CN110787161A - 噻唑类化合物用于抗鱼类病毒的新用途 - Google Patents
噻唑类化合物用于抗鱼类病毒的新用途 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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Abstract
本发明公开了噻唑类化合物用于抗鱼类病毒的新用途,所述噻唑类化合物为硝唑尼特,其结构式如式1所示:
Description
技术领域
本发明涉及噻唑类化合物的新用途,尤其是噻唑类化合物用于抗鱼类病毒的新用途。
背景技术
硝唑尼特是一种四氢噻唑类化合物,二十世纪七十年代首次在抗寄生虫化合物氯硝柳胺的框架上合成(Rossignol 1975)。硝唑尼特最初作为一种抗寄生虫药物的活性成分在墨西哥和美国上市,随后在细胞模型、动物模型以及人类临床试验中发现其具有良好的抗病毒活性。研究表明,硝唑尼特对许多呼吸道病毒如流感病毒H1N1、H7N9和非呼吸道病毒如肝病毒HBV、HCV感染具有良好的治疗效果。然而硝唑尼特对鱼类病毒的抗病毒作用却鲜有报道。
针对抗病毒机制的研究显示,硝唑尼特能够抑制不同的病毒增殖阶段,这取决于病毒和宿主细胞的特性。对于牛痘病毒(vaccinia virus),硝唑尼特能够抑制病毒基因组的复制(Hickson,Margineantu et al. 2018)。对于奇昆古尼亚病毒(chikungunyavirus),硝唑尼特则抑制病毒的吸附过程和病毒释放过程(Wang,Lu et al.2016)。而对于丙肝病毒(hepatitis C virus,HCV),硝唑尼特激活细胞中的PKR蛋白激酶,磷酸化真核启动因子eIF2α,启动细胞先天免疫反应,抑制病毒在细胞中的增殖(Rossignol 2014)。但是硝唑尼特对鱼类病毒的抗病毒机制仍然缺乏研究。
病毒性出血性败血症(Viral Hemorrhagic Septicemia,VHS)是由VHSV(ViralHemorrhagic Septicemia Virus,VHSV)引发的鱼类烈性传染病。VHSV宿主范围广,能够感染鲑鱼、鳟鱼、大菱鲆等经济鱼类,引发严重的出血性败血症,病鱼死亡率高。在病毒学研究方面,国内外的学者对VHSV的基因组结构与进化关系有了清晰的认识。
目前已知VHSV属于弹状病毒科(Rhabdoviridae),是一种负链 RNA病毒,全基因组长度为11kb,从3’到5’依次表达6个基因。VHSV 根据基因组的差别可细分为四类病毒株(Pereiro,Figueras et al.2016)。尽管国内外的研究对这种病毒的病毒学性质有了一定程度的了解,但对于病毒与宿主的相互作用机制,宿主的免疫应答通路的研究还不够透彻和深入,而这也阻碍了新型水产药物的研发进程。VHS主要流行于欧洲、北美、日本及韩国,曾造成严重的经济损失,是出现疫情后必须向世界动物卫生组织汇报的水产疫病之一。近十年来科学家陆续在各种太平洋野生海洋鱼类中发现并分离出VHSV,在我国多种养殖鱼类,如大口黑鲈等经济鱼类也检测到VHSV。尽管VHSV危害巨大,目前市场上仍缺乏有效的VHSV疫苗,疫病防控以严格监测和预防为主,因此研发抗VHSV药物有助于提高我国水产养殖鱼类品质和国际竞争力,助力水产养殖业的健康发展。
发明内容
本发明旨在提供噻唑类化合物用于抗鱼类病毒的新用途。
为了实现上述目的,本发明提供的技术方案是:噻唑类化合物用于抗鱼类病毒的新用途,所述噻唑类化合物为硝唑尼特,其结构式如式1所示:
所述噻唑类化合物为替唑尼特,其结构式如式2所示:
所述噻唑类化合物包括硝唑尼特/替唑尼特的几何异构体,及其药物上可接受的盐和其溶剂化物或其水合物。
所述其药物上可接受的盐包括其无机或有机酸盐,以及无机或有机碱盐。
所述其药物上可接受的盐包括钠盐、钾盐、钙盐、锂盐、葡甲胺盐、盐酸盐、氢澳酸盐、氢腆酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、丙酸盐、丁酸盐、草酸盐、三甲基乙酸盐、己二酸盐、藻酸盐、乳酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、马来酸盐、富马酸盐、苦味酸盐、天冬氨酸盐、葡糖酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和/或双羟萘酸盐。但并不限于上述盐的形式。
所述噻唑类化合物用于抑制病毒性出血性败血症病毒(Viral HemorrhagicSepticemia Virus,VHSV)在胖头鱥上皮细胞(FHM) 细胞中的增殖,消除细胞病变效应(cytopathic effects,CPE)。
所述噻唑类化合物可显著减缓细胞因病毒感染所导致的CPE,并在FHM细胞上抑制病毒增殖,减少细胞中的病毒基因拷贝数
所述噻唑类化合物在体外抗病毒实验中,以微摩尔级浓度降低 VHSV感染的细胞CPE程度。
所述噻唑类化合物在微摩尔级浓度下降低VHSV感染的细胞中病毒基因拷贝数。
所述噻唑类化合物用于阻止VHSV侵入FHM细胞。
附图说明
图1为硝唑尼特和替唑尼特在不同浓度下保护VHSV感染的 FHM细胞活性的效果图;
图2为利巴韦林在不同浓度下保护VHSV感染的FHM细胞活性的效果图;
图3为硝唑尼特和替唑尼特能够极显著降低感染了VHSV感染的FHM细胞中病毒基因拷贝数的效果图;
图4为硝唑尼特能够抑制VHSV侵入FHM细胞的过程,显著降低感染VHSV的FHM细胞中病毒基因的拷贝数的效果图;
图5为硝唑尼特显著减缓感染VHSV的FHM细胞CPE的效果图;其中,A为8μM硝唑尼特处理组,B为8μM利巴韦林处理组, C为DMSO处理组。
具体实施方式
下面结合具体实施方式对本发明的权利要求作进一步的说明,但不构成任何限定。
实施例1:硝唑尼特和利巴韦林对FHM细胞的毒性测试。
(1)FHM细胞培养
实验过程中使用的FHM细胞在本实验室保存,来源以及传代次数明确。细胞生长使用的完全细胞培养基为10%血清浓度的M199培养基,急性攻毒实验使用的维持培养基为2%血清浓度的M199培养基,稀释病毒和化合物使用无血清的M199培养基。细胞培养于28℃培养箱中,传代时使用0.25%EDTA胰酶消化细胞2分钟,通常按照 1:2-1:3的浓度传代至细胞培养瓶,培养约16小后细胞铺满单层。
(2)细胞活性检测
使用MCE公司的Cell Counting Kit-8检测细胞活性。用 0.25%EDTA胰酶消化铺满瓶底的FHM细胞2分钟,消化结束后使用完全培养基重悬制备单细胞悬液,用无血清培养基将完全培养基血清浓度稀释至2%,进行细胞计数后以10000细胞/孔的密度接种至96 孔板,培养基用量为100μL/孔。在28℃培养箱中培养16小时。使用无血清培养基稀释硝唑尼特和利巴韦林并加入96孔板,使终浓度为 0.25μM、0.5μM、1μM、2μM、4μM、8μM、16μM和32μM。设置无药物的细胞空白对照和无细胞的培养基对照。处理细胞48小时后,弃去上清液,更换维持培养基。每孔细胞加入CCK-8试剂10μL,避光显色4小时,使用BioTek公司的活细胞成像仪检测OD450。
硝唑尼特与利巴韦林对FHM细胞毒性使用以下公式计算:
实施例2:硝唑尼特和替唑尼特保护FHM细胞活性实验。
使用MCE公司的Cell Counting Kit-8检测细胞活性。用 0.25%EDTA胰酶消化铺满瓶底的FHM细胞2分钟,消化结束后使用完全培养基重悬制备单细胞悬液,用无血清培养基将完全培养基血清浓度稀释至2%,进行细胞计数后以10000细胞/孔的密度接种至96 孔板,在28℃培养箱中培养16小时。使用无血清M199培养基稀释 VHSV,加入96孔板,使病毒浓度为50TCID50。将硝唑尼特稀释加入96孔板,使终浓度为0.25μM、0.5μM、1μM、2μM、8μM、16μM和32μM,设置无药物和病毒的细胞空白对照和无药物但有病毒的阴性对照组。处理细胞24小时后,弃去上清液,更换维持培养基,培养基用量为100μL/孔。每孔细胞加入CCK-8试剂10μL,避光显色4 小时,使用BioTek公司的活细胞成像仪检测OD450。
药物对细胞活性的保护作用即对病毒增殖抑制率使用以下公式计算:
硝唑尼特半数有效浓度使用GraphPad Prism 8.0软件计算得到。
实施例3:硝唑尼特和替唑尼特能够降低感染VHSV的FHM细胞中病毒基因拷贝数并减缓CPE实验。
(1)急性攻毒和药物处理
使用0.25%EDTA胰酶消化铺满瓶底的FHM细胞2分钟,消化结束后使用完全培养基重悬制备单细胞悬液,用无血清培养基将完全培养基血清浓度稀释至2%,进行细胞计数后以1.5×105细胞/孔的密度接种至12孔板,在28℃培养箱中培养16小时。用无血清培养基稀释VHSV,加入12孔板细胞中,使VHSV终浓度为50TCID50。用无血清培养基将硝唑尼特和利巴韦林稀释,加入12孔板细胞中,使最终浓度为8μM。
(2)观察并拍摄细胞图片
进行攻毒后的细胞在28℃培养箱中培养24小时后,使用Carl Zeiss AG公司生产的倒置荧光显微镜观察细胞并在10倍镜下拍摄具有代表性的视野。如图4所示,硝唑尼特处理组细胞状态正常,没有出现CPE,而DMSO处理组和利巴韦林处理组出现大量细胞聚集、变圆、飘浮死亡等CPE。
(3)细胞RNA提取
1)收集细胞:使用0.25%EDTA消化12孔板中的细胞,用维持培养基将细胞重悬,收集至无RNA酶离心管中。
2)裂解细胞:1300rpm常温离心2分钟,弃去上清液,轻弹离心管使细胞沉淀分散开,每管加入500μL 4℃预冷的Trizol试剂。
3)抽提蛋白质:每管加入100μL氯仿,剧烈震荡,常温静置5 分钟。
4)分离RNA:4℃13000rpm离心15分钟,将260μL上清液转移至新的无RNA酶离心管。
5)沉淀RNA:每管加入260μL异丙醇,轻柔混匀,常温静置 10分钟。
6)分离RNA:4℃13000rpm离心12分钟,弃去上清液。
7)清洗RNA沉淀:每管加入800μL DEPC水配置的75%乙醇溶液。
8)分离RNA:4℃7600rpm离心7分钟,将乙醇溶液弃去,常温干燥10分钟。
9)溶解RNA:每管加入10μL无RNA酶水溶解RNA沉淀。
10)测RNA样品浓度和纯度:使用Nanodrop仪器测RNA样品浓度和纯度。
(4)RNA反转录
实验采用TaKaRa公司生产的反转录试剂盒(PrimeScriptTM RT reagent Kit withgDNA Eraser)进行RNA反转录,步骤如下。
1)gDNA去除:收集各实验组RNA样品,分别取2μg进行反转录。首先,向各实验组RNA中加入5×gDNA Eraser Buffer(2μL),用无RNase水补足反应体系至10μL,充分混匀,42℃水浴2min去除样品中可能存在的gDNA;
2)反转录:向①所得样品中加入1μL Mix酶溶液和1μL引物 Mix及4μL反应缓冲液,用无RNA酶水补足体积至20μL,放入PCR 仪中进行反转录得到cDNA。反转录程序是37℃ 15分钟,85℃ 5 秒。
(5)定量PCR与数据处理
定量PCR使用Promega公司生产的GoTaq qPCR Master Mix试剂盒,步骤如下:
选取FHMβ-actin基因作为内参基因。定量PCR反应体系为10μL 体系:1μL模板,上下游引物各0.5μL,5μL 2×Mix酶溶液,3μL无 RNA酶水。扩增条件为40个循环,95℃ 15秒、60℃ 15秒、72℃ 15 秒。实验完成后使用2-ΔΔCT法进行相对定量,计算各组细胞中的病毒基因拷贝数。使用GraphPad Prism 8.0软件绘制柱状图。
实施例4:硝唑尼特抑制侵入FHM细胞过程实验。
(1)急性攻毒和药物处理
使用0.25%EDTA胰酶消化铺满瓶底的FHM细胞2分钟,消化结束后使用完全培养基重悬制备单细胞悬液,用无血清培养基将完全培养基血清浓度稀释至2%,进行细胞计数后以1.5×105细胞/孔的密度接种至12孔板,在28℃培养箱中培养16小时。用无血清培养基稀释VHSV、硝唑尼特和利巴韦林,与FHM细胞一起放入4℃冰箱中预冷1小时。将预冷的VHSV加入FHM细胞中,使病毒最终浓度为50TCID50。将攻毒后的细胞放入4℃冰箱中,让VHSV吸附FHM细胞4个小时。用4℃预冷的PBS溶液洗FHM细胞3次,更换维持培养基并加入硝唑尼特和利巴韦林至终浓度为8μM。将细胞放入28℃培养箱中培养24小时。
(2)细胞RNA提取:具体步骤同实施例3。
(4)RNA反转录:具体步骤同实施例3。
(5)定量PCR与数据处理:具体步骤同实施例3。
上述实施例1-4的结果分析图详见图1-图5,其中:
图1显示了硝唑尼特和替唑尼特能够在8μM浓度下保护VHSV 感染的FHM细胞活性。硝唑尼特在不同浓度下,能够对50TCID50/ 孔VHSV感染的FHM细胞活性产生保护作用,其半数有效浓度(EC50) 为1.190±0.521μM。硝唑尼特抗病毒效果在浓度为0μM-8μM之间具有浓度依赖效应。由于化合物具有一定毒性,浓度大于8μM时,硝唑尼特的保护作用减弱。
图2显示了利巴韦林能够在8μM浓度下保护VHSV感染的FHM 细胞活性。利巴韦林在不同浓度下,能够对50TCID50/孔VHSV感染的FHM细胞活性产生保护作用,其半数有效浓度(EC50)为 0.6421±0.189μM。
图3显示了硝唑尼特和替唑尼特能够极显著降低感染了VHSV 感染的FHM细胞中病毒基因拷贝数。图中N为硝唑尼特,R为已知具有抗病毒活性的利巴韦林,D为溶剂DMSO。8μM的不同化合物与50TCID50/孔VHSV同时加入FHM细胞中,病毒感染24小时和 36小时后硝唑尼特处理组细胞中病毒基因拷贝数均极显著低于DMSO处理组(p<0.001)。利巴韦林在36小时失去保护作用。
图4显示了硝唑尼特能够抑制VHSV侵入FHM细胞的过程,显著降低感染VHSV的FHM细胞中病毒基因的拷贝数。N为硝唑尼特处理,R为阳性对照利巴韦林处理,D为阴性对照DMSO处理。50 TCID50/孔VHSV在4℃条件下吸附FHM细胞后,使用PBS洗去游离病毒,加入8μM化合物处理细胞4小时,再用PBS洗去游离化合物,28℃培养24小时后检测细胞中病毒基因拷贝数。硝唑尼特与利巴韦林均能显著降低细胞中的基因拷贝数(p<0.01)。
图5显示了硝唑尼特显著减缓感染VHSV的FHM细胞CPE。 A为8μM硝唑尼特处理组,B为8μM利巴韦林处理组,C为DMSO 处理组。病毒浓度均为50TCID50/孔。细胞在28℃培养36小时后, DMSO对照组和利巴韦林处理组出现明显CPE,但硝唑尼特处理组细胞状态良好。图片标尺为50μm。
Claims (10)
3.根据权利要求1-2任一所述噻唑类化合物用于抗鱼类病毒的新用途,其特征在于,所述噻唑类化合物包括硝唑尼特/替唑尼特的几何异构体,及其药物上可接受的盐和其溶剂化物或其水合物。
4.根据权利要求3所述噻唑类化合物用于抗鱼类病毒的新用途,其特征在于,所述其药物上可接受的盐包括其无机或有机酸盐,以及无机或有机碱盐。
5.根据权利要求4所述噻唑类化合物用于抗鱼类病毒的新用途,其特征在于,所述其药物上可接受的盐包括钠盐、钾盐、钙盐、锂盐、葡甲胺盐、盐酸盐、氢澳酸盐、氢腆酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、丙酸盐、丁酸盐、草酸盐、三甲基乙酸盐、己二酸盐、藻酸盐、乳酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、马来酸盐、富马酸盐、苦味酸盐、天冬氨酸盐、葡糖酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和/或双羟萘酸盐。
6.根据权利要求1-5任一所述噻唑类化合物用于抗鱼类病毒的新用途,其特征在于,所述噻唑类化合物用于抑制病毒性出血性败血症病毒在胖头鱥上皮细胞细胞中的增殖,消除细胞病变效应。
7.根据权利要求1-5任一所述噻唑类化合物用于抗鱼类病毒的新用途,其特征在于,所述噻唑类化合物可显著减缓细胞因病毒感染所导致的CPE,并在FHM细胞上抑制病毒增殖,减少细胞中的病毒基因拷贝数。
8.根据根据权利要求1-5任一所述噻唑类化合物用于抗鱼类病毒的新用途,其特征在于,所述噻唑类化合物在体外抗病毒实验中,以微摩尔级浓度降低VHSV感染的细胞CPE程度。
9.根据根据权利要求1-5任一所述噻唑类化合物用于抗鱼类病毒的新用途,其特征在于,所述噻唑类化合物在微摩尔级浓度下降低VHSV感染的细胞中病毒基因拷贝数。
10.根据根据权利要求1-5任一所述噻唑类化合物用于抗鱼类病毒的新用途,其特征在于,所述噻唑类化合物用于阻止VHSV侵入FHM细胞。
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