CN115192590A - 甘草皂苷a3对新型冠状病毒刺突蛋白的抑制及其药物用途 - Google Patents
甘草皂苷a3对新型冠状病毒刺突蛋白的抑制及其药物用途 Download PDFInfo
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Abstract
本发明公开了甘草中存在的三萜化合物甘草皂苷A3的医药新用途。本发明发现甘草皂苷A3可以有效抑制新型冠状病毒刺突蛋白,并对其存在较好的亲和力,同时,验证了该化合物对新型冠状病毒有高效的抑制作用,为新冠病毒的绿色候选抑制剂。基于以上发现,甘草皂苷A3及其药学上可接受的盐、酯、溶剂化物、立体异构体、互变异构体、前药以及其混合物可用于制备治疗和/或预防抗新型冠状病毒或其他冠状病毒感染的药物及保健品。
Description
技术领域
本发明涉及甘草皂苷A3的药物新用途,具体涉及甘草皂苷A3在抗新型冠状病毒刺突蛋白(Spike)中的应用。
背景技术
目前,由新型冠状病毒引起的流行性疾病(COVID-19)是当前世界范围内亟待解决的首要任务。该疾病是由新型冠状病毒(SARS-CoV-2)引起的,对全球公共卫生造成了巨大威胁。它于2019年底被发现,据统计截至到2020年9月,死于此疾病的人数已超过100万。然而,目前仍没有针对COVID-19的特效药物或疫苗。
冠状病毒(CoVs)是迄今为止鉴定出的最大的RNA病毒,是一组带有包膜且具有正链的单链RNA基因组。在SARS-CoV-2之前,人类致命的肺炎仅由严重的急性呼吸综合征冠状病毒(SARS-CoV)和中东呼吸综合征冠状病毒(MERS-CoV)引起,它们是源自蝙蝠冠状病毒(CoVs)家族的人畜共患病原体。经过序列比较,SARS-CoV-2与蝙蝠SARS样冠状病毒有96.2%的相似性,并识别ACE2受体。根据人类从MERS-CoV到SARS-CoV-2的反复感染现象来看,这些大基因组冠状病毒的未来传播事件可能还会继续。
为了迅速开发用于预防和治疗COVID-19的特定抗冠状病毒预防剂和治疗剂,人们更加关注刺突蛋白(S)。刺突蛋白是一种三聚体I类病毒融合蛋白,通过与血管紧张素2(ACE2)受体的相互作用介导病毒进入人宿主细胞。目前,细胞受体ACE2结合SARS-CoV-2刺突蛋白RBD区域的晶体结构已确定,并且SARS-CoV-2RBD中已鉴定出的残基与SARS-CoV RBD中残基高度保守。有研究显示,丹参酸C可通过结合S蛋白而抑制新型冠状病毒感染(Liu SW等,Signal Transduction and Targeted Therapy 2020,5,220)。同时,黄酮化合物橙皮苷和蒽醌化合物大黄素等天然药物成分可有效结合S-ACE2复合物,从而治疗新型冠状病毒感染(Maulik U等,Scientific Reports 2020,10,17699)。此外,通过临床试验证实,金银花汤剂中的miRNA可通过饮用被人体有效吸收,并在体内有效抑制新冠病毒复制,加速新冠患者转阴,表明金银花汤剂治疗可能会极大地帮助治愈新冠患者并阻止COVID-19大流行(YiYX等,Cell Discovery 2020,6,54)。
甘草(Glycyrrhizae Radix et Rhizoma)是常用中药,具有保肝、抗溃疡、抗病毒、抗氧化、抗炎、抗菌、抗疟等药理活性,含有黄酮、黄酮苷、三萜皂苷等化学成分。其中,三萜化合物在自然界种类繁多,分布广泛,资源丰富。其生物活性具有溶血、抗癌、抗炎、抗菌、抗病毒、降低胆固醇等活性。早在2013年就有报道指出,三萜化合物甘草酸可治疗SARS冠状病毒(Doerr HW等,Lancet 2003,361,2045–46)。也有报道,甘草酸可与S在内的多种新型冠状病毒靶点结合而抑制病毒(Zarrabi M等,Journal of Diabetes&MetabolicDisorders2020)。因此,从甘草中发现有效的新型抗病毒药物具有重要的现实意义和良好的应用前景。
发明内容
本发明的目的在于为预防和/或治疗新型冠状病毒和其他冠状病毒提供药物。
本发明通过研究发现,甘草提取物甘草皂苷A3具有抑制冠状病毒刺突蛋白的作用,从而为抗新型冠状病毒等冠状病毒感染提供了新的途径。
甘草皂苷A3的结构式如下:
本发明所述甘草皂苷A3是一种三萜类化合物,该化合物本身或其药学上可接受的盐、酯、溶剂化物、立体异构体、互变异构体、前药中的至少一种,以及其混合物,能够抑制冠状病毒的刺突蛋白(Spike),可用于预防和治疗新型冠状病毒或其它冠状病毒的感染。
以上述活性化合物或其药学上可接受的盐、酯、溶剂化物、立体异构体、互变异构体、前药以及它们的混合物为有效成分制备的用于预防和/或治疗冠状病毒感染的药物也属于本发明的保护范围。
需要的时候,在上述药物中还可以加入一种或多种药学上可接受的载体或辅料。所述载体或辅料包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
利用上述活性化合物或其药学上可接受的盐、酯、溶剂化物、立体异构体、互变异构体以及前药作为活性成分,单独或组合使用,或与其它药物、辅料等配合制备成各种剂型,包括但不限于片剂、散剂、丸剂、注射剂、胶囊剂、膜剂、栓剂、膏剂、冲剂等多种形式。上述各种剂型的药物均可以按照药学领域的常规方法制备。
本发明提供的甘草皂苷A3是甘草中的三萜化合物,这类成分多具有抗炎、抗免疫、抗肿瘤、抗氧化等药理活性,但其抗新冠病毒活性未见报道。本发明首次发现甘草皂苷A3对冠状病毒的刺突蛋白有抑制作用,从而起到抗冠状病毒活性,可用于制备治疗和/或预防冠状病毒感染的药物或保健品。
附图说明
图1为实施例1检测甘草皂苷A3对新冠病毒S蛋白抑制率的实验结果。
图2为实施例2检测甘草皂苷A3对假病毒感染Vero E6细胞的抑制率与细胞毒性的实验结果。
图3为实施例3检测甘草皂苷A3对新型冠状病毒的抑制率与细胞毒性的实验结果。
图4为实施例4的甘草皂苷A3(0.11μM和0.33μM)对新型冠状病毒的免疫荧光检测图。
图5为实施例5甘草皂苷A3对新型冠状病毒S蛋白的亲和力检测结果。
具体实施方式
下面结合实施例进一步阐述本发明,应理解,以下实施例仅用于说明本发明而不用于限制本发明的保护范围。
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1、甘草皂苷A3对新冠S蛋白抑制率检测。
一、实验材料和方法。
S-RBD蛋白抑制剂筛选采用酶联免疫吸附法(ELISA)(Diagnostics 2021,11,271)。该方法常用于检测RBD抗体,很少用于小分子检测。本发明对体系进行了优化,专门用于小分子抑制剂的筛选。96孔酶标板固相表面包被三聚体S蛋白DRA49(1μg/mL),包被液使用Na2CO3-NaHCO3(pH 9.6)。4℃孵育过夜,洗涤(洗涤液为含0.05%Tween 20的PBS,下同)。加入2%BSA封闭40min,洗涤。加入候选化合物(10μM)或阳性药(抗体S-hIgG1,0.0001-10μg/mL)孵育,洗涤。加入ACE2蛋白CY51(5μg/mL),孵育1小时,洗涤。ACE2蛋白和候选化合物溶于PBS,以1%BSA稀释。加入酶联抗体SA-HRP(1:15000),孵育1小时,洗涤。加入TMB显色,5分钟后,再加入1M盐酸作为终止液,酶标仪OD 450nm检测。测试IC50值时,化合物浓度梯度为80,40,20,10,5,2.5μM。
二、实验结果。
甘草皂苷A3可抑制S蛋白,IC50值为8.3±1.6μM,如图1所示。
实施例2、甘草皂苷A3对假病毒感染Vero E6细胞的抑制率与细胞毒检测。
一、实验材料和方法。
首先,使用CCK-8试剂盒测试候选化合物的细胞毒活性。Vero E6细胞(20000个/孔)接种于装有100μL培养基的96孔板中,加入候选化合物(20μM),孵育24小时后,加入10μLCCK-8溶液,37℃下孵育2h,酶标仪450nm检测细胞活性。为检测对病毒进入细胞的抑制活性,Vero E6细胞(20000个/孔)接种于96孔板中,加入候选药物(20μM)与SARS-CoV-2混合假病毒(650×TCID50/孔,TCID50为组织半数感染剂量)。混合后培养24h,荧光显微镜绿色通道检测荧光强度。对抑制率较高的化合物,测试IC50值,化合物浓度梯度为80,40,20,10,5,2.5μM。
二、实验结果。
在假病毒系统中,甘草皂苷A3可抑制病毒感染,IC50为9.3μM,同时,在高浓度时,不影响细胞活力,如图2所示。
实施例3、甘草皂苷A3对新型冠状病毒的抑制率与细胞毒性。
一、实验材料和方法。
活病毒模型活性筛选过程与假病毒模型类似。毒性较低的化合物,SARS-CoV-2以MOI=0.1的比例感染Vero E6细胞(MOI为每个细胞对应的病毒数),同时给药。孵育2小时后,采用CCK-8试剂盒测试化合物细胞毒性;通过qPCR测试病毒拷贝数,评价化合物抗病毒活性。
二、实验结果
在新型冠状病毒活毒体系中,甘草皂苷A3可抑制病毒感染,IC50为0.075μM,如图3所示。
实施例4、甘草皂苷A3对新型冠状病毒的免疫荧光测试
一、实验材料和方法。
将Vero E6细胞孵育在载玻片上24小时。化合物以0.11μM和0.33μM的浓度与病毒液加入到细胞中。感染后24小时后,室温下将细胞用4%多聚甲醛处理15分钟。将细胞与1:1000稀释的荧光标记的新冠抗体溶液室温下孵育1小时。彻底清洗15分钟后,除去未结合的抗体。然后将细胞与1:500稀释的Alexa Fluor 594偶联山羊抗人IgG抗体(Invitrogen,Thermo Fisher Scientific)一起孵育1小时。将载玻片洗涤,15分钟后用DAPI(Sigma)进行核染色,然后用共聚焦荧光显微镜(UltraVIEW VoX;PerkinElmer,美国)成像。
二、实验结果
甘草皂苷A3能够抑制新型冠状病毒感染,如图4所示。
实施例5、甘草皂苷A3对S蛋白亲和力检测
一、实验材料和方法。
对于S蛋白,使用氨基偶联试剂盒将其固定在CM5芯片上。S蛋白用10mM乙酸钠缓冲液(pH=4.5)稀释至终浓度20μg/mL,PBS-T固定,蛋白偶联值约为13000RU。抑制剂小分子溶于缓冲液(含5%DMSO和0.05%T20的PBS)中,由200μM稀释6个浓度。缓冲液流速为30μL/min,结合时间60s,解离时间60s。Biacore软件拟合计算蛋白质-配体结合的平衡解离常数KD。SPR仪使用Biacore T200或Biacore 8K。
二、实验结果。
等离子共振结果显示,甘草皂苷A3能够亲和S蛋白,KD=55.1μM,如图5所示。
Claims (7)
2.如权利要求1所述的应用,其特征在于,所述冠状病毒是新型冠状病毒。
4.如权利要求3所述的药物或保健品,其特征在于,所述冠状病毒是新型冠状病毒。
5.如权利要求3所述的药物或保健品,其特征在于,所述药物或保健品还含有一种或多种药学上可接受的载体或辅料。
7.如权利要求6所述的用途,其特征在于,所述冠状病毒刺突蛋白是新型冠状病毒刺突蛋白。
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