CN113440518A - 一种穿心莲内酯类药物在制备治疗新型冠状病毒药物中的应用 - Google Patents
一种穿心莲内酯类药物在制备治疗新型冠状病毒药物中的应用 Download PDFInfo
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- CN113440518A CN113440518A CN202010217535.XA CN202010217535A CN113440518A CN 113440518 A CN113440518 A CN 113440518A CN 202010217535 A CN202010217535 A CN 202010217535A CN 113440518 A CN113440518 A CN 113440518A
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Abstract
本发明公开了一种穿心莲内酯药物(优选喜炎平注射液)在制备治疗新型冠状病毒药物中的应用，临床上取得显著疗效，对于新型冠状病毒感染的治疗具有积极的社会意义。
Description
技术领域
本发明涉及药物领域，特别涉及一种穿心莲内酯类药物在制备治疗新型冠状病毒药物中的应用。
背景技术
穿心莲内酯(andrographolide)是穿心莲提取物中含量最高的成分之一。其具有多靶点作用机制，因此，具有广泛的药理活性，例如解热、抗炎、镇痛、抗菌、降血糖等，随着对穿心莲内酯药理作用的不断深入研究，发现其在免疫调节、抗病毒和抗肿瘤等方面均具有广泛的应用(戴桂馥等，中成药，2006,28(7):1032)。穿心莲内酯具体结构如下：
目前，有文献及专利报道(Lin HQ,et al.Biol.Pharm.Bull.2006,29(2):220，CN101012211B，CN1666985A，US20050215628A1)，穿心莲内酯及其衍生物可以抑制LPS诱导的TNF-α、IL1β和IL-6的表达，从而抑制机体的炎性反应。TNF-α是一种前体炎症细胞因子，参与许多炎症反应过程。通过抑制TNF-α可用于治疗多种自身免疫性疾病(类风湿性关节炎、克罗恩病、系统性红斑狼疮、银屑病等)、神经系统疾病(阿兹海默症、帕金森病、艾滋病痴呆综合症、抑郁症)、癌症及呼吸道病毒感染等(Ogata H,Hibi T.et al.Curr PharmDes.2003,9(14):1107；Sack M.et al.Pharmacol Ther.2002,94(1-2):123-135；BarnesPJ.Et al.Annu Rev Pharmacol Toxicol.2002,42:81；Goldring MB.Et al.Expert OpinBiol Ther.2001Sep；1(5):817)。IL1β是由单核巨噬细胞、树突细胞和纤维母细胞等产生的细胞因子，可刺激T细胞及B细胞的增殖和分化，参与炎症反应。抑制IL1β可用于治疗包括病毒感染在内的各种炎症反应(Taylor PC.et al.Curr Pharm Des.2003；9(14):1095；Dellinger RP et al Clin Infect Dis.2003May 15；36(10):1259)。IL-6又称为B细胞刺激因子，多种细胞能自发或在其它刺激下产生IL-6，其在外周和中枢神经系统发育、分化、再生和变性中起重要作用。
近些年发现穿心莲内酯及其衍生物在抗病毒感染方面有一定的作用，例如CN104042621A公开了穿心莲内酯类药物具有预防和减缓手足口病病毒感染所造成的严重后果；但并没有文献报道穿心莲内酯药物在治疗新型冠状病毒药物中的应用。
发明内容
本发明提供了穿心莲内酯类药物在制备治疗新型冠状病毒药物中的应用，并揭示了穿心莲内酯药物对COVID-19的潜在治疗机制。
本发明的第一方面，提供穿心莲内酯类药物在制备治疗新型冠状病毒药物中的应用。
优选的，所述的穿心莲内酯类药物，包括穿心莲内酯及其衍生物，例如穿心莲内酯、新穿心莲内酯、穿心莲内酯磺化物、三乙酰穿心莲内酯、脱水穿心莲内酯琥珀酸半酯等。
更优选的，所述的穿心莲内酯类药物，包含17-氢-9-去氢穿心莲内酯、17-氢-9-去氢穿心莲内酯-19-硫酸酯钠、17-氢-9-去氢穿心莲内酯-3-硫酸酯钠、17-氢-9-去氢穿心莲内酯-3,19-二硫酸酯钠的一种或多种活性成分。
优选的，所述新型冠状病毒为β冠状病毒；更优选为SARS-CoV-2(2019-nCoV)。
优选的，所述穿心莲内酯类药物可与药物载体制成各种剂型，包括片剂、颗粒剂、注射液、粉剂、胶囊剂、悬浮剂，优选注射液，更优选为喜炎平注射液；
更优选的，注射液可肌肉注射，也可静脉滴注，还可雾化吸入；
当肌肉注射时：成人使用量为100-300mg/人/日；小儿酌减；
当静脉滴注时：成人使用量为250-500mg/人/日；儿童用量可按体重5-10mg/kg(0.2-0.4ml/kg)，最高剂量不超过250mg；以0.9％氯化钠注射液或5％葡萄糖注射液100ml～250ml稀释后静脉滴注；控制滴速每分钟30～40滴；每日一次。
优选的，穿心莲内酯类药物可单独或与其他药物组合使用。
更优选的，所述其他药物选自：Remdesivir、α-干扰素、洛匹那韦、利巴韦林、磷酸氯喹、阿比朵儿。
更优选的，所述其他药物可以和所述的穿心莲内酯类药物做成单一给药的治疗剂型，或者分别先后给药的治疗剂型。
本发明的第二方面，一种关于穿心莲内酯药物对COVID-19的治疗机制的分析方法，包括如下步骤：
(1)化合物靶标搜集：查询数据库、靶标预测获取该药物中活性成分的靶标信息；
(2)构建靶标网络及分析；
(3)靶标的功能富集分析：识别靶标网络干预的疾病通路和基本生物学通路。
优选的，所述穿心莲内酯药物为喜炎平注射液；
优选的，所述的数据库为ETCM和/或PubChem；
优选的，所述靶标预测采用的TargetNet；
优选的，所述的活性成分选自17-氢-9-去氢穿心莲内酯、17-氢-9-去氢穿心莲内酯-19-硫酸酯钠、17-氢-9-去氢穿心莲内酯-3-硫酸酯钠、17-氢-9-去氢穿心莲内酯-3,19-二硫酸酯钠的一种或多种活性成分；优选为17-氢-9-去氢穿心莲内酯、17-氢-9-去氢穿心莲内酯-19-硫酸酯钠、17-氢-9-去氢穿心莲内酯-3-硫酸酯钠和17-氢-9-去氢穿心莲内酯-3,19-二硫酸酯钠；
优选的，构成靶标网络采用的STRING平台；
优选的，分析靶标网络采用的Cytoscape软件；
优选的，靶标的功能富集分析采用的STRING平台；
优选的，所述方法包括如下步骤：
(1)化合物靶标收集：从ETCM和PubChem数据库搜索化合物靶标，用TargetNet预测化合物靶标；ETCM里的靶标是用MedChem Studio预测的，并只保留可靠性分值大于0.8的靶标；PubChem里的靶标来自PubMed里的文献报道；TargetNet是基于量化结构活性关系模型QSAR预测靶标；
(2)靶标网络构建和分析：用STRING平台构建靶标间相互关联的网络，取关联可信度分>＝0.9，且只保留最大的连通分支，得到靶标网络；用Cytoscape软件分析靶标网络；
(3)靶标的功能富集分析：用STRING平台进行靶标的功能富集分析，识别靶标网络干预的疾病通路和基本生物学通路。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
有益技术效果：
本发明提供了穿心莲内酯类药物(优选喜炎平注射液)在制备治疗新型冠状病毒药物中的应用，通过给予新冠状病毒患者施用穿心莲内酯药物(优选喜炎平注射液)，在临床上获得了显著的疗效，对于新型冠状病毒感染的治疗具有积极的社会意义。
本发明通挖掘出穿心莲内酯药物(优选喜炎平注射液)对COVID-19的潜在治疗机制，从而揭示穿心莲内酯药物(优选喜炎平注射液)对COVID-19作用的中医辩证用药依据和多成分、多靶标的分子机制，为穿心莲内酯类药物(优选喜炎平注射液)治疗新型冠状病毒进一步提供依据。
附图说明
图1喜炎平的靶标网络；其中：节点大小与连接度成比例，节点的颜色深浅与靶标的受调控分成比例，颜色越深的靶标，受调控分越大。
图2喜炎平的靶标网络里包含的连接紧密的子模块，其中：节点的颜色深浅与靶标的受调控分成比例。
图3喜炎平的靶标中与ACE2共表达的蛋白所调控的信号通路。
图4喜炎平的靶标中与ACE2共表达的蛋白所调控的信号通路的靶标-通路网络；其中：圆形节点是靶标，方形节点是信号通路。
具体实施方式
在新冠肺炎(COVID-19)疫情期间，穿心莲内酯药物(喜炎平注射液，由江西青峰药业有限公司生产)在临床应用中取得了显著的疗效。
1方法
1.1化合物靶标收集
从ETCM和PubChem数据库搜索喜炎平注射液化合物靶标，用TargetNet预测化合物靶标。ETCM里的靶标是用MedChem Studio预测的，并只保留可靠性分值大于0.8的靶标；PubChem里的靶标来自PubMed里的文献报道；TargetNet是基于量化结构活性关系模型(quantitative structure activity relationships，QSAR)预测靶标。
1.2靶标网络构建和分析
用STRING平台构建靶标间相互关联的网络，取关联可信度分>＝0.9,且只保留最大的连通分支，得到靶标网络，用Cytoscape软件分析靶标网络。
1.3靶标的功能富集分析
用STRING平台进行靶标的功能富集分析。
2.1化合物靶标
喜炎平注射液包括四个主要成分：
FL-3:17-氢-9-去氢穿心莲内酯-19-硫酸酯钠
(Sodium 17-hydro-9-dehydro-andrographolide-19-yl sulfate)
FL-5：17-氢-9-去氢穿心莲内酯-3-硫酸酯钠
(Sodium 17-hydro-9-dehydro-andrographolide-3-yl sulfate)
FL-6：17-氢-9-去氢穿心莲内酯
(17-Hydro-9-dehydro-andrographolide)
FL-7：17-氢-9-去氢穿心莲内酯-3,19-二硫酸酯钠
(Sodium 17-hydro-9-dehydro-andrographolide-3,19-diyl disulfate)
FL-6的靶标从ETCM和PubChem数据库收集，由于这两个数据库不包含另外3个化合物，将4个化合物的Smiles结构式分别输入TargetNet预测其靶标，并取可靠性分值为0.6以上。最后获得化合物FL-3,FL-5,FL-6,FL-7分别有5、6、125、3个潜在靶标，共有120个不同的潜在靶标。
2.2靶标网络
构建的喜炎平的靶标网络见图1，此网络共91个节点、301条边。为了衡量喜炎平的化合物对靶标作用的强弱，我们定义靶标的受调控分为靶向此蛋白的化合物的数量。受调控分高的靶标即为受药物作用更强的靶标。图1显示，网络中有2个蛋白的受调控分为3,3个蛋白的受调控分为2，其余蛋白的受调控分为1。
2.3靶标网络的功能分析
将喜炎平的靶标网络输入STRING中进行功能富集分析。设定统计指标为FDR<1E-05,在KEGG通路富集的结果中限定基本生物过程部分的通路(KEGG通路数据库中的5部分：Metabolism,Genetic Information Processing,Environmental InformationProcessing,Cellular Processes,Organismal Systems),得到33个靶标富集的信号通路(见表1)。由于Reactome数据库里的通路与KEGG通路有很大的重合，我们只列出其中统计显著性最高(即FDR最小)的几个信号通路(表2)。
表1喜炎平的靶标富集的KEGG信号通路
表2喜炎平的靶标富集的Reactome信号通路
2.4靶标干预的疾病过程
STRING功能富集分析的结果中，设定统计指标为FDR<1E-06,在KEGG通路富集的结果中限定人类疾病(Human diseases)部分的通路,得到38个靶标富集的疾病通路(表3)。
表3喜炎平的重要靶标富集的KEGG疾病通路
2.5靶标网络中的功能模块
用Cytoscape的MCODE插件对靶标网络进行分解，识别到网络中的4个连接紧密的子模块(见图2)。这种子模块代表功能密切相关的蛋白之间相互作用而完成特定的分子功能。用STRING对4个进行功能注释，结果见表4。
表4喜炎平的靶标网络中子模块的功能注释
2.6重要通路和靶标分析
ACE2蛋白是SARS-CoV-2病毒在人体细胞中的受体，SARS-CoV与ACE2的结合使得ACE2的表达和活性大幅下降。我们下载了文献附件中根据结肠上皮细胞单细胞测序结果识别到的与ACE2共表达的5556个基因，通过交集分析发现，喜炎平的120个靶标中，共37个靶标是与ACE2在结肠中共表达的，占靶标总数的约30％。
这37个靶标富集的KEGG信号通路中统计显著性最高的10条通路见图3。这10条通路的靶标-通路网络见图4。此网络中，连接度最大的通路节点依次是IL-17signalingpathway，Jak-STAT signaling pathway，Th1 and Th2 cell differentiation，Th17 celldifferentiation，它们是喜炎平调控的重要信号通路；连接度至少是2的靶标节点有10个：IL4，IL5，MAPK3，IL13，CD4，CASP3，BCL2L1，CASP8，IL17A，STAT3，它们是喜炎平的重要靶标。
申请人利用网络药理学方法系统地分析了穿心莲内酯药物喜炎平注射液对于COVID-19的潜在治疗机制，通过数据库搜索和预测，获得喜炎平的靶标共120个，构建了靶标间的相互作用网络(图1)，此网络包含91个蛋白。对网络中的靶标进行功能富集分析，识别了它们显著富集的信号通路37个(表1,2)、显著富集的疾病通路38个(表3)；对靶标间相互作用网络的拓扑分析识别了4个功能模块(图2，表4)。将靶标与ACE2的共表达基因作交集分析，发现喜炎平的靶标中有37个是与ACE2共表达的。对这些ACE2共表达靶标进行功能富集分析(图3)，进一步构建和分析靶标-通路网络(图4)，识别了喜炎平调控的重要通路4个(IL-17signaling pathway，Jak-STAT signaling pathway，Th1 and Th2 celldifferentiation，Th17 cell differentiation)和重要靶标10个(IL4，IL5，MAPK3，IL13，CD4，CASP3，BCL2L1，CASP8，IL17A，STAT3)。说明喜炎平具有以下功能：
(1)调节免疫系统
SARS-CoV-2与ACE2结合，使得ACE2的表达和活性大幅下降，这引起细胞内与ACE2共表达的一系列基因的表达异常，这些基因中有一部分参与免疫、炎症相关的生物过程。喜炎平作用在与ACE2共表达的37个蛋白上，说明它对于与SARS-CoV-2感染相关的ACE2低表达而导致的症状有潜在改善作用。喜炎平作用于13条免疫系统的信号通路以及若干与细胞因子作用相关的信号通路如TNF,NFkB,MAPK信号通路等；它的靶标网络的四个功能模块中，1号和2号模块包含白介素信号通路的功能；它调控的四个重要信号通路中，3个是免疫系统信号通路。说明喜炎平的多靶标调控了免疫系统的多个生物过程，包括辅助性T细胞1,2,17的分化、Toll样受体信号通路、T-细胞受体信号通路、白介素信号通路等，起到调节免疫、避免或减轻细胞因子风暴的作用。
(2)消除炎症、改善机体代谢
喜炎平的靶标网络的四个功能模块中，2、3、4号模块参与类固醇激素生物合成、代谢，花生四稀酸代谢的生物过程。类固醇激素具有免疫调节、抗炎、抗过敏、改善代谢功能的作用，炎症刺激花生四烯酸代谢并释放其代谢产物前列腺素(PG)和白细胞三烯(leukotriene,LT)，导致发热、疼痛、血管扩张、通透性升高及白细胞渗出等炎症反应。喜炎平作用于这些生物过程，起到消除炎症、改善机体代谢的作用。
(3)抗感染
喜炎平的靶标显著富集的38个疾病信号通路中，有18个是感染类疾病，包括病毒感染(如带状疱疹、EB病毒感染、甲型流感、乙型肝炎、丙型肝炎等)和细菌感染(如百日咳、肺结核等)，说明它有潜在的抗感染的作用。结合前面的分析，喜炎平的抗感染作用可能是通过调节免疫和消除炎症实现的。
上述结果为穿心莲内酯类药物优选喜炎平注射液治疗新冠病毒进一步提供依据。
以上通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。其中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择；本发明所用试剂、原料及仪器等未经特殊说明均市售可得。
Claims (10)
1.一种穿心莲内酯类药物在制备治疗新型冠状病毒药物中的应用。
2.如权利要求1所述的穿心莲内酯类药物，包括穿心莲内酯及其衍生物，例如穿心莲内酯、新穿心莲内酯、穿心莲内酯磺化物、三乙酰穿心莲内酯、脱水穿心莲内酯琥珀酸半酯。
3.如权利要求2所述的穿心莲内酯类药物，包含17-氢-9-去氢穿心莲内酯、17-氢-9-去氢穿心莲内酯-19-硫酸酯钠、17-氢-9-去氢穿心莲内酯-3-硫酸酯钠、17-氢-9-去氢穿心莲内酯-3,19-二硫酸酯钠的一种或多种活性成分。
4.根据权利要求1所述的应用，其特征在于，所述新型冠状病毒为β冠状病毒。
5.根据权利要求4所述的应用，其特征在于，所述β冠状病毒为SARS-CoV-2(2019-nCoV)。
6.根据权利要求1所述的应用，所述穿心莲内酯类药物可与药物载体制成各种剂型，包括片剂、颗粒剂、注射液、粉针剂、粉剂、胶囊剂、悬浮剂；优选注射液；所述注射液优选喜炎平注射液。
7.根据权利要求6所述的应用，穿心莲内酯类药物可单独或与其他药物组合使用；优选的，其他药物选自Remdesivir、α-干扰素、洛匹那韦、利巴韦林、磷酸氯喹、阿比朵儿。
8.根据权利要求7所述的应用，所述其他药物可以和所述的穿心莲内酯类药物做成单一给药的治疗剂型，或者分别先后给药的治疗剂型。
9.一种关于穿心莲内酯药物对COVID-19的治疗机制的分析方法，其特征在于，包括以下步骤：
(1)化合物靶标搜集：查询数据库、靶标预测获取该药物中活性成分的靶标信息；
(2)构建靶标网络及分析；
(3)靶标的功能富集分析：识别靶标网络干预的疾病通路和基本生物学通路。
10.根据权利要求9所述的分析方法，其中，
所述穿心莲内酯药物为喜炎平注射液；
和/或，所述的数据库为ETCM和/或PubChem；
和/或，所述靶标预测采用的TargetNet；
和/或，所述的活性成分选自17-氢-9-去氢穿心莲内酯、17-氢-9-去氢穿心莲内酯-19-硫酸酯钠、17-氢-9-去氢穿心莲内酯-3-硫酸酯钠、17-氢-9-去氢穿心莲内酯-3,19-二硫酸酯钠的一种或多种活性成分；优选为17-氢-9-去氢穿心莲内酯、17-氢-9-去氢穿心莲内酯-19-硫酸酯钠、17-氢-9-去氢穿心莲内酯-3-硫酸酯钠和17-氢-9-去氢穿心莲内酯-3,19-二硫酸酯钠；
和/或，构成靶标网络采用的STRING平台；
和/或，分析靶标网络采用的Cytoscape软件；
和/或，靶标的功能富集分析采用的STRING平台；
和/或，所述方法包括如下步骤：
(1)化合物靶标收集：从ETCM和PubChem数据库搜索化合物靶标，用TargetNet预测化合物靶标；ETCM里的靶标是用MedChem Studio预测的，并只保留可靠性分值大于0.8的靶标；PubChem里的靶标来自PubMed里的文献报道；TargetNet是基于量化结构活性关系模型QSAR预测靶标；
(2)靶标网络构建和分析：用STRING平台构建靶标间相互关联的网络，取关联可信度分>＝0.9，且只保留最大的连通分支，得到靶标网络；用Cytoscape软件分析靶标网络；
(3)靶标的功能富集分析：用STRING平台进行靶标的功能富集分析，识别靶标网络干预的疾病通路和基本生物学通路。
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| US20090143279A1 (en) * | 2007-06-15 | 2009-06-04 | Vamsi Krishna Mootha | Methods and compositions for treating metabolic disorders |
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