CN117942341A - 异喹啉类生物碱在预防和治疗冠状病毒中的应用 - Google Patents
异喹啉类生物碱在预防和治疗冠状病毒中的应用 Download PDFInfo
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- CN117942341A CN117942341A CN202211328628.5A CN202211328628A CN117942341A CN 117942341 A CN117942341 A CN 117942341A CN 202211328628 A CN202211328628 A CN 202211328628A CN 117942341 A CN117942341 A CN 117942341A
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- acid
- isoquinoline
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- 241000711573 Coronaviridae Species 0.000 title claims abstract description 30
- 230000002265 prevention Effects 0.000 title description 3
- 241001678559 COVID-19 virus Species 0.000 claims abstract description 50
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 208000001528 Coronaviridae Infections Diseases 0.000 claims abstract description 9
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 claims abstract description 5
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Abstract
本发明涉及异喹啉生物碱及其药学上可接受的盐在医药方面的新用途,具体为异喹啉生物碱类化合物及其药学上可接受的盐在预防,缓解和/或治疗SARS‑CoV‑2病毒感染性疾病中的应用。实验结果表明异喹啉类生物碱在抗SARS‑CoV‑2病毒药物筛选模型穿山甲冠状病毒毒株xCoV、SARS‑CoV‑2病毒样颗粒(trVLP)系统和VSV假病毒系统上,都明显抑制了病毒的感染和复制。异喹啉类生物碱通过抑制病毒的整个生命周期来抑制病毒复制,这些结果强烈提示异喹啉类生物碱对于目前流行的新冠病毒以及其他冠状病毒感染引起的病症的潜在临床应用价值。
Description
技术领域
本发明属于医药技术领域,涉及异喹啉类生物碱在医药方面的新用途,具体为异喹啉类生物碱在预防或治疗SARS-CoV-2病毒感染性疾病中的应用。
背景技术
随着各种突变株的出现,尤其是omicron各亚型突变株(包括BA.4、BA.5、BF.7、XBB等)具有更快的传播速度以及更强的免疫逃逸能力,疫苗接种所诱导的中和抗体的保护活性似乎也在随着时间降低,新的有效药物仍然是治疗COVID-19的重点。
COVID-19包括病毒S蛋白中和抗体、瑞德西韦、洛匹那韦/利托那韦(克力芝)、I型干扰素等多种药物在体外或体内实验中表现出了抗病毒活性,但是药物的临床疗效和安全性仍存在争议。目前美国FDA还批准了瑞德西韦和几款中和抗体如Bamlanivimab、Etesevimab、Casirivimab、Imdevimab用于COVID-19住院患者的治疗,但是这些药物需要静脉滴注且价格昂贵,有效性和安全性也尚需进一步临床验证,限制了其进一步应用。2021年底,Merck和Ridgeback Biotherapeutics联合开发的口服抗新冠药物莫努匹韦(Molnupiravir)以及辉瑞公司研发的奈玛特韦片/利托那韦片(Paxlovid)有条件获批上市,这两种药物分别针对病毒的RdRp(RNA依赖RNA聚合酶)和3CLpro,但存在耐药性的威胁,且莫努匹韦可能引起DNA突变,安全性尚待进一步研究。奈玛特韦片/利托那韦片的联合用药和药物相互作用尚需进一步研究,而且这两种药物在疫苗接种人群中的临床效果还未可知。近期,阿兹夫定作为我国首款自主研发、具有完全自主知识产权的口服小分子新冠治疗药物附条件获批,其作用靶点与莫努匹韦相似,针对病毒的RdRp,同样的,其作为核苷类似物的安全性仍然需要进一步研究。
疫苗接种是预防和控制COVID-19的长期策略中最有效的方法。不同的SARS-CoV-2疫苗已被开发,截至2022年3月28日,已有153种疫苗获批进行临床试验,196种疫苗处于临床前试验阶段,10种疫苗(含3种印度疫苗)获世卫组织批准紧急使用,目前国内已有4款自主研发的新冠疫苗获批上市(https://vac-lshtm.shinyapps.io/ncov_vaccine_landscape/)。这些疫苗主要包括灭活疫苗(占总数的14%)、减毒活疫苗(1%)、病毒载体疫苗(复制和非复制;占总数的17%)、RNA疫苗(18%)、DNA疫苗(11%)、蛋白质亚单位疫苗(34%)和VLP疫苗(4%)。然而随着世界多地报道SARS-CoV-2的突变体,目前研究显示疫苗所产生的抗体对SARS-CoV-2突变株的中和能力表现出不同程度的下降甚至完全丧失。由于新冠病毒不断升级,新冠疫苗和“特效药”不断“失效”,因此迫切需要开发针对不同靶点的抗病毒新药物,或者使用联合疗法从多方面抑制病毒感染,一方面针对新冠病毒本身开发阻断病毒感染或抑制病毒复制的药物,同时考虑联合用药;另一方面针对新冠病毒与宿主的相互作用,阻断新冠引起的一系列临床症状和并发症,降低病死率。因此,研发安全有效且具有广谱性的抗病毒药物意义重大。
生物碱是存在于自然界的一类含氮的碱性有机化合物,大多有较复杂的环状结构,氮原子结合在环内。其中异喹啉生物碱的种类最多,异喹啉生物碱来源于苯丙氨酸和酪氨酸系,在植物中分布广泛,数目较多,具有多方面的生物活性。异喹啉生物碱根据连接基团的不同可分为:简单异喹啉类、苄基异喹啉类、阿朴菲类、双苄基异喹啉类、小檗碱类、普罗托品类、吗啡类和苯菲啶类。当苯基连接在异喹啉的骨架上时该衍生物便称为苄基异喹啉生物碱,单苄基异喹啉类为异喹啉母核1位连有苄基,罂粟属中具解痉作用的罂粟碱即属此类。双苄基异喹啉则为两个苄基异喹啉通过1~3个醚键相连接的一类生物碱,如存在于防己科北豆根中的主要酚性生物碱蝙蝠葛碱,汉防己中的汉防己甲素和汉防己乙素。
异喹啉生物碱广泛分布于罂粟科、巴比特科、毛茛科和防己科中。异喹啉及异喹啉衍生物是一类重要的医药化工中间体,广泛应用于一系列重要药物的合成过程,异喹啉骨架常用于设计药物分子中的活性结构基团,如阿曲库铵、诺米芬辛、莫沙维林、地莫昔林(甲基罂粟碱)、异喹卡因等。同时,异喹啉生物碱类药物具有多方面的生物活性,包括抗肿瘤、抗菌、镇痛、调节免疫功能、抗血小板凝聚、抗心律失常、降压等。大部分的异喹啉类生物碱药物都存在着异喹啉或异喹啉衍生物等基本结构,此类药物基本可以从简单的异喹啉衍生物进一步合成而衍生出来。
但异喹啉类生物碱是否可用于治疗新型冠状病毒感染,还有待进一步研究。
发明内容
本发明的目的在于提供SARS-CoV-2的有效抑制剂,其可以预防,缓解和/或治疗新型冠状病毒所致感染。
本发明首先提供了异喹啉类生物碱及其药学上可接受的盐作为新型冠状病毒抑制剂,在制备预防、缓解和/或治疗冠状病毒所致感染的产品中的应用;
所述异喹啉类生物碱选自轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱(22864-92-2)中的至少一种。
根据本发明的实施方案,所述药学上可接受的盐选自异喹啉类生物碱结构中具有足够碱性的氮原子的酸加成盐,所述酸加成盐包括异喹啉类生物碱与无机酸如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸;有机酸如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸所形成的盐。
根据本发明的实施方案,所述产品为药品、食品、护肤品、化妆品、日用品和保健品,优选为药品。
根据本发明的实施方案,其中冠状病毒为2019新型冠状病毒(SARS-CoV-2)。
根据本发明的实施方案,冠状病毒感染为新型冠状病毒感染。
根据本发明的实施方案,如上所述异喹啉类生物碱及其药学上可接受的盐可以配置成各种适合的药物制剂形式。可以单独使用,或者将其与药物辅料(例如赋形剂、稀释剂等)混合,配置成口服给药的片剂、胶囊剂、颗粒剂、糖浆剂等或注射给药的粉针剂、溶液剂,以及研制为功能食品,功能饮品、药酒,滴鼻液及漱口水等。
本发明还提供一种可预防,缓解和/或治疗冠状病毒所致感染的药物组合物,其包括轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱(22864-92-2)中的至少一种。
本发明还提供一种预防,缓解和/或治疗冠状病毒所致感染的方法,包括将异喹啉类生物碱及其药学上可接受的盐中的至少一种施用于有此需要的个体。
所述异喹啉类生物碱选自轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱或6-丙酮基二氢白屈菜红碱(22864-92-2)中的至少一种。
本发明人经过大量研究发现异喹啉类生物碱的新用途,通过利用新冠病毒药物筛选替代模型GX_P2V、SARS-CoV-2病毒样颗粒(trVLP)模型及VSV假病毒模型对异喹啉类生物碱进行抗SARS-CoV-2病毒活性评价。结果表明本发明的异喹啉类生物碱能有效抑制穿山甲冠状病毒毒株GX_P2V、SARS-CoV-2病毒样颗粒(trVLP)及VSV假病毒的感染和复制,并且在GX_P2V、SARS-CoV-2病毒样颗粒(trVLP)入胞前和入胞后、全时段均能发挥抑制作用。
其中,在新冠病毒药物筛选替代模型GX_P2V上,轮环藤宁在细胞水平的EC50=1.37μM,CC50>50μM,SI>36.50;蝙蝠葛碱在细胞水平的EC50=17.04μM,CC50>50μM,SI>2.93;蝙蝠葛苏林碱在细胞水平的EC50=14.08μM,CC50>50μM,SI>3.55;峨眉唐松草碱在细胞水平的EC50=3.31μM,CC50=49.85μM,SI=15.06;唐松明灵碱在细胞水平的EC50=1.29μM,CC50>50μM,SI>38.76;6-丙酮基二氢白屈菜红碱在细胞水平的EC50=2.47μM,CC50>50μM,SI>24.24。在SARS-CoV-2病毒样颗粒(trVLP)模型上,轮环藤宁在细胞水平的EC50=1.64μM,CC50>50μM,SI>30.49;蝙蝠葛碱在细胞水平的EC50=2.84μM,CC50>50μM,SI>17.61;蝙蝠葛苏林碱在细胞水平的EC50=~1.52μM,CC50>50μM,SI>~32.89;峨眉唐松草碱在细胞水平的EC50=~25.29μM,CC50>50μM,SI>~1.98;唐松明灵碱在细胞水平的EC50=6.20μM,CC50>50μM,SI>8.06;6-丙酮基二氢白屈菜红碱在细胞水平的EC50=2.25μM,CC50>50μM,SI>22.22。在VSV假病毒模型上,轮环藤宁在细胞水平的EC50=6.54μM;蝙蝠葛碱在细胞水平的EC50=5.91μM;蝙蝠葛苏林碱在细胞水平的EC50=8.48μM;峨眉唐松草碱在细胞水平的EC50=2.83μM;唐松明灵碱在细胞水平的EC50=2.73μM;6-丙酮基二氢白屈菜红碱在细胞水平的EC50=11.76μM。因此,发明人认为轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱可应用于针对COVID-19感染的预防,缓解和/或治疗。
与现有技术相比,本发明的技术效果如下:
本申请发明人发现异喹啉类生物碱轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱在细胞水平能够阻断冠状病毒进入细胞,也具有有效抑制冠状病毒的复制从而达到预防,缓解和/或治疗COVID-19的效果。
附图说明
图1为异喹啉类生物碱轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱抑制GX_P2V病毒感染Vero E6细胞的测试结果;
图2为异喹啉类生物碱轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱抑制GX_P2V病毒感染Vero E6细胞的不同作用阶段测试结果;
A.异喹啉类生物碱显著降低了Vero E6细胞中病毒RNA水平;
B.异喹啉类生物碱显著抑制了Vero E6细胞中病毒蛋白的表达。
图3为异喹啉类生物碱轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱抑制SARS-CoV-2病毒样颗粒(trVLP)感染Caco-2-N细胞的测试结果;
图4为异喹啉类生物碱轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱抑制SARS-CoV-2病毒样颗粒(trVLP)感染Caco-2-N细胞的不同作用阶段(细胞中病毒RNA水平)测试结果;
图5为异喹啉类生物碱轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱抑制SARS-CoV-2野生型假病毒的感染BHK21-ACE2细胞的测试结果。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
一、实验方法
1.异喹啉类生物碱抑制穿山甲冠状病毒xCoV(GX_P2V)
1)细胞病毒培养
非洲绿猴肾细胞系Vero E6是从美国模式培养物集存库(ATCC,1586号)中获得的,用含有10%胎牛血清(FBS;Gibco Invitrogen)的DMEM培养基(Gibco),在37℃、5% CO2的培养箱中培养。
穿山甲冠状病毒xCoV(GX_P2V)(GISAID:EPI_ISL_410539)为本发明人从海关查获的死亡的穿山甲中分离并培养的一株新型冠状病毒xCoV。将GX_P2V在Vero E6细胞中繁殖,用Vero E6细胞(ATCC,1586号)做噬斑实验测定病毒滴度。所有感染实验均在生物安全2级(BLS-2)实验室进行。
2)异喹啉类生物碱抑制穿山甲冠状病毒xCoV(GX_P2V)的EC50和CC50测定
EC50检测:将2.5×104个Vero E6细胞接种到96孔板中,在37℃、5% CO2的培养箱中培养24h后,在细胞培养孔中分别加入终浓度为50μM、25μM、12.5μM、6.25μM、3.125μM、1.56μM、0.78μM、0.39μM、0μM的异喹啉类生物碱轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱,37℃预孵育1h,同时将病毒(MOI=0.01)与终浓度为50μM、25μM、12.5μM、6.25μM、3.125μM、1.56μM、0.78μM、0.39μM、0μM的异喹啉类生物碱4℃预孵育1h,孵育结束后将上述病毒-药物混合物加入含对应浓度药物的细胞中,感染2h后PBS清洗3遍换液,加入含相同浓度药物的培养基,37℃、5% CO2的培养箱中进行培养。病毒感染后的48h,通过qRT-PCR的方法对细胞内病毒RNA以及细胞内参基因GAPDH的表达情况进行定量检测。用GraphPad-Prism 8软件进行数据分析计算EC50。
CC50检测:使用CellTiter-Blue法进行CC50的检测。Vero E6细胞接种至96孔细胞培养板,细胞密度达到60%-80%时进行试验。Vero E6细胞换液后加入稀释后的药物,终浓度分别为50μM、25μM、12.5μM、6.25μM、3.125μM、1.56μM、0.78μM、0.39μM、0μM。37℃5% CO2培养48h,利用CellTiter-Blue试剂检测荧光强度,激发波长554nm,发射波长593nm,GraphPad-Prism 8软件进行数据分析计算CC50。
3)加药时间实验
将1×105个Vero E6细胞接种到24孔板中,在37℃、5% CO2的培养箱中培养24h后,在全时段给药组和入胞前给药组细胞培养孔中分别加入根据药物EC50确定的终浓度的异喹啉类生物碱,37℃预孵育1h,同时将病毒(MOI=0.01)与相同浓度的异喹啉类生物碱4℃预孵育1h,孵育结束后用上述病毒-药物混合物病毒感染细胞,感染2h后PBS清洗3遍换液,在全时段给药组和入胞后给药组细胞培养孔中加入含相同浓度药物的培养基,入胞前给药组和对照组细胞培养孔加入不含药物培养基,37℃、5% CO2的培养箱中进行培养。病毒感染后的12h,通过qRT-PCR的方法对细胞内病毒RNA以及细胞内参基因GAPDH的表达情况进行定量检测。同时收集细胞内蛋白,利用Western Blot对新冠病毒N蛋白和GAPDH蛋白进行定量分析。
4)病毒样本处理和检测
按照制造商的说明,使用细胞/组织RNA提取试剂盒(北京诺贝莱生物科技有限公司,R11202109JN)提取总RNA。反转录使用可消化gDNA的Hifair II 1st strand cDNA合成试剂盒(上海翊圣生物科技,货号:11121ES60),qRT-PCR使用Quantstudio实时PCR检测试剂(Applied biosystems,Foster City,CA,USA),SYBR-Green法的qPCR扩增:95℃5min,40个循环,95℃10s,55℃20s,72℃31s。通过对GAPDH基因的检测实现均一化。
2.异喹啉类生物碱抑制SARS-CoV-2病毒样颗粒(trVLP)
1)细胞培养
Caco-2-N细胞用高糖DMEM+10%胎牛血清,在37℃5% CO2培养箱中培养。
SARS-CoV-2病毒样颗粒(trVLP)为清华大学丁强教授团队开发的具有转录和复制能力的系统,将SARS-CoV-2trVLP表达的报告基因(GFP)取代病毒基因组包装和病毒粒子组装所必需的核蛋白基因(N)(SARS-CoV-2-GFP/ΔNtrVLP),该病毒可以在异位表达SARS-CoV-2N蛋白的Caco-2-N细胞中完成完整的生命周期。由于产生的病毒颗粒核酸中没有N基因,该病毒样颗粒只能感染过表达N基因的细胞,所以对人和动物不具有感染性。该系统在保留了SARS-CoV-2生物学特性的同时保证了安全性,这一成果加快了研究人员在BSL-2实验室对新冠病毒的研究。我们在本申请中使用了丁强教授馈赠的SARS-CoV-2trVLP系统,用于异喹啉类生物碱对SARS-CoV-2的抑制作用研究。
2)异喹啉类生物碱抑制SARS-CoV-2病毒样颗粒(trVLP)的EC50和CC50测定
EC50检测:将2.5×104个Caco-2-N细胞接种到96孔板中,在37℃、5% CO2的培养箱中培养24h后,在细胞培养孔中分别加入终浓度为50μM、25μM、12.5μM、6.25μM、3.125μM、1.56μM、0.78μM、0.39μM、0μM的异喹啉类生物碱轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱,37℃预孵育1h,同时将SARS-CoV-2trVLP病毒(MOI=0.001)与终浓度为50μM、25μM、12.5μM、6.25μM、3.125μM、1.56μM、0.78μM、0.39μM、0μM的异喹啉类生物碱4℃预孵育1h,孵育结束后用上述病毒-药物混合物感染细胞。感染2h后PBS清洗3遍换液,加入含相同浓度药物的培养基,37℃、5% CO2的培养箱中进行培养。病毒感染后的48h通过qRT-PCR的方法对细胞内病毒RNA以及细胞内参基因GAPDH的表达情况进行定量检测。用GraphPad-Prism 8软件进行数据分析计算EC50。
CC50检测:使用CellTiter-Blue法进行CC50的检测。Caco-2-N细胞接种至96孔细胞培养板,细胞密度达到60%-80%时进行试验。Caco-2-N细胞换液后加入稀释后的药物,终浓度分别为50μM、25μM、12.5μM、6.25μM、3.125μM、1.56μM、0.78μM、0.39μM、0μM。37℃5%CO2培养48h,利用CellTiter-Blue试剂检测荧光强度,激发波长554nm,发射波长593nm,GraphPad-Prism 8软件进行数据分析计算CC50。
3)加药时间实验
将1×105个Caco-2-N细胞接种到24孔板中,在37℃、5% CO2的培养箱中培养24h后,在全时段给药组和入胞前给药组细胞培养孔中分别加入根据药物EC50确定的终浓度的异喹啉类生物碱,37℃预孵育1h,同时将SARS-CoV-2trVLP病毒(MOI=0.001)与相同浓度的异喹啉类生物碱4℃预孵育1h,孵育结束后用上述病毒-药物混合物感染细胞,感染2h后PBS清洗3遍换液,在全时段给药组和入胞后给药组细胞培养孔中加入含相同浓度药物的培养基,入胞前给药组和对照组细胞培养孔加入不含药物培养基,在37℃、5% CO2的培养箱中进行培养。病毒感染后12h,通过qRT-PCR的方法对细胞内病毒RNA以及细胞内参基因GAPDH的表达情况进行定量检测。用GraphPad-Prism 8软件进行数据分析。
4)病毒样本处理和检测
按照制造商的说明,使用Axygen TM多用途总RNA小提试剂盒(Axygene,货号AP-MN-MS-RNA-250G)进行RNA提取。反转录使用可消化gDNA的Hifair II 1st strand cDNA合成试剂盒(上海翊圣生物科技,货号:11121ES60),qRT-PCR使用Quantstudio实时PCR检测试剂(Applied biosystems,Foster City,CA,USA),SYBR-Green法的qPCR扩增:95℃5min,40个循环,95℃10s,55℃20s,72℃31s。通过对GAPDH基因的检测实现均一化。
EC50是指能够有效抑制50%细胞感染病毒的药物浓度,数值越小说明药物对病毒的抑制效果越好。
CC50是使得50%的细胞发生细胞毒性的药物浓度,数值越高说明药物对细胞的毒性越低。
SI:选择性指数,为CC50与EC50的比值,数值越大说明成药的可能性越高。
3.异喹啉类生物碱抑制SARS-CoV-2野生型假病毒
1)细胞培养
BHK21-ACE2、HEK-293T细胞使用高糖DMEM+10%胎牛血清培养,在37℃5%CO2温箱中孵育。
2)假病毒包装
SARS-CoV-2野生型S蛋白假病毒的制备采用VSV假病毒包装系统,假病毒的组装和测定过程基于Nie等人发表的论文中(Nie et al.,Nat Protoc.2020;15(11):3699-3715.)。将SARS-CoV-2野生型S蛋白的质粒转染到HEK-293T细胞中在细胞表面提供膜蛋白,而利用G*ΔG-VSV感染提供VSV的基因组,感染和转染后24h及48h分别收集细胞上清液以获得SARS-CoV-2野生型的S蛋白假病毒。
3)异喹啉类生物碱抑制SARS-CoV-2野生型假病毒的感染复制
将5×104个重悬的BHK21-ACE2细胞接种到96孔板中,在37℃、5% CO2的培养箱中培养24h后,使用添加10%胎牛血清和1%青霉素-链霉素的DMEM分别稀释异喹啉类生物碱轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱,然后分别加入野生型S蛋白假病毒,4℃下孵育60-90min,使轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱的终浓度为25μM、8.33μM、2.78μM、0.93μM、0.31μM、0.1μM。同时对应终浓度的异喹啉类生物碱分别与细胞在37℃下孵育60-90min,孵育结束后,假病毒-异喹啉类生物碱混合物加入对应药物浓度的BHK21-ACE2细胞中。37℃培养24h后利用萤光素酶检测系统(Luciferase Assay System)检测细胞裂解液中的萤火虫荧光素酶的表达量。
实验结果
结果见图1-5。
由图1、图2可知,异喹啉类生物碱轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱对GX_P2V病毒具有良好的抑制作用,且具有剂量依赖效应。由图1可知,在Vero E6细胞上异喹啉类生物碱轮环藤宁对于GX_P2V在细胞水平的EC50=1.37μM,CC50>50μM,SI>36.50;蝙蝠葛碱对于GX_P2V在细胞水平的EC50=17.04μM,CC50>50μM,SI>2.93;蝙蝠葛苏林碱对于GX_P2V在细胞水平的EC50=14.08μM,CC50>50μM,SI>3.55;峨眉唐松草碱对于GX_P2V在细胞水平的EC50=3.31μM,CC50=49.85μM,SI=15.06;唐松明灵碱(Thalmineline)对于GX_P2V在细胞水平的EC50=1.29μM,CC50>50μM,SI>38.76;6-丙酮基二氢白屈菜红碱对于GX_P2V在细胞水平的EC50=2.47μM,CC50>50μM,SI>24.24。可见,上述异喹啉类生物碱均对GX_P2V具有较好的抑制效果,且存在剂量依赖,毒副作用较小。
由图2可知,上述异喹啉类生物碱(轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱)在选定浓度下对GX_P2V感染Vero E6细胞入胞前、入胞后及全时段均有抑制作用。且上述异喹啉生物碱均在核酸和蛋白水平上对GX_P2V感染Vero E6细胞入胞前、入胞后及全时段均有抑制作用。
由图3、图4可知,在Caco-2-N细胞上异喹啉类生物碱(轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱)对SARS-CoV-2病毒样颗粒(trVLP)均具有良好的抑制作用,且具有剂量依赖效应。
由图3可知,在Caco-2-N细胞上异喹啉类生物碱轮环藤宁对于SARS-CoV-2病毒样颗粒(trVLP)在细胞水平的EC50=1.64μM,CC50>50μM,SI>30.49;蝙蝠葛碱对于SARS-CoV-2病毒样颗粒(trVLP)在细胞水平的EC50=2.84μM,CC50>50μM,SI>17.61;蝙蝠葛苏林碱对于SARS-CoV-2病毒样颗粒(trVLP)在细胞水平的EC50=~1.52μM,CC50>50μM,SI>~32.89;峨眉唐松草碱对于SARS-CoV-2病毒样颗粒(trVLP)在细胞水平的EC50=~25.29μM,CC50>50μM,SI>~1.98;唐松明灵碱对于SARS-CoV-2病毒样颗粒(trVLP)在细胞水平的EC50=6.20μM,CC50>50μM,SI>8.06;6-丙酮基二氢白屈菜红碱对于SARS-CoV-2病毒样颗粒(trVLP)在细胞水平的EC50=2.25μM,CC50>50μM,SI>22.22。可见,上述异喹啉类生物碱均对SARS-CoV-2病毒样颗粒(trVLP)具有较好的抑制效果,且存在剂量依赖,毒副作用较小。
由图4可知,上述异喹啉类生物碱(轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱)在选定浓度下,对SARS-CoV-2病毒样颗粒(trVLP)感染Caco-2-N细胞入胞前、入胞后及全时段在核酸水平均显示出抑制作用。
由图5可知,在BHK21-ACE2细胞上异喹啉类生物碱轮环藤宁对于SARS-CoV-2野生型假病毒在细胞水平的EC50=6.54μM;蝙蝠葛碱对于SARS-CoV-2野生型假病毒在细胞水平的EC50=5.91μM;蝙蝠葛苏林碱对于SARS-CoV-2野生型假病毒在细胞水平的EC50=8.48μM;峨眉唐松草碱对于SARS-CoV-2野生型假病毒在细胞水平的2.83μM;唐松明灵碱(Thalmineline)对于SARS-CoV-2野生型假病毒在细胞水平的EC50=2.73μM;6-丙酮基二氢白屈菜红碱对于SARS-CoV-2野生型假病毒在细胞水平的EC50=11.76μM。上述异喹啉类生物碱均对SARS-CoV-2野生型假病毒具有较好的抑制效果,存在剂量依赖。
利用SARS-CoV-2病毒进行研究需要高等级的生物防护设施,这与目前研究的迫切需要相冲突。发明人在本申请中采用了穿山甲冠状病毒毒株xCoV、SARS-CoV-2病毒样颗粒(trVLP)及基于VSV骨架的假病毒系统对几种异喹啉类生物碱进行了活性评价,在保证了安全性的前提下也实现了对SARS-CoV-2研究的有效性和可靠性,并且通过多种验证手段保证了本发明内容的真实性。
在本申请中,实验数据显示异喹啉类生物碱轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱具有显著地抑制冠状病毒的活性。发明人认为异喹啉类生物碱轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱是潜在的治疗SARS-CoV-2感染性疾病的药物。异喹啉类生物碱在抗SARS-CoV-2病毒药物筛选模型穿山甲冠状病毒毒株xCoV、SARS-CoV-2病毒样颗粒(trVLP)系统、VSV假病毒系统上,都明显抑制了病毒的感染和复制。异喹啉类生物碱在病毒的整个生命周期均能抑制病毒复制,这些结果强烈提示异喹啉类生物碱对于目前流行的新冠病毒以及其他冠状病毒感染引起的病症的潜在临床应用价值。
鉴于所观察到的异喹啉类生物碱对病毒的强烈抑制作用,异喹啉类生物碱极有可能成为新型冠状病毒感染的特效药。因此,发明人认为,作为潜在的治疗SARS-CoV-2及其他冠状病毒感染的药物,异喹啉类生物碱具有重大的药用价值,是治疗SARS-CoV-2病毒及其他冠状病毒感染性疾病的一类有前途的候选药物。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.异喹啉类生物碱及其药学上可接受的盐在制备预防、缓解和/或治疗冠状病毒感染所致疾病的产品中的应用;
所述异喹啉类生物碱选自轮环藤宁、蝙蝠葛碱、蝙蝠葛苏林碱、峨眉唐松草碱、唐松明灵碱、6-丙酮基二氢白屈菜红碱(22864-92-2)中的至少一种。
2.根据权利要求1所述的用途,其特征在于,所述药学上可接受的盐选自异喹啉类生物碱结构中具有足够碱性的氮原子的酸加成盐,所述酸加成盐包括异喹啉类生物碱与无机酸或有机酸所形成的盐。
3.根据权利要求2所述的用途,其特征在于,所述无机酸选自盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸。
4.根据权利要求2所述的用途,其特征在于,所述有机酸选自甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
5.根据权利要求1-4任一项所述的用途,其特征在于,所述产品为药品、食品、化妆品、护肤品、日用品和保健品。
6.根据权利要求1-5任一项所述的用途,其特征在于,所述冠状病毒为2019新型冠状病毒。
7.根据权利要求1-6任一项所述的用途,其特征在于,异喹啉类生物碱及其药学上可接受的盐可以配置成各种适合的药物制剂形式;可以单独使用,或者将其与药物辅料混合,配置成口服给药的片剂、胶囊剂、颗粒剂、糖浆剂;或注射给药的粉针剂、溶液剂,以及研制为功能食品,功能饮品、药酒,滴鼻液及漱口水。
8.根据权利要求1-5任一项所述的用途,其特征在于,所述药物辅料为赋形剂或稀释剂。
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