CN115734783A - 一种能够抑制冠状病毒复制的药物组合物 - Google Patents
一种能够抑制冠状病毒复制的药物组合物 Download PDFInfo
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- CN115734783A CN115734783A CN202180036007.7A CN202180036007A CN115734783A CN 115734783 A CN115734783 A CN 115734783A CN 202180036007 A CN202180036007 A CN 202180036007A CN 115734783 A CN115734783 A CN 115734783A
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Abstract
本发明涉及一种药物组合物,在向受试者施用有效量的组合物时能够抑制冠状病毒在受试者中的复制,该组合物包含从Boesenbergia sp.的植物部分获得的提取物,具有摩尔比为1:4至1:10的潘多汀A和球松素。该组合物还可包含抗病毒剂或与抗病毒剂结合或与抗病毒剂一起使用以实现抗冠状病毒的协同作用。
Description
技术领域
本公开涉及一种药物组合物,潘多汀A和球松素,或含有所述组合物的植物提取物,在使组合物或提取物与受感染的细胞或病毒接触时,其能够抑制冠状病毒,更具体来说,严重急性呼吸系统综合症冠状病毒2(SARS-CoV-2)在人类受试者中的复制。此外,所公开的组合物具有防止细胞被SARS-CoV-2感染的特性,使其也成为预防SARS-CoV-2感染的理想候选物。
背景技术
2019年12月,出现一种新型冠状病毒,科学上将其命名为严重急性呼吸系统综合症冠状病毒2(SARS-CoV-2)。世界卫生组织(WHO)将这种病毒引起的疾病称为冠状病毒病19或COVID-19。随着病毒的广泛迅速传播,病毒在短时间内成为大流行病,在全球216个国家和地区爆发。截至2020年5月21日,全球确诊的COVID-19病例总数超过4,900,000例,死亡病例超过320,000例[2]。这种灾难性局面使全体民众迫切需要有效且紧急实惠的抗病毒疗法,与这种可怕的疾病作斗争。
基本上,SARS-CoV-2是冠状病毒科的一种有包膜的正链单股RNA病毒。该病毒与严重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)一起归类为乙型冠状病毒属的成员。通常,大多数人类感染冠状病毒的病例都是轻度或无症状的。然而,2003年的SARS-CoV[3、4]、2014年的MERS-CoV[5]以及此时的SARS-CoV-2的爆发,敲响了全球公共卫生危机的警钟。目前,尚无治疗COVID-19的特效药。所有药物选择都依赖于相关病毒的治疗,如SARS-CoV、MERS-CoV、流感病毒、埃博拉病毒和HIV-1。因此,几种FDA批准的治疗窗广的药物可作为治疗COVID-19的潜在候选药物[6,7]。最有前景的再利用药物包括氯喹/羟氯喹[8-10]、法匹拉韦[11]、洛匹那韦/利托那韦[12]和瑞德西韦[13,14]。然而,这些药物的疗效程度和严重的副作用仍然存在争议[12,15,16]。除了FDA批准的药物外,基于天然产物的药物也备受关注。据报道,使用泰国传统草药,特别是它们的植物化学物质,可发挥广谱活性,如抗癌、抗炎、抗氧化治疗和抗病毒药物[17-20]。这表明它们具有作为抗SARS-CoV-2候选药物的潜力。
植物化学物质和植物提取物是寻找有前景的抗冠状病毒药物成分的理想场所[21]。目前正在研究几种植物化学物质在治疗SARS-CoV-2中的应用,这是因为许多研究小组最近报告了他们对这些材料潜在用途的研究。Jin Z.等人领导的一项研究[22]证明SARS-CoV-2的主要蛋白酶(Mpro)是一种参与病毒复制和转录的前瞻性药物靶标,可以被一种常见的植物衍生萘醌,紫草醌所靶向。对分子对接的进一步研究表明,一个合理的对接姿势表明紫草醌可以与底物袋结合[22]。Khan SA等人采用基于计算的方法从FDA批准的抗病毒药物和天然化合物库中识别出糜蛋白酶样蛋白酶抑制剂(3CLPro)[23]。三种抗病毒药物(瑞德西韦、沙奎那韦和达芦那韦)和两种天然化合物(黄酮和香豆素衍生物)确定为冠状病毒3CLPro的潜在抑制剂。另一项关于SARS-CoV-2 3CLPro结构的研究使用预测的3D结构揭示了几种潜在的植物化学黄酮类化合物,包括杨梅苷和licoleafol作为该酶的抑制剂[24]。尽管这些结果令人鼓舞,但没有足够的体外数据来进一步证实这些材料的益处和潜力。此外,美国专利公开No.2011212197教导了使用至少一种洋甘菊植物和/或蓍属植物的水性和/或有机提取物来治疗受试者中病毒病症的异常增殖。
鉴于先前研究的这些可喜的发现,很有可能从天然植物或草药中发现更有效和更理想的抗SARS-CoV-2感染的治疗剂,以增加与Covid-19作斗争的可用武器库。更重要的是,基于细胞的表型方法与高内涵成像技术相结合,近年来极大地改变了药物发现过程的布局。事实证明,这种技术在在相关细胞基础环境中发现具有所需生物学功能的分子方面是有价值和强大的[25]。由于目前形势紧急,以及如一项或多项相关研究[21、26]所证明的那样,植物化学物质作为对抗新型冠状病毒的替代疗法,本公开的发明人开始了使用高内涵筛选平台发现和识别不同植物材料中用于治疗SARS-CoV-2感染的潜在治疗剂。
发明内容
本公开的目的在于提供一种药物组合物,该药物组合物包含潘多汀A和球松素,潘多汀A和球松素基本上以1:4至1:10的摩尔比进行制备。所述的具有潘多汀A和球松素的类似组成的药物组合物可以是Boesenbergia sp的植物提取物。所公开的药物组合物能够或可用于抑制感染了冠状病毒例如SARS、MERS和/或COVID-19的受试者中病毒复制的进展。具体而言,所公开的组合物或提取物特别抑制SARS-CoV-2病毒在患有冠状病毒感染的受试者中复制。
本公开的另一个目的是公开一种组合物,该组合物优选基于植物或植物来源,在向受试者施用有效量的所公开的组合物或提取物时能够有效地抑制冠状病毒在受试者中复制。
本公开的进一步目的是通过在给定时间内摄入有效量的公开的预防剂来提供防止冠状病毒感染的预防剂。特别地,所公开的预防剂是基于植物的或植物来源的,具有理想的低毒性以掺入食品或健康补充剂中,可以每日服用这些食品或健康补充剂,以增强受试者的免疫系统以抵抗,防止管状病毒与受试者接触。
本公开的进一步目的涉及植物提取物或包含对冠状病毒有效的基于植物的治疗剂的植物提取物的用途。所公开的植物提取物可用作治疗冠状病毒感染的补充剂、预防剂或药物。优选地,所述植物提取物是通过使用一种或多种极性萃取溶剂提取Boesenbergiasp.的植物部分而获得的。
本公开全部或部分地满足了前述目的中的至少一个,其中本公开的一个实施例涉及一种组合物,该组合物包含基本上以1:4至1:10的摩尔比制备的潘多汀A和球松素作为药物使用。
在几个实施例中,Boesenbergia sp.的提取物和/或潘多汀A和球松素的组合物与选自氯硝柳胺、羟氯喹、伊维菌素和法匹拉韦中的至少一种抗病毒剂一起施用于受试者或前者掺入后者中,以获得抗冠状病毒的协同治疗效果。
在一些实施例中,Boesenbergia sp.的提取物或潘多汀A和球松素的组合物用于治疗受试者的冠状病毒感染。特别地,该组合物通过使有效量的潘多汀A和球松素与受试者的受感染的细胞接触来抑制病毒在受感染的受试者中复制。
在药物的进一步实施例中,冠状病毒是SAR-CoV-1、SAR-CoV-2或MERS-CoV。
本公开的另一方面涉及一种组合物,该组合物在以有效量或治疗量向受试者施用组合物后能够抑制冠状病毒在受试者中的复制。优选地,该组合物包含化学/物理方式与物质偶联的有效量的药学上可接受的物质、潘多汀A和球松素或从Boesenbergia sp.的植物部分获得的纯化的极性提取物。进一步地,所述药学上可接受的物质选自添加剂、粘合剂、载体、稀释剂、赋形剂、填充剂、润滑剂和稳定剂中的至少一种。
更优选地,在所公开的组合物的几个实施例中,潘多汀A和球松素的摩尔比为1:4至1:10以达到所需的治疗、预防或免疫增强效果。
优选地,在所公开的组合物的一些实施例中,Boesenbergia sp.选自Boesenbergia rotunda、Boesenbergia longiflora和Boesenbergia kingie。
在所公开的组合物的许多实施例中,所述植物部分是根茎。
在所公开的组合物的进一步实施例中,冠状病毒是SAR-CoV-1、SAR-CoV-2和/或MERS-CoV。
对于更多实施例,所述组合物是药物、补充剂或预防剂。
附图说明
图1包括B.rotunda提取物的高内涵成像分析,以及相应的图表显示右侧面板(n=3个生物学复制)上的抑制百分比(红色)和细胞毒性百分比(蓝色),其中绿色荧光信号是抗SARS-CoV-2NP mAb,蓝色荧光是Hoechst染色。
图2包括用羟氯喹处理的受感染细胞的高内涵图像和相应的图表,红色表示抑制百分比,蓝色表示细胞毒性百分比(n=3个生物学复制)。
图3包括用潘多汀A处理的受感染细胞的高内涵图像和相应的图表,红色表示抑制百分比,蓝色表示细胞毒性百分比(n=3个生物学复制)。
图4包括用球松素处理的受感染细胞的高内涵图像和相应的图表,红色表示抑制百分比,蓝色表示细胞毒性百分比(n=3个生物学复制)。
图5包括用潘多汀A和球松素的组合物处理的受感染细胞的高内涵图像和相应的图表,红色表示抑制百分比,蓝色表示细胞毒性百分比(n=5个生物学复制)。
图6是显示三种候选物的空斑测定结果的图表:(a)羟氯喹,(b)B.rotunda提取物,(c)潘多汀A(n=2个生物学复制)
图7包括B.rotunda提取物在进入前阶段表现出抗SARS-CoV-2活性的高内涵图像,以及相应的图表,红色表示抑制百分比,蓝色表示细胞毒性百分比(n=3个生物学复制)
图8包括潘多汀A在进入前阶段表现出抗SARS-CoV-2活性的高内涵图像,以及相应的图表,红色表示抑制百分比,蓝色表示细胞毒性百分比(n=3个生物学复制)
图9是显示进入前阶段的空斑测定结果的图表:B.rotunda提取物和潘多汀A(n=2个生物学复制)
图10是显示潘多汀A和球松素的空斑减数能力结果的图表
图11包括用潘多汀A和球松素处理的受感染人肺泡细胞的高内涵图像,以及相应的图表,红色表示抑制百分比,蓝色表示细胞毒性百分比(n=3个生物学复制)
具体实施方式
本公开可以以其他特定形式体现而不背离本文广泛描述和下文所要求保护的结构、方法或其它基本特征。所述实施例在所有方面都应被认为仅是说明性的,而不是限制性的。因此,本公开的范围由所附权利要求指示,而不是由前述描述指示。在权利要求等效的含义和范围内的所有变化都应包含在其范围内。
如本文所用,术语“提取物”是指通过使用一种或多种极性溶剂从Boesenbergiasp.和/或凹唇姜的基质中取出所需基于植物的化合物的来自Boesenbergia sp.和/或凹唇姜的提取物。
如本文所用,术语“潘多汀A”是指化学试剂、化合物和/或其衍生物,包括纯化的和/或未纯化的形式,其可以通过化学合成获得和/或为来自Boesenbergia sp.或凹唇姜植物的提取物。
如本文所用,术语“球松素”是指化学试剂、化合物和/或其衍生物,包括纯化的和/或未纯化的形式,其可以通过化学合成获得和/或为来自Boesenbergiasp.或凹唇姜植物的提取物。
如本文所用,术语“有效量”是指在体外或体内显示抗病毒活性,特别抗冠状病毒的效果的量或浓度。
除非另有说明,否则本文使用的术语“包括”和“包含”及其语法变体旨在表示“开放”或“包容性”语言,从而它们包括列举的元素但也允许包含额外的、未列举的元素。
如本文所用,在组分浓度、条件、其他测量值等的上下文中,术语“大约”或“约”是指所述值的+/-5%,或所述值的+/-4%,或所述值的+/-3%或所述值的+/-2%或所述值的+/-1%或所述值的+/-0.5%或+/-所述值的0%。
如本文所用,“在实施例中”的短语是指在一些实施例中但不一定在所有实施例中。
根据本公开的一个方面,一种包含潘多汀A和球松素的组合物,用于抑制受试者中冠状病毒的复制。更具体地说,本公开组合物中的潘多汀A和球松素的摩尔比为1:4至1:10,用作治疗受试者冠状病毒的药物。本公开中描述的受试者是指任何哺乳动物,特别是易感染冠状病毒的人类受试者。本公开的发明人发现,一旦药物与感染冠状病毒的细胞接触,潘多汀A和/或球松素就具有有效对抗冠状病毒的抗病毒特性。潘多汀A和/或球松素通过抑制病毒在受试者的受感染细胞内复制而表现出抗冠状病毒的抗病毒特性。尽管促进抗病毒疗效的机制尚未确定,但本公开的发明人提供了几种可能由感染冠状病毒的受试者中存在潘多拉汀A和/或球松素引发的作用。具体来说,潘多汀A和/或球松素可能与冠状病毒的病毒蛋白酶相互作用,因为之前在一些关于潘多汀A和/或球松素对HIV和登革热病毒(DENV)的影响的早期研究中已经报道了这种相互作用。因此,潘多汀A和/或球松素可通过竞争性结合冠状病毒的蛋白酶而发挥抑制剂的作用,从而中断受试者体内病毒复制的进程,并使受试者从冠状病毒感染中恢复。本公开进一步规定,在抗击冠状病毒中可能由潘多汀A和/或球松素触发的另一种机制是通过在能够减弱SARS-CoV-2感染的受感染对象中进行的抗氧化活性。抗氧化活性可以进一步证实受试者的抗炎反应,以避免受试者的健康状况因SARS-CoV-2感染引起的不受控制的炎症反应而恶化。此外,发现潘多汀A可诱导自噬,这在限制病毒复制方面起着重要作用。尽管如此,进一步的研究将确定潘多汀A通过诱导自噬抑制SARS-CoV-2感染的可能途径。
对于许多实施例,可通过所公开的组合物治疗的冠状病毒感染包括SAR-CoV-1、SAR-CoV-2或MERS-CoV。
在多个实施例中,本公开的潘多汀A和/或球松素可以来源于植物来源或通过化学合成。例如,潘多汀A和/或球松素可以是从Boesenbergia sp.例如Boesenbergia rotundaBoesenbergia logiflora和/或Boesenbergia kingii的一个或多个植物部分中提取出来。更优选地,可以使用一种或多种已知溶剂,如水、酒精、乙酸乙酯、丙酮等以渗透精制或粉碎的植物部分的基质以提取潘多汀A和/或其化合物来获得潘多汀A和/或球松素。提取的潘多汀A和/或球松素的产量和纯度可以根据Boesenbergia的种类和提取过程中使用的各个植物部分而变化。可以实施本领域已知的进一步纯化步骤以在将产生的潘多汀A和/或球松素用作药物或制造用于治疗冠状病毒感染的药物之前对其进行量化。例如,在一些实施例中,优化的高效液相色谱法(HPLC)用于潘多汀A和/或球松素的纯化。此外,本公开中的植物部分可以包括根茎。或者,也可以通过本领域已知的方法化学合成潘多汀A和/或球松素。
根据本公开的另一方面,一种组合物能够在以有效量向受试者施用组合物后抑制冠状病毒在受试者中的复制。优选地,所述组合物还包含一种或多种药学上可接受的物质;潘多汀A和球松素的混合物或从Boesenbergia sp.的植物部分获得的提取物。此外,一种或多种药学上可接受的物质是添加剂、粘合剂、载体、稀释剂、赋形剂、填充剂、润滑剂和稳定剂中的任何一种或组合。
重要的是要注意,所公开的组合物可以是用于治疗冠状病毒感染的药物、当受试者与病毒接触时被受试者摄入以预防冠状病毒感染的预防剂、或当受试者与病毒接触时每日可服用的补充剂以增强受试者的主动免疫系统以对抗冠状病毒。
取决于实施例,所公开的组合物可包含附加成分或活性剂以递送如本公开中所述的治疗或免疫增强效果。例如,在所公开的组合物采用药物形式的那些实施例中,它可以进一步掺入一种或多种除潘多汀A和/或球松素之外的活性成分以获得最佳治疗效果。其他活性成分可以是抗病毒剂,例如氯硝柳胺、羟氯喹、伊维菌素和法匹拉韦等,其可以优选但不一定与所公开的组合物采取的抗病毒机制互补,从而能够在受试者中触发各种途径以对抗冠状病毒感染。在将所公开的组合物用作补充剂的实施例中,其他附加成分可以包括维生素C、锌等,以加强潘多汀A和/或球松素或Boesenbergia sp.的提取物的抗病毒作用。为了用作针对冠状病毒感染的预防剂,所公开的组合物可包含补充剂的类似成分但具有不同剂量以达到所需疗效。
如前所述,潘多汀A和/或球松素或提取物可以通过以下方式获得,即,使Boesenbergia sp.的粉碎或精制植物部分与溶剂或极性溶剂反应,以将所需化合物溶解到极性溶剂中,然后除去极性萃取溶剂,得到含有潘多汀A和/或球松素的极性提取物。可能需要一个或多个纯化步骤来定量和/或纯化来自极性提取物中的潘多汀A和/或球松素。或者,极性提取物也可以基于提取物中潘多汀A和/或球松素的浓度或比率进行量化,使得所公开的组合物获得的治疗或预防效果以更可控和可预测的方式进行。可用于提取的植物部分是根茎。
尽管本公开内容的发明人观察到单独使用潘多汀A或球松素也显示出对冠状病毒复制抑制的巨大影响,但在许多实施例中联合使用潘多汀A和球松素作为活性成分以抑制冠状病毒感染的进展表现出协同作用效果,使得所公开的组合物在阻止病毒在受感染受试者体内复制方面比其他目前市售的药物如伊维菌素或羟氯喹更有效。因此,通过将所公开的组合物作为药物施用于受感染的受试者以中断病毒复制周期,所公开的组合物允许受试者的免疫系统有足够的时间来发展抵抗冠状病毒的主动免疫,而不会使受试者受大量的病毒载量诱导的严重症状的影响。
更优选地,在几个实施例中,所公开的组合物的潘多汀A和球松素以1:4至1:10的摩尔比制备以达到所需的治疗、预防或免疫增强效果。
所公开的组合物很可能竞争性地抑制冠状病毒的病毒蛋白酶,从而使所公开的组合物可用于对抗相对更广谱的冠状病毒。特别地,所公开的组合物对包含SAR-CoV-1、SAR-CoV-2或MERS-CoV的冠状病毒有效。如前所述,可以将其他活性成分掺入所公开的组合物中,以更好地对抗本领域已知的广泛的冠状病毒,从而用作药物、预防剂或补充剂。
以下实施例旨在进一步说明本发明,并不意味着将本发明限定于其中所描述的具体实施例。
根据本公开,Vero E6细胞、非洲绿猴(Cercopithecus aethiops)肾上皮细胞(ATCC#C1008)用于抗病毒筛选。细胞在含有10%胎牛血清(FBS)(Gibco,USA)的Dulbecco改良Eagle培养基(DMEM)(Gibco,USA)中生长。对于Vero细胞(非洲绿猴上皮细胞),这些细胞在补充有10%FBS和L-谷氨酰胺(Gibco,USA)的最低必需培养基(MEM(Gibco,USA)中培养。所有培养物均在37℃和5%CO2气氛中生长,并用于以下实施例中描述的实验。
实施例1
用于筛选的植物材料是泰国常见的草药,其中大部分被列入2018年泰国草药药典(https://bdn.go.th/th/sDetail/10/34/)。Boesenbergia rotunda根茎购自泰国巴吞他尼的供应商。在提取工艺开始之前,对植物进行鉴定并与ECDD的保藏植物材料进行比较
具体而言,在室温下用95%EtOH(6L,4次x 7天)将风干和细粉状B.rotunda根茎(2.5kg)过滤,除去溶剂后得到粗EtOH提取物(190.5g)。将得到的EtOH提取物分成两部分。每部分通过硅凝胶上的VLC(每个250g,Merck Art.No.7731)分离,填充在烧结玻璃漏斗(内径12.5cm×填充高度4.5cm)上,分别使用EtOAc-己烷和MeOH-EtOAc梯度作为洗脱液。收集馏分(每个500mL)并根据其TLC行为组合,得到馏分:A1-A5。馏分A4(60.1g,用25–100%EtOAc己烷洗脱),在三次连续的Si-gel CC(Si-gel:Merck,Art.No7734,第1次CC:20%EtOAc-己烷;第2次CC:60%CH2Cl2-己烷;第3次CC:10%CH3COCH3-己烷)提供了三个分离的馏分B1-B3。馏分B3(5.37g)通过Sephadex LH-20CC(Sephadex LH-20:GE Healthcare Bio-Sciences AB,10%MeOH-CH2Cl2)进一步纯化,然后从EtOH-CH2Cl2中重结晶以提供纯潘多汀A(3.18g)。
实施例2
针对冠状病毒的抗病毒活性测试,采用基于免疫荧光细胞的技术对冠状病毒的生物活性物质进行测试,该技术以Vero E6细胞为模型细胞,在96孔板中感染SARS-CoV-2并在37℃下孵育2小时。然后在37℃下用不同浓度的B.rotunda、潘多汀A和球松素处理Vero E6细胞48小时。此后,收集培养上清液,将细胞固定并用抗SARS-CoV NP mAb和Alexa Fluor488标记的二抗体染色。使用高内涵成像系统、Operetta、PerkinElmer对细胞表型进行了分析,并保留羟氯喹治疗作为对照组。
如图1所示,实验结果表明,B.rotunda的提取物(10ug/mL)在所有病毒感染细胞的50%的3.62ug/mL的活性化合物浓度(50%抑制浓度,IC50)下对冠状病毒具有抑制作用。同样,羟氯喹对照组的50%抑制浓度(IC50)为5.08uM(1.71ug/mL),如图2所示。有趣的是,来自提取物的两种纯化的化合物;潘多汀A(10uM)和球松素(10uM)的测试显示出比羟氯喹对照组更好的冠状病毒抑制结果,分别在0.81uM和0.44uM时显示出50%的抑制浓度(IC50),如图3和图4所示。因此,进行了进一步的实验,将提取物中的两种活性化合物以不同浓度的潘多汀A和球松素按如下摩尔比混合:0.2:0.2、0.2:0.4、0.2:0.8、0.2:1.0、0.2:1.2、0.2:1.4、0.2:1.6、0.2:1.8和0.2:2.0。包含潘多汀A和球松素的B.rotunda提取物随后表现出非常有效的抗SARS-CoV-2活性,IC50为0.97ug/mL,高于羟氯喹对照,如图5所示。
实施例3
对于使用MTT比色法的细胞毒性测试,将Vero E6细胞在96孔板中进行培养,每孔10,000个细胞,并在培养箱中保持24小时。然后,将细胞与来自B.rotunda提取物的两种活性化合物:潘多汀A和球松素,在培养箱中培养48小时。当给定时间结束时,加入100uL0.5g/mL MTT溶剂,细胞在培养箱中再培养3小时。除去MTT溶剂并加入100uL DMSO。通过酶标仪在570nm处测量吸光度,并计算每个复制品的50%细胞毒性浓度(CC50)。
B.rotunda提取物对Vero E6细胞的细胞毒性试验结果显示,羟氯喹对照组的50%细胞毒性浓度(CC50)为28.06ug/mL,高于如图1和图2所示的100uM。
潘多汀A和球松素的50%细胞毒性浓度(CC50)分别为14.71uM和高于100uM,如图3和图4所示。此外,潘多汀A和球松素的组合物的50%细胞毒性浓度(CC50)高于如图三所示的100uM,这意味着B.rotunda提取物或凹唇姜提取物这两种活性化合物的新组合比羟氯喹对照组具有更好的抑制作用,并且对细胞没有细胞毒性作用(图5)。
实施例4
对于空斑测定的测试,将96孔板中的Vero E6细胞固定并用50%(v/v)丙酮的甲醇溶液在冰上渗透20分钟。将细胞用含有0.5%洗涤剂(PBST)的磷酸盐缓冲盐水洗涤一次,并在室温下在含有2%(w/v)BSA的PBST中封闭1小时。封闭后,将细胞与1:500稀释比的SARS-CoV核蛋白特异性一抗(RabbitmAb)(中国Sino Biological Inc)在37℃下孵育1小时。虽然它最初是针对SARS-CoV核蛋白(NP),但该抗体也能够与SARS-CoV-2的NP蛋白发生交叉反应。通过用PBST洗涤3次去除未结合的抗体。然后,以1:500的稀释比使用山羊抗兔IgG(H+L)高度交叉吸附的二抗Alexa Fluor 488(Thermo FisherScientific,USA)。用Hoechst染料(Thermo Fisher Scientific,USA)对细胞核进行染色。通过高内涵成像系统(Operetta,PerkinElmer)在40x下检测和分析荧光信号。使用Harmony软件(PerkinElmer)从每孔13张图像中自动获得每孔中受感染细胞的百分比。
此外,本公开中的SARS-CoV-2的病毒输出被报告为通过空斑测定确定的感染滴度。简而言之,在感染前24小时将Vero细胞单层接种到6孔板中。用连续稀释的病毒接种细胞,并在37℃下孵育1小时以进行病毒吸附。然后,用3mL/孔的覆盖培养基覆盖细胞,该培养基含有补充有5%FBS和1%琼脂糖的MEM。为了让空斑形成,将培养物在37℃和5%CO2下培养3天。之后,通过用0.33%中性红溶液(Sigma,USA)染色5小时来观察空斑表型。对空斑数进行计数并计算为每毫升(mL)的空斑形成单位(PFU)。
试验结果证实,B.rotunda提取物或凹唇姜提取物在潘多汀A浓度较高时对冠状病毒的复制具有抑制作用。此外,治疗病毒感染细胞的潘多汀A的有效量或浓度显著低于羟氯喹(图6)。
实施例5
B.rotunda提取物和潘多汀A在进入前阶段的抗SARS-CoV-2作用。B.rotunda提取物和潘多汀A在感染后阶段具有非常有效的抗SARS-CoV-2活性。为了扩大这种影响,有趣的是了解B.rotunda提取物和潘多汀A是否也会干扰病毒进入。在此过程中,将B.rotunda提取物和潘多汀A与SARS-CoV-2在37℃下预孵育1小时,然后接种到Vero E6细胞中。在提取物/化合物存在下允许病毒吸附2小时。然后,用新鲜培养基洗涤细胞以去除未结合的病毒颗粒和提取物/化合物。补充新鲜培养基并在收获前将细胞进一步培养48小时。有趣的是,B.rotunda提取物和潘多汀A在进入前阶段也表现出抗SARS-CoV-2活性。B.rotunda提取物和潘多汀A的IC50分别为20.42μg/mL(CC50>100μg/mL)和5.30μM(CC50=43.47μM)(图7和图8)。尽管它不如感染后条件有效,但病毒输出分析表明,在用B.rotunda提取物处理后,感染性病毒粒子的产生减少了大约五倍(图9)。同样,潘多汀A在50μM的高剂量下绝对抑制了感染性病毒粒子的产生(图9)。
实施例6
为了证明B.rotunda提取物、潘多汀A和球松素在人类主要靶细胞中的功效,将原代人肺泡细胞模型用于空斑测定。人肺泡细胞模型是由从肺组织中分离出来的原代人肺泡上皮细胞和原代肺泡巨噬细胞形成,如Ruenraroengsak等人先前所述(2005年)。将原代人肺泡细胞接种并培养到12孔TranswellTM板的每个孔中,该板具有1%I型胶原蛋白包被板、DCCM1(Cadama,UK)、10%新生小牛血清(Invitrogen,UK)和1%PSG。原代肺泡巨噬细胞在补充有1%青霉素/链霉素/l-谷氨酰胺(PSG)的无血清RPMI培养基中培养并铺板到TranswellTM板上。细胞培养物在37℃5%CO2下孵育,以使细胞在接种后48小时内沉淀并粘附在板上。除去培养基,用无血清DCCM1和无血清RPMI培养基仔细冲洗细胞。24小时后,用SARS-CoV-2以0.1感染复数(MOI)将细胞接种到顶部表面2小时。然后,将培养物洗涤3-4次以去除未结合的病毒。收集顶部洗涤的用于分析并通过空斑测定进行滴定。
结果表明,潘多汀A和球松素以剂量依赖性方式降低病毒滴度(图10)。在72小时时,病毒滴度为4.5log PFU/mL用于载体处理,2.0log PFU/mL与50μM球松素。因此,5μM潘多汀A和25μM球松素在3log PFU/mL中降低了病毒滴度。此外,通过免疫荧光染色对传染性病毒的分析表明,在用25-50μM球松素和/或5μM潘多汀A处理后,感染细胞减少了60–70%(图11)。
参考上述描述和实施例,本公开提供了一种新的潘多汀A和球松素的组合物或从Boesenbergia sp.的植物部分获得的提取物,用于抑制受试者体内冠状病毒,特别是SAR-CoV-2的复制。在某些情况下,所公开的组合物可能无法完全治愈受试者的冠状病毒感染,但以预定剂量将组合物施用于受试者应显著降低病毒载量,从而使受试者有更多时间对病毒产生主动免疫力,不会出现由受试者体内大量病毒载量引发的症状。
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Claims (10)
1.一种组合物,当向受试者施用有效量的组合物时,能够抑制冠状病毒在受试者中的复制,所述组合物包含摩尔比为1:4至1:10的潘多汀A和球松素。
2.根据权利要求1所述的组合物,其特征在于,还包含一种药学上可接受的物质,该药学上可接受的物质选自添加剂、粘合剂、载体、稀释剂、赋形剂、填充剂、润滑剂和稳定剂中的至少一种,其中所述提取物与所述载体化学和/或物理偶联。
3.根据权利要求1或2所述的组合物,其特征在于,还包含抗病毒剂,该抗病毒剂选自氯硝柳胺、羟氯喹、伊维菌素和法匹拉韦中的至少一种。
4.根据权利要求1或2的组合物,其特征在于,冠状病毒选自SAR-CoV-1、SAR-CoV-2和MERS-CoV。
5.如权利要求1所述的组合物为从Boesenbergia sp.的植物部分获得的提取物。
6.根据权利要求5所述的组合物,其特征在于,所述植物部分是根茎。
7.根据权利要求5所述的组合物,其特征在于,Boesenbergia sp.选自Boesenbergiarotunda、Boesenbergia longiflora和Boesenbergia kingii。
8.如权利要求1所述的组合物是药物、补充剂或预防剂。
9.一种Boesenbergia sp.的植物部分获得的提取物,包含摩尔比为1:4至1:10的潘多汀A和球松素,用于通过抑制冠状病毒复制来治疗受试者的冠状病毒感染。
10.根据权利要求9所述的提取物,其特征在于,还包含抗病毒剂,该抗病毒剂选自氯硝柳胺、羟氯喹、伊维菌素和法匹拉韦中的至少一种。
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