CN114469912A - 内昔酚盐酸盐在制备治疗新型冠状病毒所致疾病的药物中的应用 - Google Patents
内昔酚盐酸盐在制备治疗新型冠状病毒所致疾病的药物中的应用 Download PDFInfo
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Abstract
本发明公开了内昔酚盐酸盐在制备预防和/或治疗新型冠状病毒所致疾病的药物中的应用。内昔酚盐酸盐是小分子化合物,其CC50为124.7μM。本发明首次发现内昔酚盐酸盐能够剂量依赖的抑制新型冠状病毒SARS‑CoV‑2复制,其IC50(半数抑制浓度):细胞内为0.91μM,细胞外为0.77μM,选择指数(SI)约为137(细胞内)和162(细胞外),说明内昔酚盐酸盐是低毒高效的抗新型冠状病毒SARS‑CoV‑2的药物。
Description
技术领域
本发明涉及医药技术领域,具体涉及内昔酚盐酸盐(Endoxifen hydrochloride,CAS:1032008-74-4)在制备预防和/或治疗新型冠状病毒所致疾病的药物中的应用。
背景技术
新型冠状病毒(SARS-CoV-2)是新型冠状病毒肺炎(COVID-19)的病原体。 SARS-CoV-2与SARS-CoV病毒均属于冠状病毒科(Coronaviridae),冠状病毒β属。 SARS-CoV-2是一种正链单股RNA冠状病毒。其RNA序列长度约30kb。COVID-19 病毒粒子外膜由4种结构蛋白组成,包括N蛋白(Nucleocapsid,核衣壳蛋白)、S蛋白 (Spikeprotein)、E蛋白(Envelopeprotein)和M蛋白(Membrane protein)。其中的S蛋白决 定了病毒的宿主范围和特异性。到目前为止,尚且没有任何特效药物能够治愈新型冠状 病毒肺炎。因此,要完全战胜新冠病毒,相应的抗新冠病毒药物的研发也是至关重要的。
内昔酚盐酸盐,英文名:Endoxifen hydrochloride,CAS:1032008-74-4,其结构式如下式(I)所示,
内昔酚盐酸盐是Tamoxifen的活性代谢产物,是一种有效的选择性雌激素受体拮抗剂。 具有抗乳腺肿瘤的活性。但未见其抗新型冠状病毒的报道。
发明内容
为克服现有技术中存在的不足,本发明的目的是提供内昔酚盐酸盐在制备预防和/或 治疗新型冠状病毒SARS-CoV-2所致疾病的药物中的应用。
具体而言,为解决本发明的技术问题,采用如下技术方案:
第一方面,本发明提供式(I)化合物内昔酚盐酸盐在如下X1)-X5)中任一种的 应用:
X1)制备预防和/或治疗新型冠状病毒SARS-CoV-2所致疾病的产品;
X2)制备预防和/或治疗新型冠状病毒SARS-CoV-2感染的产品;
X3)制备新型冠状病毒SARS-CoV-2抑制剂;
X4)制备抑制新型冠状病毒SARS-CoV-2增殖的产品;
X5)制备抑制新型冠状病毒SARS-CoV-2产生细胞病变效应的产品。
优选地,上述应用中,式(I)化合物可以作为唯一活性成分,或者可以与一种、 两种或更多种其他抗病毒药物一起作为活性成分。
优选地,其他抗病毒药物选自更昔洛韦、阿昔洛韦、金刚烷胺、金刚乙胺、奥司他韦、阿巴卡韦、醋孟南、阿昔洛韦钠、阿德福韦、阿洛夫定、阿韦舒托、盐酸三环癸胺、 阿拉诺丁、阿立酮、阿替韦啶甲磺酸酯、阿夫立定、西多福韦、西潘茶碱、恩曲他滨、 盐酸阿糖胞苷、甲磺酸地拉韦啶、地昔洛韦、去羟肌苷、二噁沙利、依度尿苷、乙米韦 林、依曲西他平、恩韦拉登、恩韦肟、贺普丁、泛昔洛韦、盐酸氯苯氢异喹、非西他滨、 非阿尿苷、磷利酯、膦甲酸钠、膦乙酸钠、甘西洛维钠、碘苷、茚地那韦、乙氧丁酮醛、 拉米夫定、洛布卡韦、洛德腺苷、洛匹那韦、盐酸美莫汀、甲红硫脲、那非那韦、奈韦 拉平、喷昔洛韦、吡罗达韦、利巴韦林、甲磺酸沙奎那韦、利托那韦、盐酸索金刚胺、 索立夫定、匍枝青霉菌素、司他夫定、替诺福韦、盐酸梯络龙、曲氟尿苷、盐酸伐昔洛 韦、阿糖腺苷、磷酸阿糖腺苷、阿糖腺苷磷酸钠、替拉那韦、韦罗肟、扎西他滨、齐多 夫定、净韦肟。
优选地,上述应用中,新型冠状病毒SARS-CoV-2所致疾病为SARS-CoV-2引起的 感染性疾病或其并发症;进一步优选地,感染性疾病为呼吸道感染疾病。
优选地,所述产品为药物。
第二方面,本发明提供一种包含式(I)化合物的药物组合物在如下X1)-X5)中 任一种应用:
X1)制备预防和/或治疗新型冠状病毒SARS-CoV-2所致疾病的产品;
X2)制备预防和/或治疗新型冠状病毒SARS-CoV-2感染的产品;
X3)制备新型冠状病毒SARS-CoV-2抑制剂;
X4)制备抑制新型冠状病毒SARS-CoV-2增殖的产品;
X5)制备抑制新型冠状病毒SARS-CoV-2产生细胞病变效应的产品。
优选地,所述药物组合物还包含药学上可接受的载体。
优选地,所述载体包括但不限于水溶性载体材料(如聚乙二醇、聚乙烯吡咯烷酮、有机酸等)、难溶性载体材料(如乙基纤维素、胆固醇硬脂酸酯等)、肠溶性载体材料(如 醋酸纤维素酞酸酯和羧甲乙纤维素等)。其中优选的是水溶性载体材料。
优选地,所述药物组合物中还可以添加常规的助溶剂、缓冲剂、pH调节剂等。
优选地,所述药物组合物中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
优选地,所述药物组合物的剂型,包括但不限于片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、冻干粉针剂 等。上述各种剂型的药物均可以按照药学领域的常规方法制备。使用上述剂型可以经注 射给药,包括皮下注射、静脉注射、肌肉注射和腔内注射等;腔道给药,如经直肠和阴 道;呼吸道给药,如经鼻腔;粘膜给药。
本发明的有益效果:
本发明首次发现式(I)化合物(内昔酚盐酸盐)可抑制新型冠状病毒SARS-CoV-2增殖及感染宿主细胞,可用作治疗新型冠状病毒感染方面的疾病。
式(I)化合物是小分子化合物,其CC50为124.7μM,能够剂量依赖的抑制新型冠 状病毒SARS-CoV-2复制,其IC50(半数抑制浓度)为0.91μM。选择指数(SI)约为 137。说明式(I)化合物是低毒高效的抗新型冠状病毒SARS-CoV-2的药物。
附图说明
图1为一种式(I)化合物细胞毒性检测示意图。
图2为一种式(I)化合物处理新型冠状病毒SARS-CoV-2感染细胞中病毒复制效 率图。
图3为一种式(I)化合物处理新型冠状病毒SARS-CoV-2感染细胞培养液上清中 病毒复制效率图。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下 列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知 方法制备。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。
定义与说明:
本文所用的术语“包含”、“具有”、“包括”或“含有”是指包括在内的或开放式的,并不排除额外的、未引述的元件或方法步骤。
本文所用的“或”的定义仅为替代物以及“和/或”,但除非明确表示仅为替代物或替代 物之间相互排斥外,权利要求中的术语“或”是指“和/或”。
除非另外定义或由背景清楚指示,否则在本公开中的全部技术与科学术语具有如本 公开所属领域的普通技术人员通常理解的相同含义。
目前,抗新型冠状病毒SARS-CoV-2药物体外筛选的细胞培养模型是最常用的筛选模型,其优点在于:可提供大量遗传性状相同的细胞为研究对象,操作方便,可消除其 它外界因素的影响,并可以检测药物的有效浓度和治疗指数,为后期机理研究提供更多 基础。本发明采用细胞培养筛选法检测式(I)所示化合物对新型冠状病毒SARS-CoV-2 感染Caco-2细胞的影响,基于对上清和细胞内病毒核酸拷贝数的检测定量分析式(I) 化合物抗新型冠状病毒SARS-CoV-2活性。
实施例1:式(I)化合物(内昔酚盐酸盐)抗新型冠状病毒活性的评价
1.实验材料
1.1细胞、病毒和药物
Caco-2细胞购自ATCC(货号:HTB-037)。
SARS-CoV-2活病毒(编号IVCAS 6.7512)。
式(I)化合物(CAS:1032008-74-4)购于Sigma公司。
1.2试剂
DMEM培养基和FBS购自GIBCO公司;CCK8细胞活性检测试剂盒购自Thermofisher公司;SYBR混合液(iTaqTMUniversalGreen Supermix)购自Bio-Rad 公司。
1.3实验仪器
定量PCR仪(Bio-Rad CFX96 TouchTMReal-Time PCR detection system)购自Bio-Rad 公司。多标记微孔板读取仪购自PerkinElmer公司。1.0R型冷冻离心机和细胞培养箱购自Thermofisher公司。
2.实验方法与结果
2.1细胞培养
37℃,5%CO2加湿培养箱中培养。使用含有10%FBS、100U/mL的青霉素和链霉 素的DMEM培养基。细胞至90%汇合度后传代,传代比例1/3–1/4。
2.2病毒培养
200μl/管分装并置-70℃冻存备用。
2.3式(I)化合物的细胞毒性检测
Caco-2细胞按8×103细胞/孔(100μl)接种于96孔细胞培养板中,细胞贴壁后备用; 用细胞维持液(DMEM+2%血清)将药物以200.0μM为最高浓度按照2倍梯度稀释共计 6个梯度(200μM,100μM,50μM,25μM,12.5μM,6.25μM,3.125μM)进行处理, 每梯度3个复孔。培养48h后弃掉培养上清,于每孔中加入10μl含有CCK8试剂,置 细胞培养箱中继续培养1h,1h后用酶标仪测定在450μM处的吸光度,计算细胞存活 率。
结果显示(图1),式(I)化合物对Caco-2细胞的CC50为124.7微摩尔/升。在小 于100μM范围内对Caco-2细胞完全没有细胞毒性,说明式(I)化合物有比较安全的适 用范围,即式(I)化合物的给药剂量按照细胞实验用量为0.25~4.0μM。
2.4基于荧光定量PCR检测式(I)化合物抑制SARS-CoV-2复制的效率
2.4.1.以下实验均在BSL-3实验室中进行:
将Caco-2细胞按1.0×104细胞/孔接种于48孔细胞培养板中,37℃细胞培养箱中培 养14~18h后,待细胞长成单层后备用。将孔板中培养基弃去,PBS清洗两遍后,加入0.5MOI病毒液和各浓度梯度药物共500μl于37℃细胞培养箱中培养。药物以4.0μM为 起始浓度,连续2倍梯度稀释5个梯度,每梯度设置3个复孔。培养48h后取各实验孔 上清和细胞提取RNA,逆转录为cDNA,然后进行荧光定量PCR检测。实验设置空白 对照组、阳性对照组(瑞德西韦)、阴性对照组(病毒感染后无药物处理)和实验药物 组。
2.4.2. 48h后收样,分别用Trizol LS收取细胞上清与细胞,病毒灭活后带出生物安全三 级(BSL-3)实验室。用于RNA提取。
2.4.3.按天漠科技公司TR205-50试剂盒说明提取上清和细胞中的RNA。
2.4.4.得到的RNA按庄盟ZR102反转录试剂盒说明逆转录为cDNA。
2.4.5.通过基因组定量PCR方法(QPCR)检测基因组复制水平。定量PCR引物针对SARS-CoV-2的S2基因序列,定量PCR引物如下:
5'-GCTGGTGCTGCAGCTTATTA-3';
5'-AGGGTCAAGTGCACAGTCTA-3'。
选择管家基因GADPH作为校正的内参对照基因,针对GADPH的定量PCR引物如下:
5'-GCTCCCTCTTTCTTTGCAGCAAT-3';
5'-TACCATGAGTCCTTCCACGATAC-3'。
2.4.6.定量的Ct值通过内参基因(GAPDH)进行校对,然后计算抑制率,计算公式:病毒复制抑制率=(1-药物组/阴性对照组)×100%。结果通过GraphPad Prism 8软件计算出平均值、标准差及IC50。
2.4.7.利用步骤(2.4.6)中的计算结果绘制式(I)化合物抑制SARS-CoV-2的复制的结 果图。结果如图2和图3所示。
图2结果显示:在Caco-2细胞中,式(I)化合物能剂量依赖地抑制SARS-CoV-2 的复制水平,其对SARS-CoV-2复制的IC50(半数抑制浓度)为0.91微摩尔/升。
图3结果显示:在Caco-2细胞培养液上清中,式(I)化合物能剂量依赖地抑制SARS-CoV-2的复制水平,其对SARS-CoV-2复制的IC50(半数抑制浓度)为0.77微摩 尔/升。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明 的保护范围之内。
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<110> 中山亿维迪科技有限公司
<120> 内昔酚盐酸盐在制备治疗新型冠状病毒所致疾病的药物中的应用
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Claims (10)
2.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SARS-CoV-2所致疾病为SARS-CoV-2引起的感染性疾病或其并发症;进一步优选地,感染性疾病为呼吸道感染疾病。
3.根据权利要求2所述的应用,其特征在于,式(I)化合物作为唯一活性成分;或者与一种、两种或更多种其他抗病毒药物的一起作为活性成分;
优选地,所述其他抗病毒药物选自更昔洛韦、阿昔洛韦、金刚烷胺、金刚乙胺、奥司他韦、阿巴卡韦、醋孟南、阿昔洛韦钠、阿德福韦、阿洛夫定、阿韦舒托、盐酸三环癸胺、阿拉诺丁、阿立酮、阿替韦啶甲磺酸酯、阿夫立定、西多福韦、西潘茶碱、恩曲他滨、盐酸阿糖胞苷、甲磺酸地拉韦啶、地昔洛韦、去羟肌苷、二噁沙利、依度尿苷、乙米韦林、依曲西他平、恩韦拉登、恩韦肟、贺普丁、泛昔洛韦、盐酸氯苯氢异喹、非西他滨、非阿尿苷、磷利酯、膦甲酸钠、膦乙酸钠、甘西洛维钠、碘苷、茚地那韦、乙氧丁酮醛、拉米夫定、洛布卡韦、洛德腺苷、洛匹那韦、盐酸美莫汀、甲红硫脲、那非那韦、奈韦拉平、喷昔洛韦、吡罗达韦、利巴韦林、甲磺酸沙奎那韦、利托那韦、盐酸索金刚胺、索立夫定、匍枝青霉菌素、司他夫定、替诺福韦、盐酸梯络龙、曲氟尿苷、盐酸伐昔洛韦、阿糖腺苷、磷酸阿糖腺苷、阿糖腺苷磷酸钠、替拉那韦、韦罗肟、扎西他滨、齐多夫定、净韦肟。
4.根据权利要求1-3任一项所述的应用,其特征在于,所述产品为药物。
6.根据权利要求5所述的应用,其特征在于,所述药物组合物还包含药学上可接受的载体;
优选地,所述载体包括但不限于水溶性载体材料(如聚乙二醇、聚乙烯吡咯烷酮、有机酸等)、难溶性载体材料(如乙基纤维素、胆固醇硬脂酸酯等)、肠溶性载体材料(如醋酸纤维素酞酸酯和羧甲乙纤维素等);进一步优选的是水溶性载体材料。
7.根据权利要求5所述的应用,其特征在于,所述药物组合物中还可以添加常规的助溶剂、缓冲剂、pH调节剂等。
8.根据权利要求6所述的应用,其特征在于,所述药物组合物中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
9.根据权利要求5-8任一项所述的应用,其特征在于,所述药物组合物的剂型,包括但不限于片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、冻干粉针剂。
10.根据权利要求9所述的应用,其特征在于,使用权利要求9中的剂型可以经注射给药,包括皮下注射、静脉注射、肌肉注射和腔内注射等;腔道给药,如经直肠和阴道;呼吸道给药,如经鼻腔;粘膜给药。
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