CN117281810A - 千金藤素在治疗和预防柯萨奇病毒感染中的应用 - Google Patents
千金藤素在治疗和预防柯萨奇病毒感染中的应用 Download PDFInfo
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- CN117281810A CN117281810A CN202210693506.XA CN202210693506A CN117281810A CN 117281810 A CN117281810 A CN 117281810A CN 202210693506 A CN202210693506 A CN 202210693506A CN 117281810 A CN117281810 A CN 117281810A
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- Prior art keywords
- acid
- cepharanthine
- coxsackievirus
- pharmaceutically acceptable
- use according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明涉及千金藤素，其药学上可接受的盐或前药在治疗和预防肠道病毒感染中的应用。发明人发现千金藤素，其药学上可接受的盐或前药对柯萨奇病毒，特别是A类9型毒株具有良好的抑制效果，这对于感染柯萨奇病毒导致的相关疾病的治疗和预防具有重要临床应用价值。
Description
技术领域
本发明属于生物药物技术领域，具体涉及千金藤素在治疗和预防肠道病毒感染中的应用。
背景技术
柯萨奇病毒(Coxsackievirus)属于人肠道病毒B族(Human Enterovirus B， HEV-B)。HEV-B具有广泛的临床急性疾病的表现，并且HEV-B被认为是造成无菌性脑膜炎的主要原因。此外，有证据表明，儿童糖尿病的发病机制可能也与HEV-B特别是CV-A9、CV-B1、CV-B3和CV-B5有关，这种疾病在西方国家的发病率正在上升。柯萨奇病毒可分为A(CV-A)和B(CV-B)两类，其中柯萨奇病毒A9(CV-A9)是在柯萨奇A型病毒(CV-A)中唯一一种属于HEV-B的病毒，被认为是病毒性脑炎的重要病原体之一。
虽然肠道病毒属含有许多重要的人类病原体，但目前还没有获得许可的治疗或预防肠道病毒感染的药物。病毒全生命周期的每个阶段都可作为潜在药物的作用靶点，但是考虑到药物的有效性及安全性，进入全球市场的药物少之又少。此外，针对肠道病毒的疫苗还没有普及，并且肠道病毒种类繁多，存在多种突变体，未来疫苗的设计面临巨大挑战。考虑到小RNA病毒易突变的性质针对所有肠道病毒设计疫苗的难度较大，而当前已经应用于临床的疫苗只有针对脊髓灰质炎病毒(poliovirus,PV)和肠道病毒A组71型(EV-A71)这两类肠道病毒。因此，研究针对肠道病毒的有效抗病毒药物意义重大。
千金藤素作为一类双苄基异喹啉类生物碱已被证实具有抗病毒效果。然而目前尚未有千金藤素抑制柯萨奇病毒的相关报道。
发明内容
为解决上述技术问题，本发明提供千金藤素，其药学上可接受的盐或前药在制备预防，缓解或治疗柯萨奇病毒感染的药物中的应用；
所述千金藤素结构如下所示：
根据本发明的实施方案，所述千金藤素药学上可接受的盐选自其结构中具有足够碱性的氮原子的酸加成盐，所述酸加成盐包括千金藤素与无机酸如盐酸、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；
例如，所述千金藤素药学上可接受的盐选自盐酸盐千金藤素，甲磺酸盐千金藤素或丙酮酸盐千金藤素。
在本发明中，所述盐酸盐千金藤素是盐酸和千金藤素形成的酸加成盐。
在本发明中，所述甲磺酸盐千金藤素是甲磺酸和千金藤素形成的酸加成盐。
在本发明中，所述丙酮酸盐千金藤素是丙酮酸和千金藤素形成的酸加成盐。
根据本发明的实施方案，对所述千金藤素前药的讨论提供于T.HiguchiandV.Stella,Pro-drugs as Novel Delivery Systems(1987)14of the A.C.S.SymposiumSeries和Bioreversible Carriers in Drug Design, (1987)EdwardB.Roche,ed.,American Pharmaceutical Association and Pergamon Press中。术语“前药”是指在体内转化以提供千金藤素或其药学上可接受的盐的化合物(例如药物前体)。转化可以通过各种机制(例如通过代谢过程或化学过程)发生，例如通过在血液中的水解。举例来说，如果千金藤素或其药学上可接受的盐包含胺官能团，则可以通过用诸如以下的基团代替胺基中的氢原子来形成前药：R-羰基-，RO-羰基-，NRR’-羰基，其中R和R’各自独立地为C1-12烷基、C3-12环烷基、苄基、天然α-氨酰基、-C(OH)C(O)OY1(其中Y1是H、C1-12烷基或苄基)、-C(OY2)Y3(其中Y2是C1-12烷基，Y3是C1-12烷基；羧基C1-12烷基；氨基C1-12烷基或单-N-C1-12烷基氨基烷基或二-N,N-C1-12烷基氨基烷基； -C(Y4)Y5(其中Y4是H或甲基，Y5是单-N-C1-12烷基氨基吗啉基或二-N,N-C1-12烷基氨基吗啉基；哌啶-1-基或吡咯烷-1-基等。
根据本发明的实施方案，所述千金藤素或其药学上可接受的盐及前药能够治疗和/或预防由于柯萨奇病毒感染所致疾病，能够改善由于柯萨奇病毒感染所致症状。
根据本发明的实施方案，所述千金藤素或其药学上可接受的盐及前药可在机体水平或细胞水平抑制柯萨奇病毒。
根据本发明的实施方案，所述抑制柯萨奇病毒可理解为预防、治疗柯萨奇病毒，千金藤素或其药学上可接受的盐及前药可干预病毒在宿主细胞上的吸附 (包括特异性吸附/结合、非特异性吸附/结合)、抑制病毒的入胞过程、抑制病毒感染的入胞后过程、抑制病毒复制，上述抑制、预防、治疗过程都在本发明的范围内。
根据本发明的实施方案，所述柯萨奇病毒感染所致疾病可为疱疹性咽峡炎，急性出血性结膜炎、手足口病、胸膜痛，心肌炎，心包炎和肝炎等。由柯萨奇病毒感染所致症状可为发热、打喷嚏、咳嗽、出疹等。
根据本发明的实施方案，所述柯萨奇病毒可为柯萨奇病毒A类，B类或其它柯萨奇病毒。
根据本发明的实施方案，所述柯萨奇病毒A类可为柯萨奇病毒A类9型或其它型的柯萨奇病毒A类。
在本发明的具体实施方式中，所述柯萨奇病毒A类9型为所述柯萨奇病毒 A类9型毒株BUCT01，其在中国微生物菌种保藏管理委员会普通微生物中心的保藏编号为CGMCCNo.20091。
本发明还提供一种可预防，缓解或治疗柯萨奇病毒感染的药物组合物，其包括千金藤素，其药学上可接受的盐或前药。
根据本发明的实施方案，所述药物组合物中千金藤素，其药学上可接受的盐或前药的浓度为12.5μM-1.56μM。
本发明还提供一种用于治疗下述疾病的药物组合物，所述组合物包含千金藤素，其药学上可接受的盐或前药，所述疾病包括疱疹性咽峡炎，急性出血性结膜炎、手足口病、胸膜痛，心肌炎，心包炎和肝炎。
根据本发明的实施方案，所述疾病由柯萨奇病毒感染所致。
根据本发明的实施方案，所述的药物组合物还包括药学上可接受的辅料。
根据本发明的实施方案，所述的药学上可接受的辅料包括生理或药学上可接受的载体、稀释剂、媒介物和/或赋形剂中的一种，两种或更多种。
根据本发明的实施方案，所述药物组合物可以配置成各种适合给药的药物制剂形式。
根据本发明的实施方案，所述制剂形式选自片剂、胶囊、溶液剂、混悬剂和半固体制剂。
本发明还提供千金藤素，其药学上可接受的盐或前药在制备缓解或治疗下述疾病的药物中的应用，所述疾病包括疱疹性咽峡炎，急性出血性结膜炎、手足口病、胸膜痛，心肌炎，心包炎和肝炎等。
根据本发明的实施方案，所述疾病由柯萨奇病毒感染所致。
本发明还提供一种预防，缓解或治疗柯萨奇病毒的方法，包括将千金藤素，其药学上可接受的盐或前药，或上述药物组合物施用于有此需要的个体。
有益效果
本发明人发现千金藤素，其药学上可接受的盐或前药对柯萨奇病毒，特别是A类9型毒株具有良好的抑制效果，这对于感染柯萨奇病毒导致的相关疾病的治疗和预防具有重要临床应用价值。
附图说明
图1示出了千金藤素对CV-A9的EC50、CC50和SI。
图2示出了甲磺酸盐千金藤素对CV-A9的EC50、CC50和SI。
图3示出了丙酮酸盐千金藤素对CV-A9的EC50、CC50和SI。
图4示出了盐酸盐千金藤素对CV-A9的EC50、CC50和SI。
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。
如下实施例中使用的柯萨奇病毒A类9型(CV-A9)毒株BUCT01从患手足口病的幼儿粪便中分离并培养所得。经高通量测序鉴定，确认其为一株柯萨奇病毒A类9型，全基因组序列分析结果显示其与2013年中国分离出的一株柯萨奇病毒(GenBank accession number：KP289434)的核苷酸同源性最高为91.38％，与2013年中国分离出来的一株柯萨奇病毒A类9型(GenBank accession number：KP290111)氨基酸同源性最高为97.91％。CV-A9毒株BUCT01已经于2020年10月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心(地址：北京市朝阳区北辰西路1号院3号)，保藏编号为CGMCC No.20091；使用的生物材料为BUCT01；分类命名：柯萨奇病毒（Coxsackievirus）。
实施例1、千金藤素，其药学上可接受的盐(盐酸盐，丙酮酸盐和甲磺酸盐) 抑制柯萨奇病毒A类9型毒株BUCT01(CV-A9)
1)细胞病毒培养
人横纹肌肉瘤细胞系RD是从美国模式培养物集存库(ATCC， CRL-3216TM)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。
柯萨奇病毒A类9型毒株BUCT01(GenBank accession number：KP290111) 为从北京患有手足口病的儿童腹泻粪便中分离获得。将CV-A9在RD细胞中繁殖，用RD细胞(ATCCCCL-136)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)千金藤素及其药学上可接受的盐抑制柯萨奇病毒A类9型毒株BUCT01 (CV-A9)的EC50和CC50测定
EC50检测：将2.5×104个RD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100μM、50μM、25μM、 12.5μM、6.25μM、3.125μM、1.56μM、0.78μM、0.39μM、0.195μM、0μM 的千金藤素或者其药学上可接受的盐，37℃预孵育1h，同时将病毒与终浓度为 100μM、50μM、25μM、12.5μM、6.25μM、3.125μM、1.56μM、0.78μM、0.39μM、0.195μM、0μM的千金藤素或者其药学上可接受的盐4℃预孵育1h，孵育结束后用终MOI＝0.001的病毒感染细胞，感染2h后PBS清洗3遍换液，加入只含药物的培养基，终浓度分别为100μM、50μM、25μM、12.5μM、6.25 μM、3.125μM、1.56μM、0.78μM、0.39μM、0.195μM、0μM，37℃、5％CO2的培养箱中进行培养。病毒感染后的48h显微镜镜下观察细胞病变，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。RD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RD细胞换液后加入稀释后的药物，终浓度分别为100μM、50μM、25μM、12.5μM、6.25μM、3.125μM、 1.56μM、0.78μM、0.39μM、0.195μM、0μM，37℃5％CO2培养48h，利用 CellTiter-Blue试剂检测593nm发光强度，GraphPad-Prism 8软件进行数据分析计算CC50。
EC50是指能够有效抑制50％细胞感染病毒的药物浓度，数值越小说明对病毒的抑制效果越好。
CC50是使得50％的细胞发生病变时的药物浓度，数值越高说明对细胞的毒性越低。
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)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值指的是病毒被抑制一半时成分的浓度，CC50值指的是一半的细胞死亡时成分的浓度。前者反映成分的效用，后者反映成分的毒性大小。根据细胞内病毒mRNA的相对表达量，用Graphpad Prism软件中非线性分析中的log (inhibitor)vs.response公式计算得到千金藤素的半数有效浓度(EC50)为 0.5443μM，CC50值为>12.5μM，结果如图1所示。结果显示，千金藤素在 12.5μM～1.56μM等4个浓度范围内均有抗病毒感染的效果(99％～95％)。
甲磺酸盐千金藤素对CV-A9的EC50＝1.450μM、CC50＞6.25μM(图2)。甲磺酸盐千金藤素在6.25μM浓度有抗病毒感染的效果(84.76％)。强烈提示甲磺酸盐千金藤素是潜在的强力抗CV-A9感染细胞抑制剂。
丙酮酸盐千金藤素对CV-A9的EC50＝1.485μM、CC50＞6.25μM(图3)。丙酮酸盐千金藤素在6.25μM-1.56μM浓度有明显抗病毒感染的效果 (71.68％-91.47％)。强烈提示丙酮酸盐千金藤素是潜在的强力抗CV-A9感染细胞抑制剂。
盐酸盐千金藤素对CV-A9的EC50＝1.140μM、CC50＞6.25μM(图4)。盐酸盐千金藤素在6.25μM浓度有明显抗病毒感染的效果(81.53％)。强烈提示盐酸盐千金藤素是潜在的强力抗CV-A9感染细胞抑制剂。
在本发明中，发明人在RD细胞感染柯萨奇病毒A类9型毒株BUCT01后加入千金藤素及其药学上可接受的盐发现千金藤素及其药学上可接受的盐有较好的剂量依赖的抗柯萨奇病毒效果。而目前没有针对柯萨奇病毒A类9型或其它类似柯萨奇病毒或其它肠道病毒B族的特异性药物，因此，上述发现对千金藤素及其药学上可接受的盐抑制柯萨奇病毒A类9型或其它类似柯萨奇病毒或其它肠道病毒B族在临床用药具有重要参考意义。
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)
1.千金藤素，其药学上可接受的盐或前药在制备预防，缓解或治疗柯萨奇病毒感染的药物中的应用；
所述千金藤素结构如下所示：
2.根据权利要求1所述的用途，其特征在于，所述千金藤素药学上可接受的盐选自其结构中具有足够碱性的氮原子的酸加成盐，所述酸加成盐包括千金藤素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4所述的用途，其特征在于，所述千金藤素药学上可接受的盐选自盐酸盐千金藤素，甲磺酸盐千金藤素或丙酮酸盐千金藤素。
6.根据权利要求1所述的用途，其特征在于，所述柯萨奇病毒可为柯萨奇病毒A类或B类。
7.根据权利要求6所述的用途，其特征在于，所述柯萨奇病毒A类为柯萨奇病毒A类9型。
8.根据权利要求1-7任一项所述的用途，其特征在于，所述柯萨奇病毒感染所致疾病为疱疹性咽峡炎，急性出血性结膜炎、手足口病、胸膜痛，心肌炎，心包炎和肝炎。
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