CN113440507A - 益母草碱在制备抗乙肝病毒药物中的用途 - Google Patents
益母草碱在制备抗乙肝病毒药物中的用途 Download PDFInfo
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Abstract
本发明属医药技术领域，涉及针对乙型肝炎病毒表面抗原(HBsAg)的化合物。具体涉及一种针对乙型肝炎病毒表面抗原(HBsAg)的化合物益母草碱(Leonurine hydrochloride，Leonurine)(CAS：24697‑74‑3)，该化合物是从中药益母草中提取并化学合成的单体，经试验表明，其能有效降低体外上清HBsAg，并对降低体外上清乙型肝炎e抗原(HBeAg)有作用。所述的化合物益母草碱可用于针对性降低胞外HBsAg与HBeAg，为研发HBV持续性感染中有效降低HBsAg、HBeAg的治疗药物及方法提供支持。
Description
技术领域
本发明属医药技术领域，涉及抗乙肝病毒的化合物药物，尤其针对乙型肝炎病毒表面抗原(HBsAg)的化合物药物。具体涉及一种针对乙型肝炎病毒表面抗原(HBsAg)的化合物益母草碱(Leonurine hydrochloride，Leonurine)(CAS：24697-74-3)，经试验表明，所述化合物益母草碱能有效降低体外上清HBsAg，并对降低体外上清乙型肝炎e抗原(HBeAg)有作用，可制备抗乙肝病毒的药物。
背景技术
据报道，乙型肝炎病毒(HBV)感染是一个世界性的健康问题，据估计,全世界约有2.6亿人慢性感染HBV[WHO 2019]。2015年报道，全球病毒性肝炎死亡人数达134万，与结核病死亡人数相当，均高于艾滋病病毒感染人数和疟疾死亡人数，其中96％的死亡是由于慢性肝炎并发症，包括肝硬化、肝细胞癌和肝功能衰竭，其中大多数(66％)是由HBV引起的[WHO.Global hepatitis report,2017]。虽然目前已有用于临床的抗病毒药物，但实践证实，所述的抗病毒药物抗HBV作用有限，不能持续性清除乙型肝炎表面抗原(HBsAg)，造成乙肝久治不愈，甚至危及生命。
现有技术公开了乙型肝炎病毒属于嗜肝DNA病毒科，其基因组由结构紧凑的3.2kb的双链DNA组成。HBV为有包膜病毒，主要感染肝细胞；完整病毒颗粒外部为宿主来源的包膜，其上镶嵌了病毒的3种包膜蛋白，其内部为由核心蛋白组装成的核心颗粒，保护3.2kb的DNA基因组；包膜蛋白分为大、中、小三种类型(即LHBs、MHBs、SHBs)，统称为乙肝表面抗原(HBsAg)，由HBV的S基因(分为pre S1、pre S2和S区)编码，但转录起始位点不同[Seeger C,Mason WS.Molecular biology ofhepatitis B virus infection.2015]。HBsAg还可以直接以22nm的亚病毒颗粒的形式释放，研究显示，在大多数患者血清中，这种内部不含核心颗粒的亚病毒颗粒含量远远超过成熟病毒颗粒并难以自体清除，甚至在检测不到病毒DNA的情况下，HBsAg仍能持续大量存在。该种独特的现象是乙肝病毒所特有的，其中S蛋白构成了包膜蛋白的主体，而L蛋白在病毒与宿主细胞受体结合、病毒粒子组装及其从细胞释放过程中起着至关重要的作用，这表明HBsAg在HBV感染过程中具有特殊作用，在乙肝持续性感染致病机制方面扮演了重要角色。还有研究显示，HBsAg的减少与肝硬化或HCC进展的显著减少相关，而HBeAg在病毒组装中没有作用，另有报道称它在调节宿主免疫反应中发挥作用[Walsh,R.,Locarnini,S.et al.Hepatitis B precore protein:pathogenic potentialand therapeutic promise.2012]，HBeAg与大量的亚病毒颗粒等病毒学因素造成HBV持续性感染；因此，持续性降低或清除HBsAg、HBeAg可成为实现慢性乙肝治愈的潜在靶点。
目前，被批准的治疗慢性乙型肝炎病毒感染(CHB)的药物包括，核苷类似物逆转录酶抑制剂(NUCs)和干扰素，其表现出明显的抗病毒活性，但由于HBsAg清除率低、NUCs停药后病毒反弹率高，加之干扰素存在较多副作用[Gish RG,Given BD,et al.Chronichepatitis B:Virology,natural history,current management and a glimpse atfuture opportunities.2015]，包括流感样综合征，头痛、肌痛、疲劳、抑郁和局部注射部位反应等，总体治疗效果不尽如人意。
传统中药益母草(Herba Leonuri)属于唇形科，研究表明，其活性成分益母草碱具有多种有益的药理作用，包括抗凋亡、抗氧化、镇痛、降血糖和抗炎作用[OjewoleJA.Antinociceptive,anti-inflammatory and antidiabetic effects ofLeonotisleonurus(L.)R.BR.[Lamiaceae]leafaqueous extract in mice and rats.2005]。此外，益母草碱还通过不同机制发挥其心血管保护作用，其对细胞内Ca2+稳态的调节可能是其中重要途径之一。研究表明，益母草碱对TNF-α诱导的炎性生物标志物表达的抑制作用是通过抑制胞内ROS的产生和p38丝裂活化蛋白激酶(p38mitogen-activatedprotein kinase，MAPK)的激活从而引起抑制IκBα降解与NF-κB的活化作用而介导的[Liu XH,Pan LL,etal.Leonurine protects against tumor necrosis factor-α-mediated inflammationin human umbilical vein endothelial cells.2011]。
基于现有技术的现状，本申请的发明人提供益母草碱新的药物用途，具体涉及化合物益母草碱(Leonurine hydrochloride，Leonurine)(CAS：24697-74-3)在制备抗乙肝病毒的药物中的用途，所述化合物益母草碱能有效降低体外上清HBsAg，并对降低体外上清乙型肝炎e抗原(HBeAg)有作用。
发明内容
本发明的目的是基于现有技术的现状，提供益母草碱新的药物用途，具体涉及化合物益母草碱(Leonurine hydrochloride，Leonurine)(CAS：24697-74-3)在制备抗乙肝病毒HBV的药物中的用途，所述化合物益母草碱能有效降低体外上清HBsAg，并对降低体外上清乙型肝炎e抗原(HBeAg)有作用。
本发明从中药益母草中提取并化学合成单体益母草碱(Leonurinehydrochloride，Leonurine)(CAS：24697-74-3)，并进行HBV持续性感染的联合治疗的研究与应用，经试验表明，其能有效降低体外上清HBsAg，并对降低体外上清乙型肝炎e抗原(HBeAg)有作用。
本发明的化合物单体益母草碱(盐酸盐)，分子量365.81，分子式C14H21O5N3.HCl.H2O，CAS号24697-74-3，结构式如下：
如本领域的普通技术人员所知，本发明的化合物益母草碱可通过商业途径购买获得，亦可用本领域的常规方法从益母草中提取获得。其纯度均符合药用标准。
本发明提供了能够持续且有效降低HBsAg水平的化合物单体益母草碱，所述益母草碱在体外均具有良好的降低HBsAg作用。因此，所述益母草碱可制备为一种抗HBV的慢性乙肝治疗药物或者联合用药的重要部分。
本发明的能持续且有效降低HBsAg水平的化合物单体益母草碱，为治疗慢性乙型肝炎提供新疗法。
较优选地，所述的益母草碱是作为有效的活性成分应用于慢性乙肝的治疗及其联合用药方案中。
较优选地，所述的慢性乙肝为人乙型肝炎病毒持续性感染并分泌乙肝表面抗原。
本发明的益母草碱可以单独使用或以药物组合物的形式使用。药物组合物包括作为活性成分的本发明的益母草碱及可药用载体。较佳地，本发明的药物组合物含有0.1～99.9％重量百分比的作为活性成分的本发明的益母草碱。所述的“可药用载体”不会破坏本发明的益母草碱的药学活性，同时其有效用量，即能发挥药物载体作用时的用量对人体无毒。
所述可药用载体包括但不限于：软磷脂、硬脂酸铝、氧化铝、离子交换材料、自乳化药物传递系统、吐温或其他表面活性剂、血清蛋白、缓冲物质如磷酸盐、氨基乙酸、山梨酸、水、盐、电解质如硫酸盐精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅酸镁、饱和脂肪酸部分甘油酯混合物等。
其他常用的药物辅料如粘合剂(如微晶纤维素)、填充剂(如淀粉、葡萄糖、无水乳糖和乳糖珠粒)、崩解剂(如交联PVP、交联羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素)、润滑剂(如硬脂酸镁)以及吸收促进剂、吸附载体、香味剂、甜味剂、赋形剂、稀释剂、润湿剂等。
本发明的益母草碱以及其药物组合物可按本领域常规方法制备并可以通过肠道或非肠道或局部途径给药。口服制剂包括胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等；非肠道给药制剂包括注射液等；局部给药制剂包括霜剂、贴剂、软膏剂、喷雾剂等。优选为口服制剂。
本发明的益母草碱以及其药物组合物的给药途径可以为口服、舌下、经皮、经肌肉或皮下、皮肤粘膜、静脉、尿道、阴道等。
附图说明
图1.益母草碱对HBV稳转细胞系Hep G2.2.15HBsAg分泌的影响，其中，
Hep G2.2.15细胞传代并铺板后24h，接受1μM益母草碱(DMSO溶解)处理，此后，每间隔24h换成含1μM益母草碱的新培养基，并收集之前的细胞上清，用酶联免疫吸附法检测不同时间点的细胞上清中HBsAg水平，HBsAg变化差异显著性由t检验计算所得，数据表示为平均值±SD，(****p<0.0001，***0.0001<p<0.001，*0.01<p<0.05，ns p>0.05)。
图2.益母草碱对HBV稳转细胞系Hep G2.2.15HBeAg分泌的影响，其中，HepG2.2.15细胞传代并铺板后24h，接受1μM益母草碱(DMSO溶解)处理，此后，每间隔24h换成含1μM益母草碱的新培养基，并收集之前的细胞上清，用酶联免疫吸附法检测不同时间点的细胞上清中HBeAg水平，HBeAg变化差异显著性由t检验计算所得，数据表示为平均值±SD。(****p<0.0001，***0.0001<p<0.001，**0.001<p<0.01)。
图3.与图4.不同浓度的益母草碱对HBV稳转细胞系Hep G2.2.15对HBsAg分泌的影响，其中，Hep G2.2.15细胞传代后24h，接受不同浓度梯度的益母草碱(DMSO溶解)处理，在此期间每间隔24h换成含有相应浓度益母草碱的新培养基，用酶联免疫吸附法检测益母草碱处理72h时细胞上清中HBsAg水平，其变化差异显著性由t检验计算所得，数据表示为平均值±SD，(****p<0.0001，**0.001<p<0.01，*0.01<p<0.05，ns p>0.05)。
图5.与图6.益母草碱对Hep G2.2.15细胞系的细胞增殖的影响，其中，每组设置2个重复孔，CCK8试剂检测细胞增殖情况，统计学差异由t检验计算所得。数据表示为平均值±SD。
图7.、图8.与图9.益母草碱与抗病毒药物联用的抗HBV作用及对细胞增殖的影响，其中，每组设置2～3个重复孔，处理细胞72h，酶联免疫吸附法测细胞上清HBsAg，实时荧光定量PCR检测益母草碱及其与抗病毒药物联用对细胞内HBV DNA拷贝数的影响，CCK8试剂检测细胞增殖情况，统计学差异由t检验计算所得，数据表示为平均值±SD，(****p<0.0001，***0.0001<p<0.001，**0.001<p<0.01，*0.01<p<0.05，ns p>0.05)。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例或数量按照酶标仪OD值计。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此，除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
实施例1
Hep G2.2.15细胞系：使用稳定表达HBV的人肝母细胞瘤细胞系Hep G2.2.15。HepG2.2.15细胞置于37℃、5％浓度CO2条件下培养，并在G418药物压力下筛选、传代，所有实验均按照细胞实验规范进行，并获得复旦大学基础医学院分子病毒实验室的许可，所有细胞分组实验均以同等起始条件并随机分组进行。
药品：使用G418 Sulfate(450-130-ZL，WISENT，20mL)维持Hep G2.2.15细胞持续稳定表达HBsAg、HBeAg，将益母草碱(24697-74-3，HPLC>98％)及Lamivudine(134678-17-4，Macklin，5g)溶解在DMSO(D2650，Sigma-Aldrich，100mL)中，并均匀加入细胞培养基中，不同剂量组分别将益母草碱调整至相应终浓度梯度，所有药物及溶液均在实验前现配现用。
HBsAg和HBeAg检测：根据试剂盒说明书，使用上海科华HBsAg抗原ELISA试剂盒与HBeAg抗原ELISA试剂盒分别检测细胞上清中HBsAg与HBeAg水平，每个样品做3复孔，对于检测同种抗原的实验，各反应孔加入相应等量适当稀释的细胞上清，37℃恒温避光孵育，加入50μL酶结合物，37℃孵育30min，洗涤液洗板后，分别加入对应的显色液A和B，继续37℃孵育适当时间，加入终止液终止反应，酶标仪测450nm波长的OD值。
益母草碱对Hep G2.2.15细胞增殖的影响：将Hep G2.2.15传代并铺板于96孔板，每组设置2复孔，将益母草碱按照浓度梯度分别加入对应孔，每24h更换成含有益母草碱的新培养基，检测不同时间点的细胞增殖情况，弃尽对应孔培养基，加入PBS清洗细胞，将cck8试剂与无血清培养基按1：9比例混匀配成工作液，在待测各孔分别加入100μL工作液，37℃孵育20min，酶标仪检测450nm处OD值，将待测各孔OD值减掉无细胞空白孔OD值所得差值进行比较；数据表示为平均值±SD，各组数据统计学差异显著性分析由t检验计算所得，P值小于0.05被认为具有统计学意义。
试验结果显示：
益母草碱抑制胞外HBsAg：使用不同浓度梯度益母草碱处理Hep G2.2.15细胞后，显示1μM浓度时对降低HBsAg作用出现明显拐点(如图3.图4.所示)；选取单剂量益母草碱浓度1μM继续施以不同时间的处理，在使用单剂量1μM益母草碱处理Hep G2.2.15细胞后，其降低HBsAg呈现时间依赖性(如图1所示.)，出现逐步显著降低HBsAg现象；
益母草碱抑制胞外HBeAg：与此同时，使用单剂量1μM益母草碱处理Hep G2.2.15细胞，与对照组相比，表现出不同时间点均具有显著降低HBeAg作用(如图2所示.)；
益母草碱不抑制人肝细胞增殖，有较高的安全性：利用持续产生HBV的细胞系，检测益母草碱的肝脏毒性，利用不同剂量、不同时长的益母草碱处理肝源稳转HBV细胞系HepG2.2.15，经CCK8试剂检测，与对照组(DMSO组)相比，显示随浓度梯度及随时间均未对细胞活性产生抑制作用，证明其对肝细胞的安全性(如图5.与图6所示)；
益母草碱与抗病毒药物联用表现出有效抗HBV作用，且无明显细胞毒性：设置对照组、Lamivudine组(1μM)、益母草碱组(50nM)、联合用药组(Lamivudine+益母草碱)，按照上述分组，分别处理Hep G2.2.15细胞72h，对比发现，益母草碱与抗病毒药Lamivudine联合用药，可显著降低上清中HBsAg，并且该降低作用均强于各自单独用药(如图7所示.)；与Lamivudine联用时，对HBV DNA的抑制作用均强于各自单独用药，具有统计学显著差异(如图8所示)；益母草碱可与现有的用于慢性乙肝抗病毒治疗药物产生一定的协同抗HBV作用，同时在上述处理条件下，均未产生对细胞增殖产生明显影响(如图9所示)，依然显示较高安全性。
Claims (4)
1.益母草碱在制备抗乙肝病毒药物中的用途，所述的益母草碱其分子式为：C14H21O5N3.HCl.H2O，分子量365.81，
2.如权利要求1所述的用途，其特征在于：所述的益母草碱降低人乙型肝炎病毒表面抗原。
3.如权利要求1所述的用途，其特征在于：所述的益母草碱作为有效的活性成分联合其他药物用于制备治疗慢性乙肝的药物组合物。
4.如权利要求1所述的用途，其特征在于，所述的慢性乙肝为人乙型肝炎病毒持续性感染并分泌乙肝表面抗原。
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