CN110694065A - 组胺受体抑制剂及其衍生物在制备抗寨卡病毒药物中的应用 - Google Patents
组胺受体抑制剂及其衍生物在制备抗寨卡病毒药物中的应用 Download PDFInfo
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- CN110694065A CN110694065A CN201911011698.6A CN201911011698A CN110694065A CN 110694065 A CN110694065 A CN 110694065A CN 201911011698 A CN201911011698 A CN 201911011698A CN 110694065 A CN110694065 A CN 110694065A
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- zika virus
- histamine receptor
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Abstract
本发明提供组胺受体抑制剂及其衍生物在制备抗寨卡病毒药物中的应用，优选地所述组胺受体抑制剂为美海屈林萘二磺酸盐、富马酸酮替芬、盐酸氟桂利嗪、盐酸赛庚啶、JNJ‑7777120、地氯雷他定、马来酸溴苯那敏、马来酸氯苯那敏、盐酸西替利嗪中的一种或多种。本发明首次提出组胺受体抑制剂及其衍生物具有明确的抗寨卡病毒作用，可显著抑制寨卡病毒蛋白及寨卡病毒RNA的表达水平。本发明还筛选出对寨卡病毒抑制效果较好的组胺受体抑制剂，包括美海屈林萘二磺酸盐、盐酸赛庚啶、JNJ‑7777120、地氯雷他定等，它们浓度为10μM时对寨卡病毒的抑制作用与浓度40μM的利巴韦林相当，可作为良好的抗寨卡病毒药物的候选药物。
Description
技术领域
本发明涉及医药技术领域，更具体地，涉及一种组胺受体抑制剂及其衍生物在制备抗寨卡病毒药物中的应用。
背景技术
寨卡病毒属于蚊媒传播的黄病毒属病毒，基因组为单股正链RNA，全长约11kb，编码一个开放读码框(Open reading frame,ORF)，可形成一个多聚蛋白。寨卡病毒最早于1947年在乌干达恒河猴体内分离得到。1952年首次记录了人类感染寨卡病毒的病例。2007年在太平洋雅普岛出现了寨卡病毒疫情的爆发。2016年世界卫生组织(WHO)公布的数据显示，73个国家或地区发生了寨卡病毒感染。人感染寨卡病毒后，主要临床表现为皮疹、发热、肌肉酸痛、非化脓性结膜炎、头痛等。此外，巴西寨卡疫情爆发后，越来越多的证据显示出寨卡病毒感染与新生儿小头畸形存在密切关联。由于寨卡病毒疫情严峻，并且没有特异针对寨卡病毒感染的治疗药物及疫苗，因此亟待研发抗寨卡病毒药物。
组胺(Histamine)是一种重要的化学介质，具有多种重要的生理功能，多存在于中枢神经系统、外周组织及胃粘膜等组织，通过组氨酸脱羧作用合成。组胺功能的发挥依赖于其相应的组胺受体。人体内的组胺受体可分为4个亚型：H1R、H2R、H3R和H4R。组胺H1受体主要分布于胃肠道、气管、子宫、血管等多种组织的细胞中，H1受体作为细胞膜的成分，被组胺激活后，可引起平滑肌收缩、增加毛细血管通透性、心室应激性等效应。组胺H2受体主要分布于中枢组胺能神经元中及心脏、皮肤等组织中，可以调节胃酸分泌，与胃肠道疾病相关。组胺H3受体主要分布于中枢组胺神经元细胞中，以突触前自身受体的方式表达，中枢神经系统的H3受体与认知、体温调节、焦虑及通过等密切相关。最新发现的组胺H4受体广泛表达于多种细胞中，如角质形成细胞，中性粒细胞，树突状细胞等，参与集体的免疫反应。
组胺受体抑制剂可以竞争性结合组胺受体，进而阻断组胺与受体的相互作用，从而抑制组胺发挥生物学功能。组胺H1受体抑制剂可分为第一代传统抗组胺药物，其可透过血脑屏障与相关受体发生亲和反应，从而导致中枢镇静作用，而二代组胺H1受体抑制剂又被称为非镇静抗组胺药，其中枢镇静作用显著下降，且耐受性较好，主要代表药物有苯海拉明、巴比妥、阿片类等。组胺H2受体抑制剂可竞争性地抑制组胺与H2受体的结合，从而减少胃酸的分泌，第一个应用于临床的H2受体阻断药为西米替丁。组胺H3受体抑制剂可根据结构分为咪唑类及非咪唑类，可用于治疗哮喘、腹泻等病症。组胺H4受体抑制剂在与H1受体拮抗剂联合使用时能抑制皮肤瘙痒和炎症等病症。
现已有研究表明组胺受体抑制剂具有抗埃博拉及流感病毒的活性，但是文献及临床应用中均未见组胺受体抑制剂及其衍生物在抗寨卡病毒方面的应用。
发明内容
针对现有技术存在的问题，本发明提供组胺受体抑制剂及其衍生物在制备抗寨卡病毒药物中的应用，为抗寨卡病毒药物提供了候选药物。
本发明提供组胺受体抑制剂及其衍生物在制备抗寨卡病毒药物中的应用。
进一步地，所述组胺受体抑制剂为美海屈林萘二磺酸盐、富马酸酮替芬、盐酸氟桂利嗪、盐酸赛庚啶、JNJ-7777120、地氯雷他定、马来酸溴苯那敏、马来酸氯苯那敏、盐酸西替利嗪中的一种或多种。
优选地，所述组胺受体抑制剂为美海屈林萘二磺酸盐、富马酸酮替芬、盐酸赛庚啶、JNJ-7777120或地氯雷他定。
进一步优选地，所述组胺受体抑制剂为美海屈林萘二磺酸盐、盐酸赛庚啶、JNJ-7777120或地氯雷他定。
进一步地，所述抗寨卡病毒药物含有药学上有效量的所述组胺受体抑制剂或其衍生物以及药学上可接受的载体。
进一步地，所述组胺受体抑制剂或其衍生物在所述抗寨卡病毒药物中的浓度为10～20μM。
进一步地，所述抗寨卡病毒药物制成药学上可接受的任一剂型。
进一步地，所述剂型包括混悬剂、乳剂、片剂、胶囊剂、颗粒剂、口服液、注射剂。
本发明还提供一种抗寨卡病毒药物，含有药学上有效量的组胺受体抑制剂或其衍生物以及药学上可接受的载体。
进一步地，所述组胺受体抑制剂为美海屈林萘二磺酸盐、富马酸酮替芬、盐酸氟桂利嗪、盐酸赛庚啶、JNJ-7777120、地氯雷他定、马来酸溴苯那敏、马来酸氯苯那敏、盐酸西替利嗪中的一种或多种。
本发明首次提出组胺受体抑制剂及其衍生物具有明确的抗寨卡病毒作用，可显著抑制寨卡病毒蛋白的表达水平以及抑制寨卡病毒RNA的表达水平。本发明还筛选出对寨卡病毒抑制效果较好的组胺受体抑制剂及其衍生物，包括美海屈林萘二磺酸盐、盐酸赛庚啶、JNJ-7777120、地氯雷他定等，它们浓度为10μM时对寨卡病毒的抑制作用与浓度40μM的利巴韦林相当，可作为良好的抗寨卡病毒药物的候选药物。
附图说明
图1为不同组胺受体抑制对寨卡病毒RNA的抑制效果；
图2为不同组胺受体抑制对寨卡病毒蛋白的抑制效果；
图3为不同MOI下美海屈林萘二磺酸盐对寨卡病毒RNA的抑制效果和对寨卡病毒蛋白的抑制效果；
图4为不同MOI下盐酸赛庚啶对寨卡病毒RNA的抑制效果和对寨卡病毒蛋白的抑制效果；
图5为不同MOI下JNJ-7777120对寨卡病毒RNA的抑制效果和对寨卡病毒蛋白的抑制效果；
图6为不同MOI下地氯雷他定对寨卡病毒RNA的抑制效果和对寨卡病毒蛋白的抑制效果。
具体实施方式
下面结合实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。
实施例1
(1)细胞的培养
取Vero E6细胞进行培养，待细胞长满培养瓶后，弃旧培养基，用消化液消化。待细胞变圆，弃消化液，立即加入培养基，用吸管轻轻吹打瓶底，使细胞完全脱离瓶底且使之分散为单细胞悬液。血球计数板计数后，取细胞悬液接种于6孔板，接种细胞密度为2.5×105个/mL。
(2)化合物对寨卡病毒抑制活性的测定
本实施例选用了23种组胺受体抑制剂(具体化合物信息见表1)，分别测定其对寨卡病毒RNA的抑制效果和对寨卡病毒蛋白的抑制效果。
表1 23种组胺受体抑制剂化合物信息
a.对寨卡病毒RNA的抑制效果
将Vero E6细胞接种于6孔板，每孔细胞为5×104个。在37℃，5％CO2孵箱中培养24h后，寨卡病毒(MOI＝0.05)感染Vero E6细胞，分别加入二甲基亚砜(DMSO)、阳性药物利巴韦林(终浓度40μM)、待测化合物(终浓度10μM)处理，继续培养96h后，提取细胞内总RNA，检测细胞内寨卡病毒RNA的表达。
具体检测方法为：根据TRIzol使用说明提取细胞的总RNA。6孔板中每孔加入1mlTRIzol溶液，收集细胞。室温静置2h灭活病毒。取2μg RNA、2μl随机引物，根据M-MLV反转录酶说明进行逆转录。以逆转录的cDNA为模板，进行实时荧光PCR检测。cDNA扩增反应体系：SsoFast EvaGreen Supermix 10μl，正向引物(10μM)1μl，反向引物(10μM)1μl，模板cDNA0.5μl，无RNA酶水7.5μl。反应条件为95℃，30sec；然后是40次循环，每次循环条件为95℃，5sec；60℃，34sec。熔解曲线为65℃～95℃，连续。其中正向引物和反向引物具体如下：
ZIKV正向引物：5’-CCACGCACTGATAACAT-3’；
ZIKV反向引物：5’-AAGTAGCAAGGCCTGCTCT-3’；
gapdh正向引物：5’-GTCCACTGGCGTCTTCACCA-3’；
gapdh反向引物：5’-GTGGCAGTGATGGCATGGAC-3’。
以管家基因gapdh为内对照，用2-ΔΔCT法分析寨卡mRNA转录水平的变化，结果如图1所示。从图中可以看出，10μM的富马酸酮替芬、盐酸氟桂利嗪、JNJ-7777120、地氯雷他定、马来酸溴苯那敏、马来酸氯苯那敏均可以抑制寨卡病毒RNA的转录。
b.对寨卡病毒蛋白的抑制效果
将Vero E6细胞接种于6孔板，每孔细胞为5×104个。在37℃，5％CO2孵箱中培养24h后，寨卡病毒(MOI＝0.05)感染Vero E6细胞，分别加入二甲基亚砜(DMSO)、阳性药物利巴韦林(终浓度40μM)、待测化合物(终浓度10μM)处理，继续培养96h后，收集细胞，进行Westernblot检测。
具体检测方法为：刮取6孔板中细胞，1ml预冷PBS重悬，2×103g离心5min收集细胞，去上清，加入50μl预冷PBS重悬，再加入50μl 2×上样缓冲液裂解细胞，沸水浴10min，每隔3min涡旋振荡。SDS-PAGE分离蛋白样品。转PVDF膜后，先后与一抗和二抗孵育，然后ECL显色。一抗使用如下浓度的兔源多克隆Envelop抗体(1:1000)，鼠源单克隆β-actin抗体(1:2000)；辣根过氧化物酶标记的二抗使用如下浓度的山羊抗小鼠(1:2000)，山羊抗兔(1:5000)。
结果如图2所示，从图中可以看出，美海屈林萘二磺酸盐、富马酸酮替芬、盐酸氟桂利嗪、盐酸赛庚啶、JNJ-7777120、地氯雷他定、马来酸溴苯那敏、马来酸氯苯那敏、盐酸西替利嗪均可以抑制寨卡病毒蛋白的表达。
通过上述测定得到9个阳性化合物，对寨卡病毒具有抑制活性，具体结果见表2。
表2对寨卡病毒具有抑制活性的阳性化合物
其中，RNA抑制率由图1结果按照如下公式：RNA抑制率＝1-RNA化合物/RNADMSO×100％计算得到；
蛋白水平抑制率由采用Image软件对Western blot结果进行分析得到，其中以DMSO为参照，其蛋白水平抑制率为1。
实施例2
分别测定对寨卡病毒抑制效果较好的美海屈林萘二磺酸盐、盐酸赛庚啶、JNJ-7777120和地氯雷他定四种化合物的EC50、CC50，结果如表3所示。
表3四种化合物的EC50和CC50
| 化合物 | EC50(μM) | CC50(μM) | SI(CC50/EC50) |
| 美海屈林萘二磺酸盐 | 3.3 | 50.5 | 15.3 |
| 盐酸赛庚啶 | 8.6 | 33 | 3.8 |
| JNJ-7777120 | 1.2 | 64.2 | 53.5 |
| 地氯雷他定 | 0.7 | 23.7 | 33.9 |
从表3可以看出，美海屈林萘二磺酸盐、盐酸赛庚啶、JNJ-7777120和地氯雷他定四种化合物均具有较强的抗寨卡病毒作用，且细胞毒性较低，适宜作为抗寨卡病毒药物的候选药物。
实施例3
以不同MOI的寨卡病毒感染细胞，按照与实施例1中相同的方法分别测定美海屈林萘二磺酸盐、盐酸赛庚啶、JNJ-7777120和地氯雷他定四种化合物对寨卡病毒RNA的抑制效果和对寨卡病毒蛋白的抑制效果，结果如图3-6所示。可以看出，美海屈林萘二磺酸盐、盐酸赛庚啶、JNJ-7777120和地氯雷他定这四种化合物在不同MOI下均可以抑制寨卡病毒。
最后，本发明的实施例仅为较佳的实施方案，并非用于限定本发明的保护范围。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
序列表
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Claims (10)
1.组胺受体抑制剂及其衍生物在制备抗寨卡病毒药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述组胺受体抑制剂为美海屈林萘二磺酸盐、富马酸酮替芬、盐酸氟桂利嗪、盐酸赛庚啶、JNJ-7777120、地氯雷他定、马来酸溴苯那敏、马来酸氯苯那敏、盐酸西替利嗪中的一种或多种。
3.根据权利要求2所述的应用，其特征在于，所述组胺受体抑制剂为美海屈林萘二磺酸盐、富马酸酮替芬、盐酸赛庚啶、JNJ-7777120或地氯雷他定。
4.根据权利要求1～3任一项所述的应用，其特征在于，所述抗寨卡病毒药物含有药学上有效量的所述组胺受体抑制剂或其衍生物以及药学上可接受的载体。
5.根据权利要求4所述的应用，其特征在于，所述组胺受体抑制剂或其衍生物在所述抗寨卡病毒药物中的浓度为10～20μM。
6.根据权利要求1～5任一项所述的应用，其特征在于，所述抗寨卡病毒药物制成药学上可接受的任一剂型。
7.根据权利要求6所述的应用，其特征在于，所述剂型包括混悬剂、乳剂、片剂、胶囊剂、颗粒剂、口服液、注射剂。
8.一种抗寨卡病毒药物，其特征在于，含有药学上有效量的组胺受体抑制剂或其衍生物以及药学上可接受的载体。
9.根据权利要求8所述的一种抗寨卡病毒药物，其特征在于，所述组胺受体抑制剂为美海屈林萘二磺酸盐、富马酸酮替芬、盐酸氟桂利嗪、盐酸赛庚啶、JNJ-7777120、地氯雷他定、马来酸溴苯那敏、马来酸氯苯那敏、盐酸西替利嗪中的一种或多种。
10.根据权利要求8或9所述的一种抗寨卡病毒药物，其特征在于，所述组胺受体抑制剂或其衍生物在所述抗寨卡病毒药物中的浓度为10～20μM。
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| WO2023010329A1 (zh) * | 2021-08-04 | 2023-02-09 | 杭州浙大迪迅生物基因工程有限公司 | 一种检测人组胺受体HRH4 mRNA表达水平的试剂、试剂盒和检测方法 |
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