CN115770246B - 卡莫氟或其药学上可接受的盐在抗冠状病毒中的应用 - Google Patents
卡莫氟或其药学上可接受的盐在抗冠状病毒中的应用 Download PDFInfo
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- CN115770246B CN115770246B CN202211104669.6A CN202211104669A CN115770246B CN 115770246 B CN115770246 B CN 115770246B CN 202211104669 A CN202211104669 A CN 202211104669A CN 115770246 B CN115770246 B CN 115770246B
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Abstract
本发明公开了卡莫氟或其药学上可接受的盐在抗冠状病毒中的应用。卡莫氟在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。本发明通过体外酶活实验发现卡莫氟可以很好地抑制冠状病毒中的主蛋白酶的活性，填补了现有技术缺乏治疗冠状病毒引发的疾病的不足。
Description
本专利申请为申请号为：CN202110219570.X，申请日为2021年02月26日，发明名称为《多酚类物质在抗冠状病毒中的应用》的分案申请。
技术领域
本发明属于生物医药技术领域，涉及卡莫氟或其药学上可接受的盐在抗冠状病毒中的应用。
背景技术
冠状病毒是一类与人畜密切相关的病毒。冠状病毒HCoV-229E和HCoV-OC43会引起普通感冒(van der Hoek,L.,Pyrc,K.,Jebbink,M.et al.Identification of a newhuman coronavirus.Nat Med 2004,10,368–373)。2004年鉴定出的HCoV-NL63 同样能引起类似感冒的呼吸道疾病(van der Hoek,L.,Pyrc,K.,Jebbink,M.et al. Identificationof a new human coronavirus.Nat Med 2004,10,368–373)。人冠状病毒HKU1 株(HCo V-HKU1)属于β-冠状病毒，于2005年由香港大学研究人员发现，该病毒引起上呼吸道感染。最近流行的SARS-CoV-2病毒会引发COVID-19，临床表现为发烧，干咳和呼吸困难，重症会造成死亡(Jeannette Guarner,MD,Three Emerging Coronaviruses in Two Decades:TheStory of SARS,MERS,and Now COVID-19,American Journal of Clinical Pathology,,aqaa029)。
冠状病毒对于畜牧业影响巨大：猪流行性腹泻病毒(PEDV)可引起猪流行性腹泻(Pocine Epidemic Diarrhea,PED)，肠胃炎病毒(TGEV)可引起猪传染性胃肠炎(TGE)，猪丁型冠状病毒(Porcine delta coronavirus，PDCoV，也叫猪德尔塔病毒)可引起5-15日龄哺乳仔猪腹泻和呕吐,迅速脱水,衰竭而亡，给养猪业带来巨大的损失(Akimkin V,Beer M,Blome S,et al.New Chimeric Porcine Coronavirus in Swine Feces,Germany,2012.Emerg Infect Dis.2016,22(7):1314–1315)。猫传染性腹膜炎病毒(FIPV)可引起的猫科动物的致死性疾病：猫传染性腹膜炎(FIP)。禽传染性支气管炎病毒(IBV)感染禽类，引起鸡传染性支气管炎，是一种分布广泛的家禽疾病，对家禽业造成了巨大的经济影响。
冠状病毒在系统分类上属套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)冠状病毒亚科(Orthocoronavirinae)，日前SARS-CoV-2冠状病毒基因组序列已经公布，该序列与SARS-Cov的核苷酸相似度约为90％，蛋白质序列与SARS-CoV有约80％的序列相似性。冠状病毒的基因组为单股正链RNA，长度约28kb，主要编码病毒包装所需的结构蛋白以及与复制转录相关的非结构蛋白。开发治疗冠状病毒相关疾病的药物和疫苗主要针对上述两类蛋白。病毒基因组的三分之二的基因主要编码非结构蛋白。病毒编码了两种多聚酶蛋白pp1a和pp1ab，用于参与病毒的复制过程。pp1a和pp1ab通过两种由病毒编码的木瓜蛋白酶和主蛋白酶(main protease)可以将其切割成16个非结构蛋白nsp1-16，只有当这些功能亚基被病毒编码的蛋白酶切割成独立的蛋白单元，病毒才能完成正常的转录、复制功能，进而组装成复制转录复合物，完成病毒的复制和转录。其中，木瓜蛋白酶有3个酶切位点；主蛋白酶在pp1a和pp1ab上存在11个酶切位点。可见主蛋白酶在病毒的转录、复制过程中发挥关键的调节作用，因此成为研究的焦点(Ziebuhr,J.； Snijder,E.J.；Gorbalenya,A.E.Virus-encoded proteinases and proteolytic processing in theNidovirales.J Gen Virol 2000,81,853-79.；Ziebuhr,J.Molecular biology of severeacute respiratory syndrome coronavirus.Curr Opin Microbiol 2004,7,412-9.)。由于主蛋白酶对冠状病毒扩增复制的重要性，因此寻找针对主蛋白酶催化位点专一性强、安全性高的抑制剂对于药物开发显得尤其重要。
卡莫氟(Carmofur，分子式为C11H16FN3O3；CAS号：61422-45-5)是氟尿嘧啶的衍生物，是一种抗肿瘤药，口服后从肠道迅速吸收，在体内缓缓释出氟尿嘧啶，借氟尿嘧啶的抗代谢作用而发挥抗肿瘤作用。卡莫氟口服后有效血药浓度较氟尿嘧啶静注长久。抗瘤谱广，治疗指数高，对多种实验肿瘤有较好的抗肿瘤作用。临床上对胃癌、结直肠癌及乳腺癌有一定疗效，尤以结直肠癌的有效率较为突出(KAMIKAMA KANEHITO； KIKUCHIMASAHIKO.STABLE CARMOFUR-BETA-CYCLODEXTRIN CLATHRATE COMPOUND[P].；JPS60185772,1985-09-21.)。
现有技术中尚无卡莫氟可用于治疗冠状病毒引发的相关疾病。
发明内容
本发明所要解决的技术问题是，针对现有技术中尚无有效抑制冠状病毒的药物，本发明提供卡莫氟或其药学上可接受的盐在抗冠状病毒中的应用，具体涉及卡莫氟或其药学上可接受的盐在制备抑制冠状病毒的药物中的应用。
本发明主要通过以下技术方案解决上述技术问题。本发明提供卡莫氟(CAS号：61422-45-5)或其药学上可接受的盐在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。
卡莫氟(CAS号：61422-45-5)或其药学上可接受的盐在制备治疗和/或预防新型冠状病毒引发的疾病的药物中的应用。
本发明还提供卡莫氟或其药学上可接受的盐在制备抑制冠状病毒的药物中的应用。
较佳地，所述的疾病为哺乳动物所患疾病或者禽类所患疾病。
较佳地，所述的哺乳动物包括人、猪和猫。
所述的疾病或病症可包括：感冒、类似感冒的呼吸道疾病、中东呼吸综合征、发烧、干咳或呼吸困难；以及猪所患的肠炎、腹泻、呕吐或脱水。
本发明所述的冠状病毒，其定义为本领域熟知，在系统分类上属套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)冠状病毒亚科(Orthocoronavirinae)。冠状病毒是具有囊膜(envelope)、基因组为单股正链的RNA病毒，是自然界广泛存在的一大类病毒。
本发明的目的是提供冠状病毒感染引起的疾病的潜在治疗方案。本发明所述的冠状病毒较佳地属于正冠状病毒亚科(Orthocoronavirinae)，更佳地属于Alpha冠状病毒属、Beta冠状病毒属、Gamma冠状病毒属或者Delta冠状病毒属。
在本发明一较佳实施例中，卡莫氟或其药学上可接受的盐除可用于治疗SARS-CoV- 2(Beta冠状病毒属)引发的疾病以外，还应可治疗其他冠状病毒SARS-CoV(Beta冠状病毒属)和MERS-CoV等引起的重大传染病，亦可作为普通感冒药，治疗HCoV-HKU1 (Humancoronavirus HKU1；Beta冠状病毒属)、HCoV-NL63(Human coronavirus NL63； Alpha冠状病毒属)、HCoV-OC43(Human coronavirus OC43)以及HCoV-229E(Human coronavirus 22E；Alpha冠状病毒属)等冠状病毒引起的疾病；还可作为兽药，治疗猪传染性胃肠炎病毒(Transmissible gastroenteritis virus,TGEV；Alpha冠状病毒属)、猪流行性腹泻病毒(Porcine epidemic diarrhea virus,PEDV；Alpha冠状病毒属)、猪丁型冠状病毒(Porcinedelta coronavirus，PDCoV；Delta冠状病毒属)、猫传染性腹膜炎病毒(Feline infectiousperitonitis virus,FIPV；Alpha冠状病毒属)、禽传染性支气管炎病毒(Infectiousbronchitis virus,IBV；Gamma冠状病毒属)等动物疾病。
因此，本发明所述冠状病毒的较佳地选自SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-HKU1、HCoV-NL63、HCoV-OC43、HCoV-229E、TGEV、PEDV、PDCoV、FIPV 或者IBV。
在某一方案中，所述卡莫氟(CAS号：61422-45-5)或其药学上可接受的盐在制备抑制新型冠状病毒的药物中的应用。
在某一方案中，本发明的所述卡莫氟或其药学上可接受的盐以包含其的药物组合物的形式存在；较佳地，所述药物组合物以本发明所述卡莫氟和/或其药学上可接受的盐作为所述药物组合物的唯一活性成份；和/或，所述药物组合物还包含药学上可接受的载体，例如药学上可接受的药用辅料。
在某一方案中，本发明的所述卡莫氟或其药学上可接受的盐以包含其的套装药盒的形式存在，所述套装药盒还包括治疗与冠状病毒相关的疾病的药物和/或治疗其他病毒引起的疾病的药物。
本发明中，所述卡莫氟或其药学上可接受的盐还可以与其他一种或多种药物活性成分联用。所述其他一种或多种药物活性成分包括：多酚类物质、质子泵抑制剂、对苯醌及其衍生物、苏木的活性成分、TDZD-8、硫柳汞、紫草素、Tideglusib、原黄素、雷贝拉唑钠、PX-12、Dixanthogen、胆酸甲酯、柯里拉京、二氢杨梅素、氯胺T、汞溴红、没食子儿茶素、秦皮素、甲异靛、乳酸乙吖啶一水合物以及南索拉唑中的一种或多种。
所述的苏木的活性成分较佳地选自苏木精、原苏木素B或者巴西木素。
所述的对苯醌衍生物较佳地选自百里香醌或者1,4-萘醌。
所述的质子泵抑制剂较佳地选自雷贝拉唑钠、艾普拉唑钠或者埃索美拉唑镁。
所述的多酚类物质较佳地选自蟛蜞菊内酯、表没食子儿茶素没食子酸酯、甲基儿茶酚、茶多酚或者迷迭香酸。
本发明中涉及的以本发明所述卡莫氟或其药学上可接受的盐作为活性成份的药物组合物，均可根据本领域公知的方法制备。可通过将本发明所述卡莫氟或其药学上可接受的盐制成适于人或动物使用的任何剂型。本发明所述卡莫氟或其药学上可接受的盐在其药物组合物中的重量含量通常为0.1-99.0％。
所述的药学可接受的载体可为本领域常规的载体，所述的载体可以为任意合适的生理学或药学上可接受的药物辅料。所述的药物辅料为本领域常规的药物辅料，较佳地包括药学上可接受的赋形剂、填充剂或稀释剂等。更佳地，所述的药物组合物包括0.01～99.99％的上述蛋白质和/或上述的抗体药物偶联物，和0.01～99.99％的药用载体，所述百分比为占所述药物组合物的质量百分比。
本发明所述卡莫氟或其药学上可接受的盐或含其的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明所述卡莫氟或其药学上可接受的盐可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。
术语“药学上可接受的盐”是指本发明所述卡莫氟与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的所述卡莫氟或其药学上可接受的盐中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的所述卡莫氟或其药学上可接受的盐中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3- 羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al., "Pharmaceutical Salts",Journal of PharmaceuticalScience 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G. Wermuth,ed.,Wiley-VCH,2002)。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明通过体外酶活实验发现卡莫氟可以很好地抑制冠状病毒中的主蛋白酶的活性，填补了现有技术缺乏治疗冠状病毒引发的疾病的不足。可对该化合物进行进一步研究、改造以进行应用。
附图说明
图1：卡莫氟对新型冠状病毒主蛋白酶的抑制活性；1：DMSO(阴性对照),2:化合物分子；3：阳性对照(N3抑制剂)。纵坐标单位为RFU(Relative Fluorescence Units；相对荧光的单位)。
图2：卡莫氟对新冠病毒主蛋白酶的酶活抑制曲线。
图3：卡莫氟在细胞水平上的抗病毒效果，数据通过qRT-PCR方法测得。
图4：卡莫氟在细胞水平上的抗病毒效果，数据通过免疫荧光法测得，以氯喹作为阳性对照。
图5：体外细胞毒性实验，测定细胞存活率。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
以下所用Vero E6细胞购自ATCC。
实施例1
从不同的化合物库中进行高通量筛选，成功筛选卡莫氟对新型冠状病毒主蛋白酶有较好的抑制效果。酶活实验条件具体为：
酶活实验荧光底物：MCA-AVLQSGFR-Lys(Dnp)-Lys-NH2，此荧光底物的激发波长和发射波长分别为320nm和405nm。
酶活反应buffer为50mM Tris–HCl(pH 7.3)，1mM EDTA；酶活反应温度：30℃。反应起始通过添加蛋白酶，蛋白酶反应终浓度为0.2μM，底物浓度为20μM，抑制剂(卡莫氟)浓度1.5μM。(Xue X,Yang H,Shen W,et al.Production of authentic SARS-CoV Mpro withenhanced activity:application as a novel tag-cleavage endopeptidase forprotein overproduction[J].Journal of molecular biology,2007,366(3):965-975.)。
所用阳性对照为N3抑制剂，已知其能够有效灭活冠状病毒主蛋白酶(杨海涛,谢卫青,Xiaoyu X,et al.Design of wide-spectrum inhibitors targeting coronavirusmain proteases[J]. 生命有机化学,2005,3(10):1742-1752.)，结构式如下所示：
根据图1可知：卡莫氟的酶活实验曲线，明显区别于阴性对照，对冠状病毒主蛋白酶有明显抑制活性。
实施例2
酶活抑制曲线测定使用的荧光底物：MCA-AVLQSGFR-Lys(Dnp)-Lys-NH2，此荧光底物的激发波长和发射波长分别为320nm和405nm。
酶活抑制曲线测定buffer为50mM Tris–HCl(pH 7.3)，1mM EDTA；反应温度： 30℃。反应起始通过添加蛋白酶，蛋白酶反应终浓度为0.2μM，底物浓度为20μM，使用11个不同浓度的卡莫氟进行测量，测试结果显示IC50值为1.82μM(图2)(Jin Z,Du X,Xu Y,etal.Structure of Mpro from COVID-19virus and discovery of its inhibitors[J].Nature,2020,582(7811):1-9.)。
体外细胞抗病毒实验使用6个不同浓度的卡莫氟处理感染SARS-CoV-2的Vero E6细胞1小时，病毒MOI(multiplicity of infection)为0.05。然后去除病毒和药物和混合物，清洗后继续使用含不同浓度卡莫氟的培养基培养。经过24小时培养后取上清进行qRT-PCR分析，同时将细胞固定通过免疫荧光法检测细胞内N蛋白水平进一步确定实验结果。实验发现卡莫氟可防止新型冠状病毒感染引起的细胞病变，EC50值为24.3μM(图3、图 4)，因此卡莫氟可用于治疗冠状病毒引发的相关疾病(Jin,Z.,Zhao,Y.,Sun,Y.et al. Structuralbasis for the inhibition of SARS-CoV-2main protease by antineoplastic drugcarmofur. Nat Struct Mol Biol 27,529–532(2020).)。
体外的细胞毒性实验使用8个不同浓度的卡莫氟处理Vero E6细胞。Vero E6细胞在 96孔板中悬浮培养。第二天，在培养基中加入不同浓度的卡莫氟。24小时后，使用细胞计数试剂盒-8(CCK8,Beyotime)测定存活细胞的相对数量。如图5所示，卡莫氟的CC50 值为133.37μM(Jin,Z.,Zhao,Y.,Sun,Y.et al.Structural basis for the inhibition ofSARS- CoV-2main protease by antineoplastic drug carmofur.Nat Struct Mol Biol27,529–532 (2020).)。
Claims (5)
1.卡莫氟或其药学上可接受的盐在制备治疗SARS-CoV-2引发的疾病的药物中的应用，所述卡莫氟或其药学上可接受的盐作为所述药物的唯一活性成分。
2.卡莫氟或其药学上可接受的盐作为唯一活性成分的组合物在制备抑制SARS-CoV-2的药物中的应用。
3.如权利要求2所述的应用，其特征在于，所述卡莫氟或其药学上可接受的盐以包含其的药物组合物的形式存在，所述的药物组合物还包含药学上可接受的载体。
4.如权利要求3所述的应用，其特征在于，所述的药学上可接受的载体为药学上可接受的药用辅料。
5.如权利要求2所述的应用，其特征在于，所述卡莫氟或其药学上可接受的盐以包含其的套装药盒的形式存在，所述套装药盒还包括治疗与SARS-CoV-2相关的疾病的药物和/或治疗其他病毒引起的疾病的药物。
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