CN113288907A - 环烯醚萜化合物在制备抗冠状病毒药物中的应用 - Google Patents
环烯醚萜化合物在制备抗冠状病毒药物中的应用 Download PDFInfo
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Abstract
本发明公开了环烯醚萜化合物在制备抗冠状病毒药物中的应用，其特征在于：所述环烯醚萜化合物为山茱萸新苷、胡黄连苷Ⅲ或新女贞苷。本发明方案的环烯醚萜化合物对冠状病毒具有良好的抑制作用，且无明显的细胞毒性，可制备成药物，用于临床抗冠状病毒，本发明方案对质量可控、低毒高效的抗冠状病毒创新药物研发具有明确的科学价值和现实意义。
Description
技术领域
本发明属于药物化学技术领域，具体涉及环烯醚萜化合物在制备抗冠状病毒药物中的应用。
背景技术
人类冠状病毒(Human Coronaviruses，HCoVs)是一类具有包膜结构的RNA病毒。目前感染人类的HCoVs主要有7种，分别是HCoV-229E、HCoV-NL63、HCoV-OC43、SARS-CoV、MERS-CoV、HCoV-HKU1和SARS-CoV-2(Zhou P,Yang XL,Wang XG,et al.A pneumonia outbreakassociated with a new coronavirus of probable bat origin.Nature,2020,Doi:10.1038/s41586-020-2012-7.)。其中，严重急性呼吸系统综合征(SARS)、中东呼吸综合征(MERS)和2019新型冠状病毒(2019-nCoV或SARS-CoV-2)的爆发流行，给社会公共卫生安全带来严峻挑战。目前针对HCoVs感染的临床治疗主要以改善症状为主。在药物治疗上，使用α-干扰素、洛匹那韦、利巴韦林等普通抗病毒药物，尚缺少直接针对HCoVs的特效药(新型冠状病毒肺炎诊疗方案(试行第七版)，国家卫生健康委员会，http://www.nhc.gov.cn)。相对而言，我国中医药在抗疫方面有着悠久的实践应用历史，无论是在2003年抗击SARS(曹丽娟，王体，中国中医科学院防控SARS十周年纪念，亚太传统医药，2014，10(1)，1-3.)还是本次治疗COVID-19(程德忠，王文菊，李毅，吴晓冬，周彪，宋七咏，51例新型冠状病毒肺炎患者应用中药连花清瘟疗效分析：多中心回顾性研究，天津中医药，2020，http://kns.cnki.net/kcms/detail/12.1349.R.20200310.1024.004.html)中，中药治疗都被证明具有明确的治疗效果和临床统计学意义，极大地改善了死亡率，并且没有应用激素等化学药物等引起的严重毒副作用。
已知可感染人7种HCoVs中，HCoV-229E和HCoV-OC43发现较早，其与后来发现的HCoV-NL63、HCoV-HKU1等HCoVs毒性较弱，一般仅引起急性上呼吸道感染，而较少影响下呼吸道，受感染患者往往也只表现出轻微感冒症状(Gralinski LE，Baric RS.Molecularpathology of emerging coronavirus infections.The Journal of Pathology,2015,235(2),185-195.)。但另外3种HCoVs毒性较强，可引起下呼吸道急性感染症状，在部分重症患者人群中致死率较高。
全基因序列比对显示，包括SARS-CoV-2在内的7种人类冠状病毒基因组均有很大程度的相似性。冠状病毒基因组分别编码棘突(spike，S)蛋白、包膜(envelope)蛋白、膜(membrane)蛋白和核衣壳(nucleocapsid)蛋白(Wilde AHD,Snijder EJ,Kikkert M,etal.Host factors in Coronavirus replication in:Tripp R.,Tompkins S.(eds)Rolesof host gene and non-coding RNA expression in virus infection.Current Topicsin Microbiology and Immunology,Springer,Cham 2018,419,1-42.)。最新研究结果显示SARS-CoV-2主要通过S蛋白介导病毒与宿主细胞膜受体结合及膜融合，S蛋白与病毒的致病性密切相关；同时已鉴定出该病毒主要作用的功能性蛋白受体也是血管紧张素转化酶2(ACE2)(Wan YS,Shang J,Graham R,et al.Receptor recognition by novelcoronavirus from Wuhan:An analysis based on decade-long structural studies ofSARS.Journal of Virology,2020,DOI:10.1128/JVI.00127-20.)。SARS-CoV 3CL蛋白酶(3C-likeprotease，Mpro)作为一种半胱氨酸水解酶，是冠状病毒的主要蛋白酶之一，在病毒的复制过程中起重要作用，因其基因具有高度的保守性，可作为药物设计的关键靶标(JoS,Kimm S,Shin DH,Kim MS.Inhibition of SARS-CoV 3CL protease byflavonoids.Journal of Enzyme Inhibition and Medicinal Chemistry,2020,35(1),145-151.)。海科技大学饶子和/杨海涛课题组已成功解析了SARS-CoV-2的3CL蛋白酶的晶体结构(Liu X,Zhang B,Jin Z,Yang H,Rao,Z.The crystal structure of COVID-19main protease in complex with an inhibitor N3.https://www.rcsb.org/structure/6lu7)，并有多个课题组开展了虚拟筛选研究(马青云，刘辰，杜海涛，张贵晟，孙启慧，刘孝云，齐冬梅，杨勇，容蓉，基于高通量分子对接虚拟筛选SARS-CoV-2 3CL水解酶中药小分子抑制剂及抗COVID-19新型冠状病毒肺炎的中药及其复方预测，中草药.)。
中医认为冠状病毒肺炎病位主要在肺、脾胃，病因病机多为疫戾之气，主要为“湿、寒、热、毒、瘀、虚”病邪致病。许禄华等(许禄华，李彦荣，郑丹如，邵宗钫，闻思齐，林丰夏，曾志聪，宋银枝，基于“因时制宜”探讨新型冠状病毒肺炎不同阶段的处方用药规律，中国实验方剂学杂志.https://doi.org/10.13422/j.cnki.syfjx.20201211)分析了COVID-19中医药诊疗方案(包括国家诊疗方案和各省中医药治疗方案)中所使用的中药用药规律，发现主要用药为补虚药、清热药、解毒药、化湿药、化痰止咳平喘药等。就中医药的现代作用机制分析，补虚药、化湿药、化痰止咳平喘药多与机体免疫力、缓解主要症状有关，而清热药，包括清热解毒药、清热泻火药、清热燥湿药、清热凉血药，则与抗病毒作用相关。金银花、地黄、栀子、玄参、秦艽、龙胆等为COVID-19中医药诊疗方案中高频使用的清热类中药。研究表明，龙胆可以显著改善SARS-CoV感染Vero细胞引起的病变效应，并可有效抑制SARS-CoV复制(WenCC,Shyur LF,Jan JT,et al.Traditional Chinese medicine herbal extracts ofCibotium barometz,Gentiana scabra,Dioscorea batatas,Cassia tora,and Taxilluschinensis inhibit SARS-CoV replication.Journal of Traditional andComplementary Medicine,2011,1(1),41-50.)；秦艽乙醇提取物具有很好的抑制SARS冠状病毒主蛋白酶活性的作用，通过进一步分离纯化获得环烯醚萜类化合物能够有效的抑制SARS冠状病毒主蛋白酶(冯金磊,王波，牛国君，郭宇，陈卫强，杨诚，饶子和，具有SARS冠状病毒主蛋白酶抑制活性的秦艽有效成分研究，中国化学会第28届学术年会，2012，112.)。从金银花中发现的一类环烯醚萜生物碱对H3N2流感病毒以及柯萨奇病毒显示出良好的抑制作用(Yu Y,Zhu C,Wang S,Song W,Yang Y,Shi J.Homosecoiridoid alkaloids withamino acid units from the flower buds of Lonicera japonica.Journal of NaturalProducts,2013,76,2226-2233)。栀子苷作为栀子中一种代表性的环烯醚萜苷，在体外筛选和体内试验中均显示出抗H1NI流感病毒的活性，并能大幅降低TNF-α、IL-6等多种炎症因子水平(Zhang Y,Yao J,Qi X,Liu X,Lu X,Feng G.Geniposide demonstrates anti-inflammatory and antiviral activity against pandemic A/Jiangsu/1/2009(H1N1)influenza virus infection in vitro and in vivo.Antiviral Therapy,2017,22(7),599-611.)。以上研究表明，这些治疗COVID-19清热类中药含有的一种同类成分：环烯醚萜类化合物，具有广谱抗病毒的活性，能够明确作用于SARS-CoV。环烯醚萜类化合物是一类存在于多种清热类中药中的单萜类化合物，大多数为苷类成分(王菲菲，张聿梅，郑笑为，戴忠，刘斌，马双成，环烯醚萜类化合物的结构和生物学活性研究进展，中国药事，2019，33(3)，323-330.)。研究表明，环烯醚萜类化合物还能够通过CYP、Nrf2、ERK/MAPK等通路保护肝脏；通过NF-κB等通路发挥良好的抗炎、抑制炎症因子表达作用(张慧娟，李菊，马晓慧，李运曼，裂环环烯醚萜苷类化合物的药理作用研究进展，药学研究，2018，37(11)，659-663.)。
综上所述，环烯醚萜类成分是多种清热类抗冠状病毒中药发挥功效的物质基础，从中有望发现质量可控、低毒高效的抗冠状病毒创新药物具有明确的科学价值和现实意义。然而环烯醚萜类化合物数量繁多，并非任意环烯醚萜化合物均可应用于抗冠状病毒。
本背景技术中所陈述内容并不代表承认其属于已公开的现有技术。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此，本发明提出一类新的能够用于抗冠状病毒的环烯醚萜化合物。
根据本发明的一个方面，提出了环烯醚萜化合物在制备抗冠状病毒药物中的应用，所述环烯醚萜化合物为山茱萸新苷、胡黄连苷Ⅲ或新女贞苷。3个环烯醚萜单体化合物分别来源于山茱萸成熟果实、胡黄连的根茎、女贞子植物。
在本发明的一些实施方式中，所述冠状病毒包括但不限于HCoV-229E、HCoV-NL63、HCoV-OC43、SARS-CoV、MERS-CoV、HCoV-HKU1或SARS-CoV-2中的至少一种。
在本发明的一些实施方式中，所述抗冠状病毒药物包括预防或治疗冠状病毒药物。
在本发明的一些实施方式中，所述抗冠状病毒药物的制备原料还包括药用辅料。可采用常用载体即可，以便于制备成不同剂型。
在本发明的一些实施方式中，所述药用辅料选自崩解剂、稀释剂、润滑剂、粘合剂、矫味剂、助悬剂、表面活性剂或防腐剂中的至少一种。
在本发明的一些实施方式中，所述崩解剂选自玉米淀粉、马铃薯淀粉、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲纤维素钠、羧甲基纤维素、羧甲基纤维素钙或藻酸中的至少一种；更优选地，所述稀释剂选自乳糖、蔗糖、甘露醇、玉米淀粉、马铃薯淀粉、磷酸钙、柠檬酸钙或结晶纤维素中的至少一种；更优选地，所述润滑剂选自微粉硅胶、硬脂酸镁、硬脂酸钙、硬脂酸、滑石粉或无水硅胶中的至少一种；更优选地，所述粘合剂选自阿拉伯胶、明胶、糊精、羟丙基纤维素、甲基纤维素或聚乙烯吡咯烷酮中的至少一种；更优选地，所述矫味剂选自阿斯巴甜、甜菊甙、蔗糖、麦芽糖醇或柠檬酸中的至少一种；更优选地，所述助悬剂选自阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素钠、羟甲基纤维素或硬脂酸铝凝胶中的至少一种；更优选地，所述表面活性剂选自卵磷脂、山梨糖醇酐单油酸酯或单硬脂酸甘油酯中的至少一种；更优选地，所述防腐剂选自对羟苯甲酸甲酯或对羟苯甲酸丙酯中的至少一种。
在本发明的一些实施方式中，所述药物剂型为固体、半固体或液体的形式；优选为水溶液、非水溶液、混悬液或膏体；更优选地为片剂、胶囊剂、软胶囊剂、颗粒剂、丸剂、口服液、乳剂、干混悬剂、干浸膏剂或注射剂。
根据本发明的另一个方面，提出了环烯醚萜化合物在制备冠状病毒主蛋白酶抑制剂中的应用，所述环烯醚萜化合物为山茱萸新苷、胡黄连苷Ⅲ或新女贞苷。
根据本发明的再一个方面，提出了环烯醚萜化合物在制备3CL蛋白酶抑制剂中的应用，所述环烯醚萜化合物为山茱萸新苷、胡黄连苷Ⅲ或新女贞苷。
根据本发明的一种优选的实施方式，至少具有以下有益效果：本发明方案的环烯醚萜化合物对冠状病毒具有良好的抑制作用，且无明显的细胞毒性，可制备成药物，用于临床抗冠状病毒，本发明方案对质量可控、低毒高效的抗冠状病毒创新药物研发具有明确的科学价值和现实意义。本发明方案的三种化合物对3CL蛋白酶具有良好的抑制活性，其中，新女贞苷的抑制作用最强，IC50为14.340μM，可抑制3CL蛋白酶活性，具有阻断病毒复制的效果。
附图说明
下面结合附图和实施例对本发明做进一步的说明，其中：
图1为本发明测试例中化合物SDD-01～SDD-08的毒性测试结果图；
图2为本发明测试例中化合物SDD-09～SDD-16的毒性测试结果图；
图3为本发明测试例中化合物SDD-17～SDD-21的毒性测试结果图；
图4为本发明测试例中化合物SDD-01～SDD-10的抑制效果对比图；
图5为本发明测试例中化合物SDD-11～SDD-21的抑制效果对比图；
图6为本发明测试例中不同浓度的化合物山茱萸新苷和新女贞苷分别对SARS-CoV-2的抑制效果图。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述，以充分地理解本发明的目的、特征和效果。显然，所描述的实施例只是本发明的一部分实施例，而不是全部实施例，基于本发明的实施例，本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例，均属于本发明保护的范围。实施例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，均可从商业途径得到的试剂和材料。
实施例1
山茱萸新苷在制备抗冠状病毒药物中的应用。
实施例2
胡黄连苷Ⅲ在制备抗冠状病毒药物中的应用。
实施例3
新女贞苷在制备抗冠状病毒药物中的应用。
对比例
栀子苷、橄榄苦苷、梓醇、马钱苷、龙胆苦苷、哈巴苷、特女贞苷、去乙酰车叶草酸甲酯、地黄苷D、鸡屎藤苷酸甲酯、8-O-乙酰山栀苷甲酯、胡黄连苷Ⅰ、胡麻属苷、桃叶珊瑚苷、水晶兰苷、山栀苷甲酯、胡黄连苷Ⅱ或哈巴俄苷在制备抗冠状病毒药物中的应用。
上述实施例或对比例中的化合物可通过现有技术从植物中提取分离得到，本实施例参照现有的文献进行提取得到，具体参考信息如下表1所示(若文献中涉及多个实验条件，则参照最佳实验条件提取得到)。
表1
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试验例
本试验例测试了实施例和对比例中的天然环烯醚萜类化合物的抗冠状病毒的性能。
1、细胞毒性测试
称取3g左右的天然环烯醚萜类化合物进行细胞毒性测试，将其溶于二甲基亚砜(DMSO)中。具体测试过程如下：
1)细胞接种：
处于对数生长期的293T细胞(市购所得)，调整细胞密度至1*10^4个/孔，分别以100μL/孔接种于96孔板，37℃细胞培养箱中培养过夜。
2)药物浓度设计：
给药前用含总体积2％胎牛血清的DMEM培养基2倍倍比稀释4个浓度梯度。
293T细胞：初始浓度设置为100μM(100、50、25、12.5μM)，取每孔100μL稀释后的药物分别加入1)中96孔板中的293T细胞中，每孔终体积200μL。每个药物浓度设置3个复孔。以不加样品的培养基为空白对照，以加入氧化苦参碱作为阳性对照药物。
3)检测吸光度：
细胞培养箱中培养48h后，每孔加入20μL噻唑兰(MTT)(5mg/kg)工作液，继续孵育4小时。酶标仪测定570nm处吸光度(OD)。
4)存活率计算：
根据测得的OD值，分别计算与对照组相比，在各个浓度药物的作用下，293T细胞的存活率。结果如图1～3所示。
图1～3中对应的编号及样品质量及溶剂信息如下表2所示。
表2
该编号通篇源引。
从图1～3中可以看出，以293T细胞为模型，评价了山茱萸新苷、胡黄连苷Ⅲ、新女贞苷等21个单体化合物的细胞毒性。结果表明，这些化合物在12.5～100μM浓度范围没有明显细胞毒性，细胞存活率可达75％以上，毒性小、安全性高。
2、天然环烯醚萜类化合物抗HCoV-OC43感染活性
1)HRT-18细胞以4*10^5个/每孔的密度接种于12孔板，于37℃、5％CO2培养过夜。
2)去上清，用PBS缓冲液洗细胞两次，将500μl相应浓度的药物与500μl稀释到感染复数(MOI)＝0.2浓度的HCoV-OC43混合均匀，置于33℃、5％CO2细胞培养箱中孵育24h。
3)去上清，用PBS缓冲液洗细胞两次。向其中加入对应浓度的药物溶液，继续在33℃、5％CO2细胞培养箱中孵育72h。
4)收集并提取RNA，参照Cell Total RNA isolation Kit(Takara)。
5)RNA逆转录成cDNA，逆转录酶：Takara Prime ScriptT Mreagent Kit(Cat:RR036A)。
6)进行qRT-PCR检测，检测病毒NP mRNA相对表达量的变化。
7)按照如下表3成分于冰上配置反应体系：
表3
引物序列如下：
OC43 NP蛋白上游引物(Forward Primer,如Seq No.1所示)：CGGTCTGGTAATGGCATCCTCAAG
OC43 NP蛋白下游引物(Reverse Primer，如Seq No.2所示)：CATTCCCTCCTGATGGTTGCTGAG
上机检测：ABI 7500定量PCR仪；
预变性：95℃，30秒，1个循环；
PCR扩增：95℃，15秒，40个循环；
退火：60℃，1min；记录。
不同化合物的抑制率柱状图如图4～5所示。从图中可以看出，安全浓度范围内(12.5～100μM)对环烯醚萜类化合物进行体外抗冠状病毒HCoV-OC43的药物筛选，用氧化苦参碱(CQ)作阳性对照，结果显示化合物山茱萸新苷和胡黄连Ⅲ在20μM时对HCoV-OC43的抑制率可达到50％以上，新女贞苷在20μM时也具有一定的抑制活性，而其他化合物，除部分在20μM有部分活性外，对HCoV-OC43均无抑制作用，因此，仅新女贞苷、山茱萸新苷和胡黄连Ⅲ对HCoV-OC43具有稳定的抑制作用。
3、抗SARS-CoV-2假病毒感染活性测试
通过HEK-293T细胞转染SARS-CoV-2的S蛋白，形成SARS-CoV-2假病毒，测定环烯醚萜类化合物对SARS-CoV-2假病毒的抑制效果。具体测试过程如下：
1)SARS-CoV-2S蛋白(pNL4-3.Luc.R-E-pcDNA3.1-SARS-CoV-2-Sipke)病毒包装：
对数生长期的HEK-293T细胞4*10^5个/ml，2ml每孔均匀接种于6孔板中。37℃、5％CO2细胞培养箱中培养24小时。转染前1小时更换新鲜培养基，分别采用100μl空白DMEM培养基配制质粒稀释液及转染试剂(PolyJet)稀释液，每孔配制比例如下(质粒DNA需采用去内毒素的提取试剂盒(市购所得)抽提)：
pNL4-3.Luc.R-E-载体质粒 1000ng
pcDNA3.1-SARS-CoV-2-Sipke 500ng
PolyJet 6μl
具体配制方法如下：pNL4-3.Luc.R-E-质粒与pcDNA3.1-SARS-CoV-2-Sipke质粒同时加入到100μl空白DMEM培养基中混匀，PolyJet采用100μl空白DMEM培养基稀释混匀。将PolyJet稀释液加入质粒稀释液中并混匀，室温孵育15分钟，均匀的添加至HEK-293T细胞中，37℃培养48小时后收集上清病毒液，4000rpm离心10分钟，0.45μm无菌滤头过滤，即得到SARS-CoV-2假病毒。
2)假病毒抑制实验：根据细胞毒性实验结果选取化合物的安全浓度进行活性检测。
药物与假病毒作用：取对数生长期稳定过表达人源SARS-CoV-2受体ACE2的293T细胞(293T/ACE2)，按1*10^4个/孔均匀铺于96孔细胞板中。37℃细胞培养箱中培养24小时。
样品初始浓度设置为20μM，给药前采用含总体积2％胎牛血清的DMEM培养基稀释3个浓度梯度(20、10、2μM)，每个浓度3个复孔。将假病毒稀释液加入梯度稀释后的药物中，混匀室温作用30分钟，取100μl/孔添加至ACE2/293T细胞中，37℃继续培养48小时。
检测：去除培养基，200μl/孔无菌PBS(pH7.4)洗涤细胞一次，每孔加入40μl 1×细胞裂解液(1×Cell lysis)，室温震荡裂解15分钟。转移30μl/孔裂解上清到96孔白色酶标板中，按照单荧光素酶检测试剂盒(Luciferase Assay System)说明书加等体积稀释后的荧光素酶底物，立即进行酶标仪检值测发光，根据发光值大小，判断样品抑制病毒吸附进入的活性。根据发光值与药物浓度的对应关系计算抑制率(Inhibition rate)，绘制曲线并计算环烯醚萜类化合物的半数抑制浓度IC50。实验结果如图6所示。
从图6中可以看出，在安全浓度范围内对山茱萸新苷、胡黄连苷Ⅲ、新女贞苷等21个单体化合物进行体外抗SARS-CoV-2的活性测试，假病毒进入实验中，用已知能够抑制SARS-CoV-2PsV进入细胞的药物-氧化苦参碱(CQ)作为阳性对照，结果表明，山茱萸新苷、胡黄连苷Ⅲ、新女贞苷具有一定抑制SARS-CoV-2PsV感染293T/ACE2细胞的作用，强于其他化合物，抑制率可达50％以上。在体外抗冠状病毒HCoV-OC43的药物筛选中，用已知氧化苦参碱(CQ)作阳性对照，结果显示山茱萸新苷和胡黄连苷Ⅲ在20μM时对HCoV-OC43的抑制率可达到50％以上。对比阳性对照药物氧化苦参碱(IC50＝20.985μM)，山茱萸新苷(SDD-12)、新女贞苷(SDD-15)具有抑制SARS-CoV-2PsV感染293T/ACE2细胞的作用，抑制率可达50％以上，可推知其IC50低于20μM。
4、对SARS-CoV-2病毒3CL蛋白酶活性影响测试
1)实验原理：
荧光共振能量转移(fluorescence resonance energy transfer,FRET)，通过测定荧光来检测3CL蛋白酶的活性。一个供体基团(EDANS)和淬灭基团(DABCYL)均被连接到3CL蛋白酶的天然底物上，当该底物未被切断时，DABCYL可淬灭EDANS，从而检测不到荧光。当该底物被3CL蛋白酶切断后，EDANS不再被DABCYL淬灭，随即可检测到EDANS荧光。
2)试剂、耗材及仪器准备：
3CL蛋白酶(镍柱纯化)
3C底物(GL Biochem，Cat No:：730985-86-1)
Tris(Sangon Biotech，Cat No:A600194)
EDTA(Sangon Biotech，Cat No:B540625)
DMSO(TCI，Cat No:D5293)
阳性对照氧化苦参碱(MCE，HY-13750，测试过程中同样使用DMSO溶解)
384-well Solid White Flat Bottom(Corning，Cat No:3701)
酶标仪(公司：Molecular Devices，型号：SpectraMax Paradigm)
离心机(公司：Beckman，型号：Allegra-15R)
震荡仪(公司：Scilogex，型号：XW-80A)
3)反应体系(20μl)
药物浓度及基本配置信息如下表4所示：
表4
4)反应过程
4.1 200×化合物溶液制备：
横向梯度稀释：将化合物母液(20mM)，按照3倍稀释方式，用DMSO将化合横向稀释9个浓度梯度(3μl化合物+6μl DMSO)，浓度分别为:20mM、6.667mM、2.222mM、0.741mM、0.247mM、0.082mM、0.027mM、0.009mM、0.003mM。
4.2将9个浓度梯度的200×化合物分别先用Buffer纵向稀释20倍至10×化合物(2μl化合物+38μl buffer)，再分别各取2μl的10×化合物加入到最终反应体系(20μl)中，再次稀释10倍至1×化合物，即化合物的终浓度分别为待测浓度：100μM、33.333μM、11.111μM、3.704μM、1.235μM、0.412μM、0.137μM、0.046μM、0.015μM；
实验组：3CL蛋白酶(1μl)+Drug(2μl)+buffer(15μl)，室温反应30min；
空白对照组(0％)：buffer(18μl)，室温反应30min；
DMSO对照组(100％)：3C(1μl)+DMSO(2μl)+buffer(15μl)，室温反应30min。
4.3每孔加入2μl的3C底物，384孔板短暂离心后，室温避光反应20min。
4.4 384孔板放入酶标仪，选择Tune卡盒，FRET模式，设置读数参数：
λexc/λem＝360nm/490nm。
4.5运行酶标仪，连续读数60min，每10min采集一次数据。
4.6读数结束后，选择酶活性达到最高值时的数据作为最终的处理数据(RLU)。
5)数据处理公式
用下列公式来计算检测化合物的抑制率：
Inhibition(％)＝100％-(RLUcompound-RLU0％control)/(RLUdmso control-RLU 0％control)*100％
在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线图和IC50值，结果如下表5所示。
表5
从表4可以看出，相比阳性对照氧化苦参碱，本发明实施例方案的天然环烯醚萜化合物效果均明显强于氧化苦参碱，尤其是新女贞苷对3CL蛋白酶的抑制作用最强，IC50可达14.340μM，其可通过抑制3CL蛋白酶活性，从而实现阻断病毒复制的效果，具有良好的应用前景。
上述实验过程利用当代药物化学和分子生物学流行技术，以一类中药有效成分为研究对象和分子探针，对人冠状病毒病开展药物发现进行研究，为发现质量可控、低毒高效的抗冠状病毒创新药物打下物质基础。从研究思想创新上，本发明以临床治疗SARS/COVID-19中药处方用药分析为出发点，通过对其进行深入思考，提出对一类中药有效成分的系统研究以发现创新药物。以传统中医中药思想与现代药学科学进行理论相互碰撞，以前期调研和研究结果为基础，进行创新设想，提出多种清热类中药通过其环烯醚萜类成分，发挥抗冠状病毒的药效。
综上所述，新女贞苷抑制、山茱萸新苷、胡黄连苷Ⅲ对不同冠状蛋白有着不同的抑制作用，均对3CL蛋白酶具有一定的活性，因此，其在抗冠状病毒中具有良好的应用前景。上述测试过程中通过与相关技术中分离出的其他具有潜在抗冠状病毒活性的天然环烯醚化合物对比，证明了本发明实施例方案的环烯醚萜类化合物具有更好的药用活性。以人类冠状病毒中的SARS-CoV-2和HCoV-OC43为代表，经药理活性研究表明，该类化合物具有一定抑制SARS-CoV-2PsV感染293T/ACE2细胞的作用；体外抗冠状病毒HCoV-OC43的药物筛选中，发现其中的山茱萸新苷和新女贞苷两个单体化合物对HCoV-OC43的抑制率作用较强。本发明以SARS-CoV-2病毒3C主蛋白酶为靶标进行活性分析，新女贞苷抑制3C蛋白酶活性较山茱萸新苷、胡黄连苷Ⅲ强，IC50为14.340μM，可抑制3C蛋白酶活性，具有阻断病毒复制的效果。
上面结合附图对本发明实施例作了详细说明，但是本发明不限于上述实施例，在所属技术领域普通技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下作出各种变化。此外，在不冲突的情况下，本发明的实施例及实施例中的特征可以相互组合。
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<110> 五邑大学
<120> 环烯醚萜化合物在制备抗冠状病毒药物中的应用
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Claims (10)
1.环烯醚萜化合物在制备抗冠状病毒药物中的应用，其特征在于：所述环烯醚萜化合物为山茱萸新苷、胡黄连苷Ⅲ或新女贞苷。
2.根据权利要求1所述的应用，其特征在于：所述冠状病毒包括但不限于HCoV-229E、HCoV-NL63、HCoV-OC43、SARS-CoV、MERS-CoV、HCoV-HKU1或SARS-CoV-2中的至少一种。
3.根据权利要求1所述的应用，其特征在于：所述抗冠状病毒药物包括预防或治疗冠状病毒药物。
4.根据权利要求1所述的应用，其特征在于：所述抗冠状病毒药物的制备原料还包括药用辅料。
5.根据权利要求4所述的应用，其特征在于：所述药用辅料选自崩解剂、稀释剂、润滑剂、粘合剂、矫味剂、助悬剂、表面活性剂或防腐剂中的至少一种。
6.根据权利要求5所述的应用，其特征在于：所述崩解剂选自玉米淀粉、马铃薯淀粉、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲纤维素钠、羧甲基纤维素、羧甲基纤维素钙或藻酸中的至少一种；更优选地，所述稀释剂选自乳糖、蔗糖、甘露醇、玉米淀粉、马铃薯淀粉、磷酸钙、柠檬酸钙或结晶纤维素中的至少一种；更优选地，所述润滑剂选自微粉硅胶、硬脂酸镁、硬脂酸钙、硬脂酸、滑石粉或无水硅胶中的至少一种；更优选地，所述粘合剂选自阿拉伯胶、明胶、糊精、羟丙基纤维素、甲基纤维素或聚乙烯吡咯烷酮中的至少一种；更优选地，所述矫味剂选自阿斯巴甜、甜菊甙、蔗糖、麦芽糖醇或柠檬酸中的至少一种；更优选地，所述助悬剂选自阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素钠、羟甲基纤维素或硬脂酸铝凝胶中的至少一种；更优选地，所述表面活性剂选自卵磷脂、山梨糖醇酐单油酸酯或单硬脂酸甘油酯中的至少一种；更优选地，所述防腐剂选自对羟苯甲酸甲酯或对羟苯甲酸丙酯中的至少一种。
7.根据权利要求1所述的应用，其特征在于：所述药物剂型为固体、半固体或液体的形式；优选为水溶液、非水溶液、混悬液或膏体。
8.根据权利要求7所述的应用，其特征在于：所述药物剂型为片剂、胶囊剂、软胶囊剂、颗粒剂、丸剂、口服液、乳剂、干混悬剂、干浸膏剂或注射剂。
9.环烯醚萜化合物在制备冠状病毒主蛋白酶抑制剂中的应用，其特征在于：所述环烯醚萜化合物为山茱萸新苷、胡黄连苷Ⅲ或新女贞苷。
10.环烯醚萜化合物在制备3CL蛋白酶抑制剂中的应用，其特征在于：所述环烯醚萜化合物为山茱萸新苷、胡黄连苷Ⅲ或新女贞苷。
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