Circ. Res. 2020; 126(10): 1456–74. https://doi.org/10.1161/circresaha.120.317015
13. Wu C., Liu Y., Yang Y., Zhang P., Zhong W., Wang Y., et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm. Sin. B. 2020; 10(5): 766–88. https://doi.org/10.1016/j.apsb.2020.02.008
14. Sisay M. 3CL(pro) inhibitors as a potential therapeutic option for COVID-19: Available evidence and ongoing clinical trials. Pharmacol. Res. 2020; 156: 104779. https://doi.org/10.1016/j.phrs.2020.104779
15. Sonawane K.D., Barale S.S., Dhanavade M.J., Waghmare S.R., Nadaf N.H., Kamble S.A., et al. Structural insights and inhibition mechanism of TMPRSS2 by experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride to control SARS-coronavirus-2: A molecular modeling approach. Inform. Med. Unlocked. 2021; 24: 100597. https://doi.org/10.1016/j.imu.2021.100597
16. Hoffmann M., Schroeder S., Kleine-Weber H., Müller M.A., Drosten C., Pöhlmann S. Nafamostat mesylate blocks activation of SARS-CoV-2: New treatment option for COVID-19. Antimicrob. Agents Chemother. 2020; 64(6): e00754-20. https://doi.org/10.1128/aac.00754-20
17. Yamamoto M., Matsuyama S., Li X., Takeda M., Kawaguchi Y., Inoue J.I., et al. Identification of nafamostat as a potent inhibitor of Middle East respiratory syndrome coronavirus S protein-mediated membrane fusion using the split-protein-based cell-cell fusion assay. Antimicrob. Agents Chemother. 2016; 60(11): 6532–9. https://doi.org/10.1128/aac.01043-16
18. Hoffmann M., Hofmann-Winkler H., Smith J.C., Krüger N., Arora P., Sørensen L.K., et al. Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine. 2021; 65: 103255. https://doi.org/10.1016/j.ebiom.2021.103255
19. Zanasi A., Mazzolini M., Kantar A. A reappraisal of the mucoactive activity and clinical efficacy of bromhexine. Multidiscip. Respir. Med. 2017; 12: 7. https://doi.org/10.1186/s40248-017-0088-1
20. Lucas J.M., Heinlein C., Kim T., Hernandez S.A., Malik M.S., True L.D., et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov. 2014; 4(11): 1310–25. https://doi.org/10.1158/2159-8290.Cd-13-1010
21. Shen L.W., Mao H.J., Wu Y.L., Tanaka Y., Zhang W. TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Biochimie. 2017; 142: 1–10. https://doi.org/10.1016/j.biochi.2017.07.016
22. Rimsza M.E., Newberry S. Unexpected infant deaths associated with use of cough and cold medications. Pediatrics. 2008; 122(2): e318–22. https://doi.org/10.1542/peds.2007-3813
23. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223): 497–506. https://doi.org/10.1016/S0140-6736(20)30183-5
24. Ansarin K., Tolouian R., Ardalan M., Taghizadieh A., Varshochi M., Teimouri S., 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
25. Li T., Sun L., Zhang W., Zheng C., Jiang C., Chen M., et al. Bromhexine hydrochloride tablets for the treatment of moderate COVID-19: an open-label randomized controlled pilot study. Clin. Transl. Sci. 2020; 13(6): 1096–102. https://doi.org/10.1111/cts.12881
26. Мареев В.Ю., Орлова Я.А., Плисюк А.Г., Павликова Е.П., Мацкеплишвили С.Т., Акопян Ж.А., и др. Результаты открытого проспективного контролируемого сравнительного исследования по лечению новой коронавирусной инфекции (COVID-19): Бромгексин И Спиронолактон для лечения КоронаВирусной Инфекции, Требующей госпитализации (БИСКВИТ). Кардиология. 2020; 60(11): 4–15. https://doi.org/10.18087/cardio.2020.11.n1440
27. Granados-Montiel J., Hazan-Lasri E., Franco-Cendejas R., ChávezHeres T., Silva-Bermudez P., Aguilar-Gaytán R., et al. New prophylaxis regimen for SARS-CoV-2 infection in health professionals with low doses of hydroxychloroquine and bromhexine: a randomised, double-blind placebo clinical trial (ELEVATE Trial). BMJ Open. 2021; 11(8): e045190. https://doi.org/10.1136/bmjopen-2020-045190
Problems of Virology. 2022; 67: 126-132
Bromhexine is a potential drug for COVID-19; From hypothesis to clinical trials
https://doi.org/10.36233/0507-4088-106Abstract
COVID-19 (novel coronavirus disease 2019), caused by the SARS-CoV-2 virus, has various clinical manifestations and several pathogenic pathways. Although several therapeutic options have been used to control COVID-19, none of these medications have been proven to be a definitive cure. Transmembrane serine protease 2 (TMPRSS2) is a protease that has a key role in the entry of SARS-CoV-2 into host cells. Following the binding of the viral spike (S) protein to the angiotensin-converting enzyme 2 (ACE2) receptors of the host cells, TMPRSS2 processes and activates the S protein on the epithelial cells. As a result, the membranes of the virus and host cell fuse. Bromhexine is a specific TMPRSS2 inhibitor that potentially inhibits the infectivity cycle of SARS-CoV-2. Moreover, several clinical trials are evaluating the efficacy of bromhexine in COVID-19 patients. The findings of these studies have shown that bromhexine is effective in improving the clinical outcomes of COVID-19 and has prophylactic effects by inhibiting TMPRSS2 and viral penetration into the host cells. Bromhexine alone cannot cure all of the symptoms of SARS-CoV-2 infection. However, it could be an effective addition to control and prevent the disease progression along with other drugs that are used to treat COVID-19. Further studies are required to investigate the efficacy of bromhexine in COVID-19.
References
1. De Wit E., van Doremalen N., Falzarano D., Munster V.J. SARS and MERS: recent insights into emerging coronaviruses. Nat. Rev. Microbiol. 2016; 14(8): 523–34. https://doi.org/10.1038/nrmicro.2016.81
2. Harrison A.G., Lin T., Wang P. Mechanisms of SARS-CoV-2 transmission and pathogenesis. Trends Immunol. 2020; 41(12): 1100–15. https://doi.org/10.1016/j.it.2020.10.004
3. Cameroni E., Bowen J.E., Rosen L.E., Saliba C., Zepeda S.K., Culap K., et al. Broadly neutralizing antibodies overcome SARSCoV-2 Omicron antigenic shift. Nature. 2022; 602(7898): 664–70. https://doi.org/10.1038/s41586-021-04386-2
4. Depfenhart M., de Villiers D., Lemperle G., Meyer M., Di Somma S. Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy? Intern. Emerg. Med. 2020; 15(5): 801–12. https://doi.org/10.1007/s11739-020-02383-3
5. To K.K., Tsang O.T., Leung W.S., Tam A.R., Wu T.C., Lung D.C., et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARSCoV-2: an observational cohort study. Lancet Infect. Dis. 2020; 20(5): 565–74. https://doi.org/10.1016/s1473-3099(20)30196-1
6. Niknam Z., Jafari A., Golchin A., Danesh Pouya F., Nemati M., Rezaei-Tavirani M., et al. Potential therapeutic options for COVID-19: an update on current evidence. Eur. J. Med. Res. 2022; 27(1): 6. https://doi.org/10.1186/s40001-021-00626-3
7. Grove J., Marsh M. The cell biology of receptor-mediated virus entry. J. Cell Biol. 2011; 195(7): 1071–82. https://doi.org/10.1083/jcb.201108131
8. Weiss S.R., Navas-Martin S. Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol. Mol. Biol. Rev. 2005; 69(4): 635–64. https://doi.org/10.1128/mmbr.69.4.635-664.2005
9. Huang Y., Yang C., Xu X.F., Xu W., Liu S.W. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol. Sin. 2020; 41(9): 1141–9. https://doi.org/10.1038/s41401-020-0485-4
10. Astuti I., Ysrafil. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response. Diabetes Metab. Syndr. 2020; 14(4): 407–12. https://doi.org/10.1016/j.dsx.2020.04.020
11. Zhang H., Penninger J.M., Li Y., Zhong N., Slutsky A.S. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020; 46(4): 586–90. https://doi.org/10.1007/s00134-020-05985-9
12. Gheblawi M., Wang K., Viveiros A., Nguyen Q., Zhong J.C., Turner A.J., et al. Angiotensin-converting enzyme 2: SARSCoV-2 receptor and regulator of the renin-angiotensin system: Celebrating the 20th anniversary of the discovery of ACE2. Circ. Res. 2020; 126(10): 1456–74. https://doi.org/10.1161/circresaha.120.317015
13. Wu C., Liu Y., Yang Y., Zhang P., Zhong W., Wang Y., et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm. Sin. B. 2020; 10(5): 766–88. https://doi.org/10.1016/j.apsb.2020.02.008
14. Sisay M. 3CL(pro) inhibitors as a potential therapeutic option for COVID-19: Available evidence and ongoing clinical trials. Pharmacol. Res. 2020; 156: 104779. https://doi.org/10.1016/j.phrs.2020.104779
15. Sonawane K.D., Barale S.S., Dhanavade M.J., Waghmare S.R., Nadaf N.H., Kamble S.A., et al. Structural insights and inhibition mechanism of TMPRSS2 by experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride to control SARS-coronavirus-2: A molecular modeling approach. Inform. Med. Unlocked. 2021; 24: 100597. https://doi.org/10.1016/j.imu.2021.100597
16. Hoffmann M., Schroeder S., Kleine-Weber H., Müller M.A., Drosten C., Pöhlmann S. Nafamostat mesylate blocks activation of SARS-CoV-2: New treatment option for COVID-19. Antimicrob. Agents Chemother. 2020; 64(6): e00754-20. https://doi.org/10.1128/aac.00754-20
17. Yamamoto M., Matsuyama S., Li X., Takeda M., Kawaguchi Y., Inoue J.I., et al. Identification of nafamostat as a potent inhibitor of Middle East respiratory syndrome coronavirus S protein-mediated membrane fusion using the split-protein-based cell-cell fusion assay. Antimicrob. Agents Chemother. 2016; 60(11): 6532–9. https://doi.org/10.1128/aac.01043-16
18. Hoffmann M., Hofmann-Winkler H., Smith J.C., Krüger N., Arora P., Sørensen L.K., et al. Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine. 2021; 65: 103255. https://doi.org/10.1016/j.ebiom.2021.103255
19. Zanasi A., Mazzolini M., Kantar A. A reappraisal of the mucoactive activity and clinical efficacy of bromhexine. Multidiscip. Respir. Med. 2017; 12: 7. https://doi.org/10.1186/s40248-017-0088-1
20. Lucas J.M., Heinlein C., Kim T., Hernandez S.A., Malik M.S., True L.D., et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov. 2014; 4(11): 1310–25. https://doi.org/10.1158/2159-8290.Cd-13-1010
21. Shen L.W., Mao H.J., Wu Y.L., Tanaka Y., Zhang W. TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Biochimie. 2017; 142: 1–10. https://doi.org/10.1016/j.biochi.2017.07.016
22. Rimsza M.E., Newberry S. Unexpected infant deaths associated with use of cough and cold medications. Pediatrics. 2008; 122(2): e318–22. https://doi.org/10.1542/peds.2007-3813
23. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223): 497–506. https://doi.org/10.1016/S0140-6736(20)30183-5
24. Ansarin K., Tolouian R., Ardalan M., Taghizadieh A., Varshochi M., Teimouri S., 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
25. Li T., Sun L., Zhang W., Zheng C., Jiang C., Chen M., et al. Bromhexine hydrochloride tablets for the treatment of moderate COVID-19: an open-label randomized controlled pilot study. Clin. Transl. Sci. 2020; 13(6): 1096–102. https://doi.org/10.1111/cts.12881
26. Mareev V.Yu., Orlova Ya.A., Plisyuk A.G., Pavlikova E.P., Matskeplishvili S.T., Akopyan Zh.A., i dr. Rezul'taty otkrytogo prospektivnogo kontroliruemogo sravnitel'nogo issledovaniya po lecheniyu novoi koronavirusnoi infektsii (COVID-19): Bromgeksin I Spironolakton dlya lecheniya KoronaVirusnoi Infektsii, Trebuyushchei gospitalizatsii (BISKVIT). Kardiologiya. 2020; 60(11): 4–15. https://doi.org/10.18087/cardio.2020.11.n1440
27. Granados-Montiel J., Hazan-Lasri E., Franco-Cendejas R., ChávezHeres T., Silva-Bermudez P., Aguilar-Gaytán R., et al. New prophylaxis regimen for SARS-CoV-2 infection in health professionals with low doses of hydroxychloroquine and bromhexine: a randomised, double-blind placebo clinical trial (ELEVATE Trial). BMJ Open. 2021; 11(8): e045190. https://doi.org/10.1136/bmjopen-2020-045190
