目的 2019年12月新型冠状病毒肺炎(COVID-19)暴发,疫情在世界范围内迅速蔓延,寻找有效抗病毒药物成为治疗新型冠状病毒的迫切需求。方法 笔者借助已有病毒学文献,对严重急性呼吸系统综合征冠状病毒2(SARS-CoV-2)感染通路进行了系统的总结,并且运用SWISSDOCK分子模拟方法对关键靶点和上市药物进行系统的虚拟药物筛选。结果 研究发现,TMPRSS2/ACE2通路是SARS-CoV-2病毒进入肺部和其他组织细胞最高效和主要的途径。而呼吸科祛痰药物溴己新体外可强烈抑制TMPRSS2蛋白酶(EC50:0.75 μmol·L-1)。溴己新不良反应少且还具备促进肺部内源活性物质释放,维持肺泡功能,促进排痰等有益作用,适合联合用药。结论 溴己新具有独特的潜在抗病毒机制,应当深入进行临床研究,发挥其对COVID-19预防,治疗和预后的作用。
Abstract
OBJECTIVE To investigate antiviral mechanism of bromhexine for the treatment of COVID-19. METHODS Based on the existing literature, the infection pathways of new coronavirus(SARS-CoV-2) were systematically summarized by us, and used the SWISSDOCK molecular simulation method to carry out virtual screen systematically for key targets and marketed drugs. RESULTS TMPRSS2/ACE2 pathway was found to be the most efficient and probably the major pathway for SARS-CoV-2 virus to infect the lung and other tissue by us. Bromhexine, an expectorant, can strongly inhibit TMPRSS2 protease (EC50:0.75 μmol·L-1) in vitro. Bromhexine has few adverse effects and also has the beneficial effects of promoting the release and maintenance of endogenous active substances in the lung, alveolar function, and promoting sputum excretion, which is suitable for use together with other COVID19 medication and therapies. CONCLUSION Bromhexine has a unique potential antiviral mechanism, and clinical research should be conducted to play its role in the prevention, treatment and prognosis of COVID19.
关键词
溴己新 /
氯喹 /
新型冠状病毒肺炎 /
严重急性呼吸系统综合征冠状病毒2 /
抗病毒机制
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Key words
bromhexine /
chloroquine /
COVID-19 /
SARS-Cov-2 /
antiviral mechanism
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中图分类号：
R969
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参考文献
[1] Office of the State Administration of Traditional Chinese Medicine, General and Health Commission. Notice regarding the issuance of a new coronavirus-infected pneumonia diagnosis and treatment plan (trial implementation of the seventh edition) [EB/OL].(2020-03-03)[2020-03-06] http://www.gov.cn/zhengce/zhengceku/2020-03/04/content_5486705.htm.
[2] MA Z, CAO G J, GUAN M. Research status and progress of human coronavirus [J]. Inter J Lab Med(国际检验医学杂志),2020,41(5):518-522.
[3] QIAN Y H, DONG J Y. 2019 New Coronavirus Laboratory Detection and Protection Study [DB/OL]. [2020-03-06]. http://kns--cnki--net--http. cnki. scrm. qfclo. com:2222/kcms/detail/50. 1167. R. 20200218. 1654. 002. html.
[4] CHEN M, TONG R S, BIAN Y,et al. Evidence-based rapid review on possibility of treatment of 2019-nCoV with subcutaneous α-interferon [DB/OL]. [2020-03-06]. http://kns--cnki--net--http.cnki.scrm.qfclo.com:2222/kcms/detail/42.1293.R.20200210.1759.002.html.
[5] LI F. Structure, function, and evolution of coronavirus spike proteins[J]. Annual Rev Virol, 2016, 3(1):237-261.
[6] XU X, CHEN P, WANG J, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission[J]. Sci China Life Sci, 2020,63(3):457-460.
[7] MORRISSEY C, CLEGG N, BROWN C M, et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis[J]. Cancer Dis, 2014, 4(11):1310-1325.
[8] ZHAO Y, ZHAO Z, WANG Y, et al. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov[DB/OL]. [2020-03-06]. https://www.biorxiv.org/content/10.1101/2020.01.26.919985v1.full.
[9] ZHOU P, YANG X L, WANG X G, et al. Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin[DB/OL]. [2020-03-06]. https://www.biorxiv.org/content/10.1101/2020.01.22.914952v2.
[10] HOFFMANN M, KLEINE-WEBER H, SCHROEDER S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor[DB/OL]. [2020-03-06]. https://doi.org/10.1016/j.cell.2020.02.052.
[11] KAWASE M, SHIRATO K, VANDERHOEK L, et al. Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry[J]. J Virol, 2012, 86(12):6537-6545.
[12] IWATA-YOSHIKAWA N, OKAMURA T, SHIMIZU Y, et al. TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection[J]. J Virol, 2019, 93(6):e01815.
[13] ZHOU Y, VEDANTHAM P, LU K, et al. Protease inhibitors targeting coronavirus and filovirus entry[J]. Antiviral Res, 2015, 116:76-84.
[14] TSEGAYE T S, NIEMEYER D, MUELLER M A, et al. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response[J]. J Virol, 2011, 85(9):4122-4134.
[15] SHEN L W, MAO HJ, WU Y L, et al. TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections[DB/OL]. [2020-03-06]. https ://www.sciencedirect.com/science/article/pii/S0300908417301876.
[16] SUN J P, HE Y X. Research progress of enzymatic hydrolysis activation mechanism during SARS infection [J]. Chin J Exp Clin Virol(中华实验和临床病毒学杂志),2013,27(1):79-81.
[17] DU L, KAO R Y, ZHOU Y, et al. Cleavage of spike protein of SARS coronavirus by protease factor Xa is associated with viral infectivity[J]. Biochm Biophys Res Commun, 2007, 359(1):174-179.
[18] SHIRATO K, KAWASE M, MATSUYAMA S. Middle east respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2[J]. J Virol, 2013, 87(23):12552-12561.
[19] FOIS G, HOBI N, FELDER E, et al. A new role for an old drug: ambroxol triggers lysosomal exocytosis via pH-dependent Ca2+ release from acidic Ca2+ stores[J]. Cell Calcium, 2015, 58(6):628-637.
[20] KLYACHKINA I L. The new possibility for the treatment of acute cough[J]. Vest Otorinolaringol, 2015, 80(5):85-90.
[21] YANG B B, ZHU Y L. Epidemiology and treatment of novel coronavirus pneumonia (COVID-19) in children and adults [J/OL]. [2020-03-06]. http://kns--cnki--net--http.cnki.scrm.qfclo.com:2222/kcms/detail/61.1399.r.20200216.1319.004.html.
[22] LIU X, WANG R S, QU G Q, et al. General observation report on system anatomy of dead corpses of COVID-19[J]. J Forensic Med(法医学杂志), 2020,36(1):21-23.
[23] PADRID P, CHURCH D B. Drugs Used in the Management of Respiratory Diseases[M]. Small Animal Clinical Pharmacology. Amsterdam: WB Saunders, 2008:458-468.
[24] GUAN W, NI Z, HU Y, et al. Clinical characteristics of 2019 novelcoronavirus infection in China[DB/OL]. [2020-02-06]. https://www.medrxiv.org/content/10.1101/2020.02.06.20020974v1#0-qzone-1-37876-d020d2d2a4e8d1a374a433f596ad1440.
[25] CHEN L, GUI C, LUO X, et al. Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro[J]. J Virol, 2005, 79(11):7095-7103.
[26] CHEN S, LUO H, CHEN L. An overall picture of SARS coronavirus (SARS-CoV) genome-encoded major proteins:structures, functions and drug development[J]. Curr Pharm Des, 2006, 12(35):4539-4553.
[27] LI P, ZHAO S L, CHEN Y F, et al. Clinical implications of 2 cases of corona virus disease positive for SARS-CoV-2 nucleic acid in feces[J]. Inter J Lab Med (国际检验医学杂志), 2020,41(4):385-388.
[28] DERETIC V, TIMMINS G S. Enhancement of lung levels of antibiotics by ambroxol and bromhexine[J]. Exp Opin Drug Metab Toxicol, 2019, 15(3):213-218.
[29] LIU H, WU Z M, GU Q L. Literature analysis of incompatibility of bromhexine hydrochloride glucose injection [J]. J Mod Med Health(现代医药卫生), 2015,31(S2):35-37.
[30] LANG J, YANG N, DENG J, et al. Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans[J]. PLoS One, 2011, 6(8):e23710.
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脚注
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基金
国家临床重点专科建设项目资助(30305030698);四川省省级公益性科研院所基本科研业务专项课题项目资助(2018YSKY0017); 四川省人民医院院级科研基金临床研究及转化项目资助 (2018LY09)
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