CN113143902A - 没食子酸和/或绿原酸治疗冠状病毒感染的用途 - Google Patents
没食子酸和/或绿原酸治疗冠状病毒感染的用途 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本发明公开了一种没食子酸和/或绿原酸或含有它们的接骨草提取物在制备预防或治疗冠状病毒感染性疾病的药物或食品中的用途。
Description
技术领域
本发明属于医药技术领域,具体涉及一种没食子酸和/或绿原酸在制备预防或治疗冠状病毒感染性疾病的药物或食品中的用途。本发明也涉及接骨草提取物的新用途,具体涉及接骨草提取物在治疗冠状病毒感染的用途。
背景技术
高致病性冠状病毒感染成了这十年来广受关注公共卫生问题。严重急性呼吸综合征(SARS,2002-2004),中东呼吸综合征(MERS,2012-至今),2019-nCoV(COVID-19),每一个对人类健康,经济发展都带了巨大的冲击。
截至2021年3月25日9时,中国累计报告确诊病例102612例,累计死亡病例4850例,累计治愈出院97315例,交通运输、住宿餐饮等行业受疫情影响巨大,给中国GDP带来巨大损失。虽然中国国内的疫情形势已经逐渐稳定,但随着新冠肺炎继续在全球蔓延,病例数不断上升,疫情已进入一个全新的阶段。世卫组织官员于2月26日首次表示,中国境外每日新增病例数已超过中国国内的新增病例数。截至2021年2月19日17时,超过200个国家和地区均已报告确诊病例,海外确诊病例125089039例,累计死亡病例2746728例,累计治愈出院96526798例,仅美国就确诊了3070097例,死亡人数突破55万人,美国已成为疫情震中。最初只是在中国局部爆发的疫情现已成为全球重大公共卫生挑战。
由于没有针对性的有效药物和疫苗,新型冠状病毒的新药研发意义重大,在这场没有硝烟的战争中,全球多家科研机构和制药公司致力于研发新型冠状病毒疫苗和治疗药物。因此发明具有重大的社会学和经济学意义。
接骨草,(学名:Sambucus chinensis Lindl.),味甘、苦,性平,归肝经。功能主治:祛风利湿;活血;止血。主风湿痹痛;痛风;大骨节病;急慢性肾炎;风疹;跌打损伤;骨折肿痛;外伤出血。在民间,接骨草因具有接骨功效而得名,并广泛用于治疗跌打损伤。近年来研究发现,其治疗黄疸型和病毒性肝炎的效果显著,而且无毒性。
接骨草化学成分,主要为黄酮、三萜、甾体、酚酸、挥发油和苯丙素类等成分。本发明首次发现接骨草提取物可以治疗冠状病毒感染,其有效成分主要是没食子酸gallicacid和绿原酸chlorogenic acid。
发明内容
本发明发明人经过广泛深入的研究,发现,接骨草提取物中没食子酸可以结合冠状病毒刺突蛋白S1,绿原酸可以结合冠状病毒受体ACE2,从而阻断病毒进入细胞,没食子酸在细胞水平EC50=8.51uM,绿原酸在细胞水平EC50=25.99uM。
鉴于此,本发明的目的在于提供冠状病毒有效广谱抑制剂,可以治疗冠状病毒引起的肺炎感染或普通感冒。本发明提供了一种没食子酸和/或绿原酸在制备预防或治疗冠状病毒感染性疾病的药物或食品中的用途。本发明还提供了一种没食子酸和/或绿原酸、接骨草提取物的新用途,用于预防和治疗冠状病毒感染性疾病。
根据本发明接骨草提取物的新用途的一个具体实施方式,所述疾病是2019新型冠状病毒肺炎,严重急性呼吸综合症肺炎(SARS),中东呼吸综合症肺炎(MERS)以及人冠状病毒OC43(HCoV-OC43)引发的普通感冒。
没食子酸和绿原酸可以市售获得。购买来源,没食子酸粉末例如可以购买于索莱宝公司,货号(SG8040);绿原酸粉末例如可以购买于阿拉丁公司,货号(C109402)。没食子酸和绿原酸也可以从中药原料接骨草等等提取获得。
没食子酸的结构式如下:
中文名称:没食子酸
英文名称:gallic acid
别称:3,4,5-三羟基苯甲酸
分子式:C7H6O5
分子量:170.12
CAS号:149-91-7
用途:没食子酸又名五倍子酸,是一种天然产物化学成分,化学命名为3,4,5-三羟基苯甲酸,具有很高的药用价值。广泛存在于掌叶大黄、大叶桉、山茱萸、干屈菜、马桑、化香树、乌桕、石榴、赶黄草、阿拉伯相思树等植物中,是自然界存在的一种多酚类化合物。没食子酸有抗肿瘤、抗乙肝病毒、抗菌等功效。
绿原酸的结构式如下:
中文名称:绿原酸
英文名称:Chlorogenic acid
别称:(1S,3R,4R,5R)-3-[[3-(3,4-二羟基苯基)-1-氧代-2-丙烯基]氧]-1,4,5-三羟基环己烷甲酸
分子式:C16H18O9
分子量:354.31
CAS号:327-97-9
用途:绿原酸是咖啡和茶中的主要酚类化合物。Chlorogenic acid具有一些重要作用,如抗氧化活性,抗菌,保肝,心脏保护,抗炎,解热,神经保护,抗肥胖,抗病毒,抗微生物,抗高血压。
本发明提供了没食子酸和绿原酸的新用途,作为冠状病毒有效的广谱抑制剂,可以治疗2019新型冠状病毒肺炎,严重急性呼吸综合症肺炎(SARS),中东呼吸综合症肺炎(MERS)以及人冠状病毒OC43(HCoV-OC43)引发的普通感冒。
本发明的化合物可以配制成各种适合的药物制剂形式。可以单独使用,或者将其与药用辅料(例如赋形剂、稀释剂等)混合,配制成口服给药的片剂、胶囊剂、颗粒剂或糖浆剂等或注射给药的粉针剂、溶液剂。
本发明具体地是通过以下技术方案实现的:
本发明提供了一种没食子酸和/或绿原酸在制备预防或治疗冠状病毒感染性疾病的药物或食品中的用途。
其中,没食子酸和绿原酸可以单独使用,也可以结合使用,可以同时或分别给药,或顺序给药。没食子酸和绿原酸可以按照本领域常规技术手段制备成常规给药制剂形式。
在本发明一种具体的实施方案中,其中所述冠状病毒为2019新型冠状病毒(2019-CoV),严重急性呼吸综合症病毒(SARS),中东呼吸综合症病毒(MERS)肺炎感染以及普通感冒病毒(HCoV-OC43)
在本发明一种具体的实施方案中,其中所述冠状病毒为人冠状病毒NL63(HCoV-NL63)、人冠状病毒229E(HCoV-229E)或人冠状病毒HKU1(HCoV-HKU1)。
在本发明一种具体的实施方案中,其中所述没食子酸和/或绿原酸来源于接骨草,包括接骨草粉碎混合物、接骨草提取物或者它们与没食子酸和/或绿原酸的混合物。
在本发明一种具体的实施方案中,其中所述药物为口服制剂,包括片剂、胶囊剂、颗粒剂;所述食品包括茶、汤、粥、菜、汁等各种形式的功能食品;优选地,所述的药物或食品还含有载体、稀释剂或赋形剂。
在本发明一种具体的实施方案中,其中所述药物还含有载体、稀释剂或赋形剂。
本发明的化合物可以配制成各种适合的药物制剂形式。
本发明还提供了一种用于预防或治疗冠状病毒感染的口服制剂,其特征在于:含治疗有效量的没食子酸和/或绿原酸和任选的其他抗冠状病毒感染的药物活性成分,以及药学上可接受的载体辅料。
在本发明一种具体的实施方案中,其中所述没食子酸和/或绿原酸来源于接骨草。
在本发明一种具体的实施方案中,其中所述接骨草为接骨草提取物,所述口服制剂是片剂、胶囊剂、颗粒剂,优选片剂。
本发明的有益效果
与现有技术相比,本发明的技术效果如下:
经鉴定,接骨草提取物抑制新冠病毒的有效成分主要是没食子酸gallic acid和绿原酸chlorogenic acid,没食子酸可以结合冠状病毒的刺突蛋白S1,绿原酸可以结合冠状病毒的受体ACE2,共同影响病毒结合受体,从而阻断病毒进入细胞。作为老药新用,接骨草提取物的安全性没有问题,因此可以应用于临床。
没食子酸在细胞水平能够结合刺突蛋白S1,阻止病毒进入细胞,从而达到治疗冠状病毒肺炎感染以及普通感冒,抑制SARS-CoV-2假病毒的EC50=8.51uM。绿原酸在细胞水平能够结合受体ACE2,阻止病毒进入细胞,从而达到治疗冠状病毒肺炎感染以及普通感冒,抑制SARS-CoV-2假病毒的EC50=25.99uM。
附图说明
图1显示没食子酸和2019新型冠状病毒S1蛋白的亲和力。
图2显示没食子酸和SARS病毒S1蛋白的亲和力。
图3显示没食子酸和MERS病毒S1+S2 ECD蛋白的亲和力。
图4显示没食子酸和OC43病毒S1+S2 ECD蛋白的亲和力。
图5显示没食子酸和NL63病毒S1+S2 ECD蛋白的亲和力。
图6显示没食子酸和HKU-1病毒S1+S2 ECD蛋白的亲和力。
图7显示绿原酸和ACE2蛋白的亲和力。
图8显示没食子酸抑制SARS-CoV-2假病毒的EC50和CC50。
图9显示绿原酸抑制SARS-CoV-2假病毒的EC50和CC50。
下面结合具体实验操作及数据,进一步说明本方面的技术方案。
以下通过试验说明没食子酸和绿原酸对各个亚型冠状病毒的抑制作用。
具体实施方式
下面结合实施例对本发明做进一步的说明,这些实施例仅是对本发明的举例说明而已,无论如何不能解释为对本发明范围的限制。
实施例1:SPR实验
实验材料与仪器
biacore T200(GE healthcare,Uppsala,Sweden),CM5芯片(GE healthcare,Uppsala,Sweden),没食子酸(索莱宝),绿原酸(阿拉丁),2019-CoV S1蛋白(义翘神州),SARS S1蛋白(义翘神州),MERS,OC43,NL63,HKU-1S1+S2ECD蛋白(义翘神州)。
冠状病毒S蛋白SPR实验
机型为GE公司的biacore T200,将2019新型冠状病毒的S1蛋白(义翘神州),SARS病毒S蛋白(义翘神州),MERS,OC43,NL63,HKU-1病毒S1+S2 ECD蛋白(义翘神州)通过氨基偶联到CM5芯片上,偶联量分别为9499.3RU,13628.8RU,14187.7RU,6082.3,14602.8RU,16061.2RU,测量化合物和S蛋白在25℃下的亲和力。以30μL/分钟的流速以100uM,50uM,25uM,12.5uM,6.25uM,3.125uM,1.5625uM,0.78125uM,0uM的浓度注入化合物,进样时间180s,解离时间300s。数据分析方式为稳态分析。
ACE2蛋白SPR实验
机型为GE公司的biacore T200,将ACE2蛋白(义翘神州)通过氨基偶联到CM5芯片上,偶联量分别为12660.7RU,测量化合物和ACE2蛋白在25℃下的亲和力。以30μL/分钟的流速以100uM,50uM,25uM,12.5uM,6.25uM,3.125uM,1.5625uM,0.78125uM,0uM的浓度注入化合物,进样时间180s,解离时间300s。数据分析方式为稳态分析。
SPR结果总结在下表中
表一.在25℃下没食子酸结合各个亚型冠状病毒S蛋白的亲和力
表二.在25℃下绿原酸结合ACE2蛋白的亲和力
蛋白 | KD(M) | Rmax(RU) | Chi<sup>2</sup>(RU<sup>2</sup>) | chi |
ACE2 | 7.154*10<sup>-7</sup> | 5.396 | 0.0194 | 0.139 |
实施例2
新型冠状病毒(SARS-CoV-2)外膜的VSV-dG-fLuc的复制缺陷型假病毒感染实验检测没食子酸和绿原酸抑制冠状病毒进入细胞的效果
实验材料
VSV-dG-luciferase来自中国食品药品检定研究员王佑春教授,VSV-dG-fLuc(Firefly Luciferase)水泡性口炎病毒(Vesicular stomatitis virus,VSV)的假病毒包装系统的反向遗传学质粒拯救(rescue)获得。其中pVSV-ΔG-Luciferase用于转录复制缺陷型的重组VSV基因组,其中VSV的糖蛋白(G)被荧火虫荧光素酶(Firefly luciferase,fLuc)所替代。
拯救与扩增含VSVG外膜的VSV-dG-fLuc复制缺陷型病毒
将HEK293细胞贴壁于3.5cm dish,第二天待细胞达到90%密度时,并用重组表达T7 RNA聚合酶的痘病毒(Vaccinia virus-T7,vv-T7)以MOI=5IU的滴度(DMEM,无血清)在37℃感染45分钟。用PBS漂洗细胞一遍后,用Lipo3000转染已混合好的反向遗传学质粒转染已被vv-T7感染过的细胞,12小时后换液,48小时后收取含有初代VSV-dG-fLuc病毒的上清,用0.22μm滤膜过滤上清除去残留的vv-T7。为进一步扩增病毒,用过表达VSV G蛋白的pMD2.G(ATCC:Plasmid#12259)转染HEK293T细胞,24小时后,初代上清与DMEM+10%血清1:1混合用于感染,24-48小时后收取上清,12000转离心2分钟后保留上清并分装,用噬斑法测定病毒滴度,并保存于-80℃。
包装含新型冠状病毒(SARS-CoV-2)外膜的VSV-dG-fLuc的复制缺陷型假病毒
用过表达SARS-CoV-2的S外膜蛋白的质粒(pcDNA3.1.S2)转染HEK293T细胞或Vero-E6细胞。24小时后,用MOI=10IU的含VSVG外膜的VSV-dG-fLuc病毒(1:30稀释)在37℃感染转染后的细胞1小时,然后加入含1:300稀释的大鼠抗VSVG抗血清的DMEM+10%FBS的培养基,用于完全中和残留的含VSVG外膜的VSV-dG-fLuc假病毒。24-48小时后收取含有病毒的上清,12000转离心2分钟后保留上清并分装,用有限稀释法通过CPE测定病毒滴度(Infectious Unit),并保存于-80℃。
用基于VSV的SARS-CoV-2假病毒感染确定药物半数有效深度(EC50)
将HEK293-ACE2细胞(Genewiz公司购买)贴壁于96孔板。24小时后,细胞密度约达到90%,在DMEM+10%FBS的培养基中将不同浓度的药物分别与不同的假病毒混合,如表达Fluc的含VSVG外膜蛋白或SARS-CoV-2外膜蛋白的VSV-dG假病毒(MOI=0.1IU),然后感染细胞。24小时后,测定细胞内的荧光素酶强度,则除去培养上清,加入20μl 1x passive lysis缓冲液(Promega),室温放置10分钟后通过One-Glo luciferase kit(Promega)和20/20生物发光测定仪(Promega)进行测定。细胞毒性通过显微镜明视野进行观察。
实施例3
化合物半数细胞毒性CC50的确证
293-ACE2细胞接种到96孔板中,次日,细胞先分别加入0.137,0.4111.1.233,3.7,11.1,33.3和100μM的化合物。药物对293-ACE2的细胞毒性用CellTiter-Glo2活性检测来测量。
实验结果
没食子酸抑制SARS-CoV-2假病毒的EC50和CC50的确证:
没食子酸抑制SARS-CoV-2假病毒的EC50=8.51uM,CC50=205.5uM,SI=24.15
绿原酸抑制SARS-CoV-2假病毒的EC50和CC50的确证:
绿原酸抑制SARS-CoV-2假病毒的EC50=25.99uM,CC50=562.1uM,SI=21.63。
上述实施例和实验例对本发明对本发明做了具体说明。任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更为同等变化的等效实施例。凡是未脱离本发明方案内容,依据本发明的技术实质对以上实施例所做的任何简单修改或等同变化,均落在本发明的保护范围内。
Claims (10)
1.没食子酸和/或绿原酸在制备预防或治疗冠状病毒感染性疾病的药物或食品中的用途。
2.根据权利要求1所述的用途,其中所述冠状病毒为2019新型冠状病毒(2019-CoV),严重急性呼吸综合症病毒(SARS),中东呼吸综合症病毒(MERS)肺炎感染以及普通感冒病毒(HCoV-OC43)。
3.根据权利要求1所述的用途,其中所述冠状病毒为人冠状病毒NL63(HCoV-NL63)、人冠状病毒229E(HCoV-229E)或人冠状病毒HKU1(HCoV-HKU1)。
4.根据权利要求1-3任一项所述的用途,其中所述没食子酸和/或绿原酸来源于接骨草,包括接骨草粉碎混合物、接骨草提取物或者它们与没食子酸和/或绿原酸的混合物。
5.根据权利要求1-3任一项所述的用途,其中所述药物还含有其他抗冠状病毒感染的药物活性成分。
6.根据权利要求1-3任一项所述的用途,其中所述药物为口服制剂,包括片剂、胶囊剂、颗粒剂;所述食品包括茶、汤、粥、菜、汁等各种形式的功能食品;优选地,所述的药物或食品还含有载体、稀释剂或赋形剂。
7.一种用于预防或治疗冠状病毒感染的口服制剂,其特征在于:含治疗有效量的没食子酸和/或绿原酸以及药学上可接受的载体辅料。
8.根据权利要求7所述的口服制剂,其中所述没食子酸和/或绿原酸来源于接骨草。
9.根据权利要求8所述的口服制剂,其中所述接骨草为接骨草提取物。
10.根据权利要求7所述的口服制剂,其中所述口服制剂是片剂、胶囊剂、颗粒剂,优选片剂。
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