CN113813366A - 罗米地辛在制备预防和治疗抗新冠肺炎新型冠状病毒的药物中的应用 - Google Patents
罗米地辛在制备预防和治疗抗新冠肺炎新型冠状病毒的药物中的应用 Download PDFInfo
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- CN113813366A CN113813366A CN202010560511.4A CN202010560511A CN113813366A CN 113813366 A CN113813366 A CN 113813366A CN 202010560511 A CN202010560511 A CN 202010560511A CN 113813366 A CN113813366 A CN 113813366A
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- romidepsin
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Abstract
本发明涉及罗米地辛在制备预防和治疗抗新冠肺炎新型冠状病毒的药物中的应用，具体公开了。罗米地辛或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。所述的冠状病毒为新型冠状病毒SARS‑Cov‑2、SARS‑CoV、HCoV 229E、NL63、OC43、HKU1和MERS‑CoV。罗米地辛对新冠肺炎新型冠状病毒的半数有效浓度为200nM，半数有效浓度低，说明抗病毒效果好。
Description
技术领域
本发明属于抗病毒药物领域，具体涉及罗米地辛在制备预防和治疗抗新冠肺炎新型冠状病毒的药物中的应用。
背景技术
新型冠状病毒肺炎(Corona Virus Disease 2019)是由新型冠状病毒(SARS-Cov-2)感染人体而引起的传染性疾病，其症状主要包括发热、乏力、干咳、呼吸困难和肾衰竭等[The Lancet,2020,395(10223):507-513；The Lancet,2020,395(10223):497-506]。冠状病毒在系统分类上属冠状病毒科(Coronaviridae)冠状病毒属(Corona virus)。冠状病毒属的病毒是具外套膜(envelope)的正链单股RNA病毒，直径约80～120nm，其遗传物质是所有RNA病毒中最大的，一般只会感染人、鼠、猪、猫、犬、禽类脊椎动物。冠状病毒于1937年被首次从鸡身上分离出来。冠状病毒粒子形状并不规则，直径约60～220nm。病毒具有包膜结构，上面有三种蛋白：刺突糖蛋白(S，Spike Protein)、小包膜糖蛋白(E，EnvelopeProtein)和膜糖蛋白(M，Membrane Protein)，少数种类还有血凝素糖蛋白(HE蛋白，Haemaglutinin－esterase)[Nederlands Tijdschrift Voor Geneeskunde,2014,158(158):A8119-A8119]。
SARS-Cov-2病毒颗粒直径在60～140nm之间，包膜外有9～12nm的尖刺，形似花冠。基因组测序表明，SARS-Cov-2是一种单链RNA冠状病毒。通过与其他病毒样品基因序列的比较，发现SARS-Cov-2与SARS-CoV(79.5％)[Nature,2020]和蝙蝠冠状病毒(96％)相似[bioRxiv,2020,2020.01.22.914952]，并推测该病毒可能起源于蝙蝠[bioRxiv,2020,2020.01.24.915157；Nature,2020]。2019-nCoV病毒属于βCoV，是区别于SARS-CoV和MERS-CoV的HCoV家族的第7个成员[New England Journal of Medicine,2020]，其余6个成员包括HCoV 229E、NL63、OC43、HKU1、SARS-CoV和MERS-CoV。
引起新型冠状病毒肺炎的是一种新型冠状病毒，它与人们熟知的引起非典型性肺炎的SARS-CoV同属冠状病毒，但类型不同，其致死率虽低于SARS-CoV但传染性远远高于SARS-CoV。到目前为止依旧没有任何特效药物能够治愈新型冠状病毒肺炎。目前的治疗方法大多是对症治疗，特别是对一些重症患者疗效较差。因此，开发有效的冠状病毒肺炎治疗特效药物成为了当下一个迫在眉睫需要解决的课题。
发明内容
本发明的目的在于提供罗米地辛在制备预防或治疗抗新冠肺炎新型冠状病毒的药物中的应用。
具体而言，为解决的本发明的技术问题，采用如下技术方案：
本发明提供了罗米地辛或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。
在本发明的技术方案中，所述的冠状病毒为新型冠状病毒SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1和MERS-CoV。
在本发明的技术方案中，冠状病毒所致疾病为SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1或MERS-CoV任一病毒引起的肺炎或其并发症。
在本发明的技术方案中，罗米地辛如结构式(1)所示的
在本发明的技术方案中，罗米地辛或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药作为唯一活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。
在本发明的技术方案中，罗米地辛或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药与其他抗病毒药物制备的组合物作为活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。
在本发明的技术方案中，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。
本发明另一个方面提供了一种治疗或预防冠状病毒科病毒所致疾病的药物组合物，其包括罗米地辛或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药。
在本发明的技术方案中，药物组合物的还包括药学上可接受的辅料。
在本发明的技术方案中，药物组合物的剂型为口服制剂、肺部吸入制剂、粘膜给药制剂、眼用制剂或注射剂。
在本发明的技术方案中，口服制剂选自颗粒剂、粉磨剂、丸剂、片剂、胶囊或口服液。
本发明另一个方面提供了罗米地辛作为抗冠状病毒科病毒的消毒剂的用途。
本发明另一个方面提供了一种用于治疗冠状病毒科病毒所致疾病的方法，包括将治疗有效量的罗米地辛或其药物学上可接受的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯或前药给药于受试者。
本发明另一个方面提供了一种用于预防受试者感染冠状病毒科病毒的方法，包括将治疗有效量的罗米地辛或其药物学上可接受的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯或前药给药在感染前给予受试者。
有益效果
本发明首次证实了罗米地辛对新冠肺炎新型冠状病毒抑制作用，其治疗指数高，半数有效浓度低；而且在染毒前施用罗米地辛可有效增加防病毒的效果。罗米地辛用作治疗抗新冠肺炎新型冠状病毒感染方面的有效药物。
具体实施方式
为了使本发明的上述目的、特征和优点能够更加明显易懂，下面对本发明的具体实施方式做详细的说明，但不能理解为对本发明的可实施范围的限定。
实施例1.病毒扩增
将非洲绿猴肾细胞(VeroE6)按3×105个/孔，接种至96孔板中，在含有10％胎牛血清(FBS；GibcoInvitrogen)的Eagle最低基础培养基(minimum Eagle’smedium,MEM；GibcoInvitrogen)中，置37℃,5％CO2培养，待长满单层。将新冠肺炎新型冠状病毒临床分离株100倍稀释接种到长满单层细胞的96孔板中，置37℃,5％CO2培养两天(含正常对照组)。
两天后病变程度高达75％以上，置于-80℃超低温冰箱，反复冻融一次，收集细胞扩增的病毒液，3000r/min离心30分钟，去沉淀物，分装小管置-80℃超低温冰箱长期保存。
实施例2罗米地辛药物毒性评价
罗米地辛粉末用DMSO溶解后，加入培养液稀释至20mg/mL，DMSO终浓度为1％,经0.22μm滤膜过滤后置4℃保存；过滤后置4℃保存。按每孔约2.5×104细胞接种到96孔板，24～48h后待细胞长成单层后，弃去培养液，加入不同稀释度的药物l00μL/孔，正常细胞对照孔加入l00μL/孔MEM，37℃5％CO2继续培养2～5天，每孔加CCK8溶液(5mg/mL)20μL，置37℃5％CO2保温箱中继续孵育4小时。吸弃培养上清液，每孔加100μL二甲基亚砜(DMSO)，低速振荡10分钟，使结晶物充分融解。选择490nm波长，在酶联免疫监测仪上测定各孔光吸收值。通过毒性评价可知药物添加浓度达到1μM时，依然未见明显细胞毒性，说明药物的细胞毒性低，具有良好的治疗窗口。
实施例3罗米地辛抗新冠肺炎新型冠状病毒药效评价
为了评估药物的抗病毒效力，将VeroE6细胞在密度为5×104细胞/孔的48孔细胞培养皿中培养过夜。添加病毒(MOI为0.05)使其感染2小时。然后加入2倍梯度稀释的药物，每个浓度设置4个复孔，以最大无毒浓度为药物起始浓度，在34℃、5％CO2培养箱中孵育2天。记录细胞病变(Cytopathogenic Effect,CPE)。细胞出现CPE按6级标准记录。记录CPE后，用CCK8染色，进行OD值测定。罗米地辛抗新冠肺炎新型冠状病毒药效评价通过CCK8法对罗米地辛进行药效评价，对新冠肺炎新型冠状病毒(SARS-Cov-2)的半数有效浓度(EC50)为200nM，半数有效浓度低，说明抗病毒效果好。
实施例4免疫荧光
免疫荧光显微镜:为了检测VeroE6细胞中病毒蛋白的表达，将细胞用4％多聚甲醛固定并用0.5％TritonX-100透化。然后在室温下用5％牛血清白蛋白(BSA)封闭细胞2小时。将细胞与一抗(蝙蝠SARS相关冠状病毒的病毒核衣壳蛋白多克隆抗体，anti-NP，以1：1000稀释度)一起孵育2小时，然后与二抗孵育抗体(488AffiniPure Donkey Anti-Rabbit IgG(H+L)。细胞核用Hoechst33258染料(Beyotime,China)染色。通过荧光显微镜观察可知罗米地辛能有效杀灭细胞中的病毒，并且对细胞影响较小，具有良好的治疗窗口。
Claims (10)
1.罗米地辛或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。
2.根据权利要求1所述的用途，所述的冠状病毒为新型冠状病毒SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1和MERS-CoV。
3.根据权利要求1所述的用途，冠状病毒所致疾病为SARS-Cov-2、SARS-CoV、HCoV229E、NL63、HCoV-OC43、HKU1或MERS-CoV任一病毒引起的感染性疾病或其并发症；感染性疾病优选为呼吸道感染疾病。
4.根据权利要求1所述的用途，罗米地辛或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药作为唯一活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用；或者
罗米地辛或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药，与其他抗病毒药物的组合物作为活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用；
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、罗米地辛、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。
5.一种治疗或预防冠状病毒所致疾病的药物组合物，所述药物组合物中包含罗米地辛或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药。
6.根据权利要求5所述的药物组合物，药物组合物的还包括药学上可接受的辅料。
7.根据权利要求5所述的药物组合物，药物组合物的剂型为口服制剂、肺部吸入制剂、粘膜给药制剂、眼用制剂或注射剂；优选地，口服制剂选自颗粒剂、粉末剂、丸剂、片剂、胶囊或口服液。
8.一种消除冠状病毒科病毒污染的消毒剂，所述消毒剂包括罗米地辛。
9.一种用于治疗或预防冠状病毒科病毒所致疾病的方法，包括将治疗有效量的罗米地辛或其药物学上可接受的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药给药于受试者。
10.根据权利要求5-7任一项所述的药物组合物或权利要求8所述的消毒剂或权利要求9所述的方法，其中冠状病毒为新型冠状病毒SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1和MERS-CoV。
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