CN116712437A - 塞卡替尼在制备抗新型冠状病毒药物中的应用 - Google Patents
塞卡替尼在制备抗新型冠状病毒药物中的应用 Download PDFInfo
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
本发明属于生物医药技术领域,具体涉及塞卡替尼在制备抗新型冠状病毒药物中的应用。所述塞卡替尼可以抑制新型冠状病毒的复制,在Vero‑E6和A549‑hACE2细胞中显著地抑制新冠状病毒活病毒的复制;并且本发明化合物塞卡替尼该药物已通过了临床安全性验证,对细胞的毒性较小,治疗指数较高,非常适合应用于抗新型冠状病毒的治疗中。
Description
技术领域
本发明属于生物医药技术领域。更具体地,涉及塞卡替尼在制备抗新型冠状病毒药物中的应用。
背景技术
新型冠状病毒(SARS-CoV-2)属于套式病毒目、冠状病毒科、正冠状病毒亚科,是一种新型的β属有包膜的冠状单股正链RNA病毒,其结构特点大部分与其他冠状病毒相同,但其内含基因较大,有29891个碱基,编码9860个氨基酸。SARS-CoV-2病毒粒子呈球形,通过包膜表面上形成独特冠状结构的刺突蛋白S中的S1亚单位的受体结合域与宿主细胞的ACE2受体形成相互作用,由S2亚单位的七肽重复区1(HR1)形成同源三聚体,再与七肽重复区2(HR2)连接形成6-螺旋束(6-helix bundle,6-HB)的方式侵入细胞内部。在SARS-CoV-2侵入人体后,会同时脱去表面的包膜释放病毒RNA,然后通过侵占细胞内部的方式来不断进行大量复制并抑制细胞原本的基因表达(魏薇,彭南求.新型冠状病毒特点及疫苗分析[J].基层医学论坛,2023,27(01):115-118.)。
目前,对于新型冠状病毒的防治主要依靠于疫苗和少量对其抑制作用较为明显的药物。其中,灭活病毒等制备的疫苗虽然对SARS-CoV-2有一定的抑制、预防作用,但是SARS-CoV-2已经衍生出了各种不同的突变株,疫苗的效果显著降低。市场已有为数不多的几种新冠特效药上市,但是这些药均存在价格高,难以购买得到的问题。为了提供更多新型冠状病毒的治疗药物,现有技术一直在研发更多的抗新型冠状病毒药物,如中国专利申请CN114073709A公开了维生素B12在制备抗新型冠状病毒SARS-CoV-2药物中的用途,其中维生素B12能够在Vero-E6细胞上抑制新型冠状病毒的感染;但这些化合物的临床效果仍未可知,因此,仍然迫切需要提供更多的抗新型冠状病毒药物,以增加临床治疗选择。
发明内容
本发明要解决的技术问题是克服现有新型冠状病毒突变使疫苗抗病毒效果降低,治疗新型冠状病毒的药物不足的缺陷,提供一种塞卡替尼在制备抗新型冠状病毒药物中的应用。
本发明上述目的通过以下技术方案实现:
塞卡替尼(Saracatinib,AZD0530)是一种口服小分子酪氨酸激酶Src抑制剂,可通过抑制Src信号通路,诱导细胞周期停滞,阻断细胞迁移、侵袭、增殖等过程,用于肿瘤疾病的治疗。另外的,塞卡替尼也可以抑制破骨细胞的活性,减弱骨吸收作用,对恶性肿瘤骨转移有增加骨密度、减轻疼痛的疗效。2019年3月,塞卡替尼还被FDA授予治疗特发性肺纤维化的孤儿药资格。
本发明研究发现,塞卡替尼在细胞中可以显著抑制新型冠状病毒复制子在HEK293T细胞中的复制,并且,所述塞卡替尼在Vero-E6和A549-hACE2细胞中对新型冠状病毒活病毒的半数有效浓度较低,对细胞毒性的CC50较高,并且还通过了药物临床安全性验证,安全性较好,计算得到的治疗指数SI大于18,具有较好的治疗新型冠状病毒效果。
因此,本发明要求保护塞卡替尼在制备抗新型冠状病毒药物中的应用。
进一步地,所述塞卡替尼还可以为塞卡替尼衍生物、塞卡替尼结构类似物的立体异构体、几何异构体、水合物、溶剂化物或药学上可接受的盐或前药。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括,但并不限于,水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
本发明所述塞卡替尼存在自由形态,或合适的、作为药学上可接受的衍生物。根据本发明,药学上可接受的衍生物包括,但并不限于,药学上可接受的前药、盐、酯、酯类的盐,或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物,本发明其他方面所描述的化合物,其代谢产物或他的残留物。
更进一步地,所述塞卡替尼抑制新型冠状病毒复制子的复制。
进一步地,所述新型冠状病毒包括SARS-CoV-2突变株D614G。
更进一步地,所述塞卡替尼对新型冠状病毒的半数有效浓度EC50为1~7μM。本发明实验发现,塞卡替尼在不同的细胞(如HEK293T细胞、Vero-E6细胞、A549-hACE2细胞)中,对所侵染的新型冠状病毒具有显著的抑制效果。
进一步地,结合所测得的EC50和CC50去计算治疗指数,所述塞卡替尼对新型冠状病毒在A549-hACE2细胞上的治疗指数为SI>18。
更进一步地,所述药物还包括药学上可接受的辅料。
进一步地,所述辅料包括:溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、絮凝剂、反絮凝剂、助滤剂、释放阻滞剂等。所述辅料根据要制备的剂型进行选择。
优选地,可作为药学上可接受辅料的物质包括,但并不限于,离子交换剂,铝,硬脂酸铝,卵磷脂,血清蛋白,如人血清蛋白,缓冲物质如磷酸盐,甘氨酸,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶体硅,三硅酸镁,聚乙烯吡咯烷酮,聚丙烯酸脂,蜡,聚乙烯-聚氧丙烯-阻断聚合体,羊毛脂,糖,如乳糖,葡萄糖和蔗糖;淀粉如玉米淀粉和土豆淀粉;纤维素和它的衍生物如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;树胶粉;麦芽;明胶;滑石粉;辅料如可可豆脂和栓剂蜡状物;油如花生油,棉子油,红花油,麻油,橄榄油,玉米油和豆油;二醇类化合物,如丙二醇和聚乙二醇;酯类如乙基油酸酯和乙基月桂酸酯;琼脂;缓冲剂如氢氧化镁和氢氧化铝;海藻酸;无热原的水;等渗盐;林格(氏)溶液;乙醇,磷酸缓冲溶液,和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁,着色剂,释放剂,包衣衣料,甜味剂,调味剂和香料,防腐剂和抗氧化剂。
更进一步地,所述药物为口服剂、注射剂或吸入剂。
优选地,所述口服剂包括片剂、胶囊剂、丸剂、颗粒剂、口服液等剂型。
另外的,本发明还要求保护一种抗新型冠状病毒的药物组合物,其特征在于,所述药物组合物含有塞卡替尼和/或其药学上可接受的盐和/或其药物前体。
进一步地,所述药物组合物还含有抗炎药、病毒进入抑制剂、病毒脱壳抑制剂、病毒逆转录酶抑制剂、病毒蛋白合成抑制剂、病毒蛋白酶抑制剂、病毒聚合酶抑制剂、病毒整合酶抑制剂、干扰素中的一种或多种。
优选地,所述病毒进入抑制剂包含但不限于马拉韦罗(maraviroc)、恩夫韦地(maraviroc)、伊巴珠单抗(ibalizumab)、福斯特沙韦(fostemsavir)、普乐沙福(plerixafor)、表没食子儿茶素没食子酸酯、韦克利韦洛克(vicriviroc)、阿拉韦罗(aplaviroc)、马拉韦罗、曲金刚胺、硝唑尼特(nitazoxanide)、乌米那韦(umifenovir)和普达菲洛(umifenovir)。
优选地,所述病毒脱壳抑制剂包含但不限于金刚烷胺、金刚乙胺和普拉康纳利(pleconaril)。
优选地,所述病毒逆转录酶抑制剂包含但不限于齐夫多定(zidovudine)、地达诺新(didanosine)、扎西他滨(zalcitabine)、司他夫定(stavudine)、拉米夫定(lamivudine)、阿巴卡韦(abacavir)、恩曲他滨(emtricitabine)、恩替卡韦(entecavir)、特鲁瓦达(truvada)、奈韦拉平(nevirapine)、雷特格韦(raltegravir)和替诺福韦酯(tenofovir disoproxil)。
优选地,所述病毒蛋白酶抑制剂包含但不限于膦沙那韦(fosamprenavir)、利托那韦(ritonavir)、阿扎那韦(atazanavir)、奈非那韦(nelfinavir)、茚地那韦(indinavir)、沙奎那韦(saquinavir)、沙奎那韦、泛昔洛韦(famciclovir)、福米韦森(fomivirsen)、洛匹那韦(lopinavir)、利巴韦林(ribavirin)、达鲁那韦(darunavir)、奥司他韦(oseltamivir)和替拉那韦(tipranavir)。
优选地,所述病毒聚合酶抑制剂包含但不限于鹅膏毒素、利福霉素、阿糖胞苷、非达霉素、万寿菊菌毒素(tagetitoxin)、膦甲酸钠、碘苷、喷昔洛韦(penciclovir)、索非布韦(sofosbuvir)、三氟尿苷、伐昔洛韦(valacyclovir)、缬更昔洛韦(valganciclovir)、阿糖腺苷和瑞德西韦(remdesivir)。
优选地,所述病毒整合酶抑制剂包含但不限于拉替拉韦(raltegarvir)、埃替拉韦(elvitegravir)、度鲁特韦(dolutegravir)、比克替拉韦(bictegravir)和卡博特韦(cabotegravir)。
优选地,所述干扰素包含但不限于I型干扰素、II型干扰素、III型干扰素和聚乙二醇干扰素α-2a。
本发明要求保护的化合物或组合物应用于制备抗新型冠状病毒药物,但不限于,使用本发明的化合物或药物组合物的有效量对患者给药来制备用于预防或治疗新型冠状病毒引发的疾病,减轻新型冠状病毒引发的疾病症状或者延缓新型冠状病毒引发的疾病的发展或发作的药品的用途。
本发明要求保护的化合物或药物除了对人类治疗有益以外,还可应用于兽医治疗宠物、引进品种的动物和农场的动物,包括哺乳动物,啮齿类,禽类动物等等。另外一些动物的实例包括马、狗、猫、猪等。
本发明具有以下有益效果:
本发明提供了塞卡替尼在制备抗新型冠状病毒药物中的应用,其中塞卡替尼在各种细胞上均能显著地抑制新型冠状病毒;并且本发明化合物塞卡替尼该药物已通过了临床安全性验证,对细胞的毒性较小,治疗指数较高,非常适于应用于抗新型冠状病毒的治疗中。
附图说明
图1为本发明实施例1中不同浓度塞卡替尼在HEK293T细胞中对新冠病毒复制子的抑制曲线图。
图2为本发明实施例2中不同浓度塞卡替尼在Vero-E6细胞中对新冠病毒活病毒的抑制曲线图。
图3为本发明实施例3中不同浓度塞卡替尼在A549-hACE2细胞中对新冠病毒活病毒的抑制曲线图。
图4为本发明实施例4中不同浓度塞卡替尼对A549-hACE2细胞活性影响的数据统计图。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,以下实施例所用试剂和材料均为市购。
实施例1塞卡替尼在新冠病毒复制子系统上可以抑制病毒复制
1、实验方法:
将HEK293T细胞以4×104个细胞每孔的密度接种到48孔细胞培养板中,并于5%CO2、37℃培养箱中培养过夜(约12h)。待细胞完全贴壁后采用InvitrogenTMLipofectamineTM2000试剂进行细胞转染,每孔转染250ng新冠病毒复制子质粒和15ng TK质粒。转染6h后更换新的培养基250μL/孔,设置细胞对照(无化合物处理)和实验组(化合物塞卡替尼处理),药物按照20μM、10μM、5μM、2μM、1μM、0.5μM、0.1μM浓度加入到细胞中。加药48h之后,通过检测双荧光值来反应病毒复制情况。
2、实验结果:
结果如图1所示,由图可见,塞卡替尼可有效抑制新冠病毒复制子的复制,半数有效浓度EC50为5.88μM,对新冠病毒有显著的抑制作用。
实施例2塞卡替尼在Vero-E6细胞中抗新冠病毒活性测试
1、实验方法:
将Vero E6细胞以2×104个细胞每孔的密度接种到48孔细胞培养板中,并于5%CO2、37℃培养箱中培养。等待细胞完全贴壁后,分别以MOI=0.05接种新冠病毒D614G株到细胞内,感染1h后更换培养基,设置细胞对照(无化合物处理,病毒感染和不感染)和实验组(化合物塞卡替尼处理)。将培养液稀释的化合物塞卡替尼加入细胞培养板,48h之后,收集细胞上清液体,提取RNA,通过qPCR检测病毒拷贝数。
2、实验结果:
结果如图2所示,由图可见,塞卡替尼在Vero-E6细胞中可以高效抑制新冠病毒D614G株的复制,半数有效浓度EC50为6.34μM。
实施例3塞卡替尼在A549-hACE2细胞中抗新冠病毒活性测试
1、实验方法:
将A549-hACE2细胞以2×104个细胞每孔的密度接种到48孔细胞培养板中,并于5%CO2、37℃培养箱中培养。等待细胞完全贴壁后,分别以MOI=0.05接种新冠病毒D614G株到细胞内,感染1小时后更换培养基,设置细胞对照(无化合物处理,病毒感染和不感染)和实验组(化合物塞卡替尼处理)。将培养液稀释的化合物塞卡替尼加入细胞培养板,48h之后,收集细胞上清液体,提取RNA,通过qPCR检测病毒拷贝数。
2、实验结果:
结果如图3所示,由图可见,塞卡替尼在A549-hACE2细胞中可以高效抑制新冠病毒D614G株的复制,半数有效浓度EC50仅为1.09μM,抑制效果显著。
实施例4:塞卡替尼在A549-hACE2细胞中的细胞毒性检测
1、实验方法:
将A549-hACE2细胞以1×104个细胞每孔的密度接种到96孔细胞培养板中,并于5%CO2、37℃培养箱中培养。等待细胞完全贴壁后,设置细胞对照(DMSO组,无细胞组)和实验组(化合物塞卡替尼处理)。将培养液稀释的化合物分别按照0μM、0.0625μM、0.125μM、0.25μM、0.5μM、1μM、5μM、10μM、20μM浓度加入细胞,待加药48h之后,使用细胞活性检测试剂Bimake Cell Counting Kit-8(CCK-8)检测每孔细胞活力。
2、实验结果:
结果如图4所示,由图可见,塞卡替尼在A549-hACE2细胞中表现出较低毒性,CC50>20μM,根据实施例3塞卡替尼在A549-hACE2细胞中对新冠病毒半数有效浓度EC50为1.09μM,通过计算得到塞卡替尼在A549-hACE2细胞上,对新冠病毒的治疗指数为SI>18.35,证明塞卡替尼非常适合用于治疗新冠病毒感染的疾病中,具有较高的安全性。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.塞卡替尼在制备抗新型冠状病毒药物中的应用。
2.根据权利要求1所述应用,其特征在于,所述塞卡替尼还可以为塞卡替尼衍生物、塞卡替尼结构类似物的立体异构体、几何异构体、水合物、溶剂化物或药学上可接受的盐或前药。
3.根据权利要求1所述应用,其特征在于,所述塞卡替尼抑制新型冠状病毒的复制。
4.根据权利要求1所述应用,其特征在于,所述新型冠状病毒包括SARS-CoV-2D614G突变株。
5.根据权利要求1所述应用,其特征在于,所述塞卡替尼对新型冠状病毒的半数有效浓度EC50为1~7μM。
6.根据权利要求1所述应用,其特征在于,所述塞卡替尼对新型冠状病毒在A549-hACE2细胞上的治疗指数为SI>18。
7.根据权利要求1所述应用,其特征在于,所述药物还包括药学上可接受的辅料。
8.根据权利要求1所述应用,其特征在于,所述药物为口服剂、注射剂或吸入剂。
9.一种抗新型冠状病毒的药物组合物,其特征在于,所述药物组合物含有塞卡替尼和/或其药学上可接受的盐和/或其药物前体。
10.根据权利要求9所述药物组合物,其特征在于,所述药物组合物还含有抗炎药、病毒进入抑制剂、病毒脱壳抑制剂、病毒逆转录酶抑制剂、病毒蛋白合成抑制剂、病毒蛋白酶抑制剂、病毒聚合酶抑制剂、病毒整合酶抑制剂、干扰素中的一种或多种。
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