吡喹酮抗日本血吸虫作用的靶分子筛选研究
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摘要
血吸虫病流行是严重的全球性公共卫生问题。化疗是目前控制血吸虫病流行和降低患病率的重要措施之一。目前用于治疗5种主要的人体血吸虫感染的药物仅吡喹酮一种。尽管关于吡喹酮药物抗血吸虫的分子机制已经有研究报道,但其抗血吸虫确切靶点仍不清楚。根据抗血吸虫药物的研究进展,本研究开展了吡喹酮的抗日本血吸虫作用靶点的研究,以期为新药研发提供有益的依据。
一、吡喹酮作用前后日本血吸虫蛋白质组的分离、鉴定与分析
利用二维-纳喷雾-液相色谱联用串联质谱技术对吡喹酮作用前后日本血吸虫的总蛋白质进行了分离和鉴定,构建了各自总蛋白信息数据库。结果表明,未经吡喹酮处理组(对照组)基于1431个肽段,鉴定到437种蛋白质,有明确功能注释的为278种;吡喹酮处理组基于2117个肽段,鉴定到73种蛋白质,有明确功能注释的为41种;其中,有16种功能明确的蛋白在两组中均能检测到。对比分析发现,吡喹酮处理组的蛋白种类明显少于正常对照组;在所有鉴定到的蛋白中,有16种发生明显上调(12种)或明显下调(4种)。参与代谢、DNA/RNA进程调节的蛋白明显下调。此外,尚有一些蛋白没有出现明显上调或明显下调,但存在差异性表达:上调蛋白主要是骨架蛋白、应激蛋白和分子伴侣、信号转导蛋白,下调蛋白主要是糖酵解和钙通路蛋白以及转录和翻译调节的蛋白质。根据蛋白在血吸虫组织中的定位分,体被蛋白在药物作用前后出现明显变化。实验结果表明参与细胞骨架构成分子、基因转录和翻译调控分子、应激反应的分子伴侣、代谢的酶类以及信息传导分子均呈现表达差异。因此,提示吡喹酮对日本血吸虫成虫的特定基因的表达具有促进或抑制作用。这些特定基因编码的蛋白与抗血吸虫药物的作用机制有关,是潜在的药物靶点,对研发新的抗血吸虫药物具有指导意义。
二、改良Drug-Western法筛选日本血吸虫cDNA文库的药靶基因
Drug-Western法是目前用于分离cDNA编码的药物靶标蛋白基因的一种便捷、有效的方法,即利用标记分子与药物结合作为探针,直接从cDNA表达文库筛选药物结合蛋白的基因,并利用二抗检测标记分子,获得阳性克隆,分离、测序,以获取目的蛋白进行结构和功能研究。本研究在文献报道Drug-Western法的基础上,结合吡喹酮自身的结构特点和性质,以~3H标记为探针标记吡喹酮,并与日本血吸虫成虫cDNA文库杂交,通过放射性X射线曝光检测探针放射性信号,获得与药物结合的阳性克隆。挑出阳性克隆,测序并对基因序列分析。结果显示通过筛选找到7个阳性克隆,测序结果表明这些阳性克隆分别代表5个基因。比对结果表明,其中一个阳性克隆为日本血吸虫细胞色素氧化酶,另一个克隆为日本血吸虫蛋白SJCHGC02820,其余为未知的新基因。提示利用改良Drug-Western法,获得与药物吡喹酮结合的融合表达蛋白。该改良Drug-Western法的建立为结构特殊的药物筛选药靶提供了新的方法。
三、日本血吸虫Ca~(2+)离子通道变异型β亚基基因的生物学特征
吡喹酮作用蛋白质组的信息以及血吸虫Ca~(2+)离子通道电生理学的研究结果提示日本血吸虫Ca~(2+)离子通道变异型β亚基(SjCavβvar)可能与吡喹酮的作用机制有关。本部分着重研究SjCavβvar在吡喹酮不同敏感期(成虫和童虫)的差异表达,以及Ca~(2+)离子通道β亚基基因在吡喹酮敏感性不同的物种间的差异。本研究分别利用系统进化树分析种间差异,Real time PCR定量检测转录水平的变化,Western blot分析蛋白水平差异,间接免疫荧光观察蛋白在组织中的定位。系统进化分析结果显示吡喹酮敏感性不同的生物之间的Ca~(2+)离子通道β亚基之间存在差异,相似性较低。该基因在成虫和童虫两个发育期的转录水平无明显差异,但相应的编码蛋白仅在成虫蛋白组中得到鉴定。SjCavβvar特异性分布在成虫体被和肠管,而在童虫中没有检测到荧光信号。因此,日本血吸虫Ca~(2+)离子通道变异型β亚基在吡喹酮敏感性发育期成虫有特异性表达,在组织中的分布位置可能是吡喹酮首先攻击的靶部位,而在童虫期低表达支持了已知的药物效应。因而,日本血吸虫Ca~(2+)离子通道变异型β亚基具备吡喹酮靶蛋白的特征,较低的相似性有可能使它成为新药潜在的药靶。
四、日本血吸虫Ca~(2+)离子通道变异型β亚基BID区域融合蛋白功能分析
日本血吸虫Ca~(2+)离子通道变异型β亚基BID区域对于调控门控通道的药物敏感性十分重要。本研究旨在分析日本血吸虫变异型β亚基BID区域融合表达蛋白(rSjccβkd)4个方面的功能,包括rSjccβkd与吡喹酮的结合力、rSjccβkd对吡喹酮的阻断作用、rSjccβkd抗血清对成虫的影响以及rSjccβkd免疫保护作用。利用放射性配基受体结合法,通过测定放射性计数(DPM,每分钟衰减率)确定变性及复性rSjccβkd与吡喹酮的结合力;体外培养体系中,观察分别加入rSjccβkd及其免疫血清后,对暴露于吡喹酮的成虫的挛缩、活动、死亡状态的影响及虫体体被的变化;对rSjccβkd蛋白免疫保护性进行分析。受体结合分析结果表明rSjccβkd可与吡喹酮特异性结合,复性蛋白显著高于变性蛋白3倍;rSjccβkd不能直接拮抗吡喹酮抗虫作用;暴露于rSjccβkd的免疫兔血清与吡喹酮组的死亡成虫数要比单独暴露于吡喹酮组的死亡数增加1/3;rSjccβkd的动物保护试验表明具有一定的免疫保护效果,减虫率为24.7%,减卵率为16.7%。结果提示放射性配基受体结合分析可以作为体外筛选药靶蛋白简便有效的方法;rSjccβkd的免疫血清对吡喹酮抗虫具有协同作用。
Schistosomiasis is recognized as one of the major global public health problems. Chemotherapy is an important measure for control the disease and reducing the prevalence of schistosomiasis.At present,praziquantel(PZQ) is the only drug for the treatment of schistosomiasis caused by five main human schistosome species.In spite of several studies have been undertaken on the mechanism of PZQ action,the molecular target of PZQ has not yet been defined.We intended to investigate the molecular target of PZQ and provide some clues as to finding new antischistosome drug.
1.Isolation,identification and analysis of differentially expressed proteins of Schistosoma japonicum proteomics between the treated group with PZQ and the untreated
At first,we performed the isolation and identification of differentially expressed proteins of Schistosoma japonicum proteomics from each group using two-dimensional-nano-liquid chromatography coupled by tandem mass spectrometry (2D-nano-LC-MS/MS).The database was established for each group.There 437 proteins based on 1431 peptides were identified and 253 proteins were annotated with known function in the control group.In the other group 73 proteins based on 2117 peptides were identified and 73 proteins were marked with function.There were 16 proteins found in both the control and the treated group.The number of total protein category of the treated group was significantly less than that of the control,in which a series of molecules involved in cellular metabolism,transcriptional/translational regulation were expressed differentially between the control and the treated.The statistics analysis showed there were 12 significantly up-regulated proteins and 4 significantly down-regulated proteins in the treated compared with the control.The former were cytoskeleton and motor proteins,response stress and chaperones, intracellular signal molecules,on the other hand,the latter were molecules of metabolism and regulation.In addition,the tegument proteins obviously changed in level and category between the control and the treated group.The result indicated there was significant difference in protein level between the two groups.It is suggested that PZQ can increased or inhabited the expression of certain genes of Schistosoma japonicum.The expressed differentially proteins may be related to the mode of PZQ action and provide some potential target for PZQ,and also permit the identification of protein candidates for the development of new targets for drug against schistosomiasis.
2.Screening the target-protein gene of PZQ antischistosoma using improved Drug-Western method from cDNA Library
Drug-Western method is a novel and convenient method to isolate genes of drug-binding proteins directly from a cDNA expression library.The combination of drug and marker molecule acted as probe,then the probe was detected using secondary antibody labeled.The positive clones obtained was separated,sequenced and expressed so as to study the function and structure of the gene.Based on structure and characteristics of PZQ,we improved the Drug-Western method:PZQ labeled ~3H was regarded as probe directly to screen cDNA expression library of schistosoma. After probing,the radioactive signal was detected by X-ray.The positive clones were obtained and the corresponding gene was sequenced and aligned.The results showed 7 positive clones belonged to 5 genes:one of them encodes cytochrome c oxidase, another was Schistosoma japonicum special protein with unknown function (SJCHGC02820),and the other three were new genes.The drug-binding proteins were gained by screening the genes of drug-binding proteins directly from a cDNA expression library of schistosoma using improved Drug-Western method.The improved method provides a new approach for screening drug target of the specific structure drug.
3.Biocharacteristics of schistosome voltage-gated calcium channel variantβsubunit
The result of PZQ proteomics analysis and the electrophysiological study suggested schistosome voltage-gated calcium channelβsubunit may be related to mode of PZQ.The expressed level was investigated in the PZQ-sensitive(adult worm) and PZQ-insensitive(schistosomula) stages.The sequence of theβsubunits were aligned in different species which are distinct in sensitivity to PZQ.The difference of the gene among species was analyzed using phylogenetic tree.We examined the transcript and protein levels of the gene by real time-PCR and Western blot analysis, and localized the encoding protein in the adult worm and schistosomula by indirect fluorescent-antibody assay.The phylogenetic analysis showed the variant and the conventionalβsubunits tended to separate,the former only was found in PZQ-sensitive parasites and the similarity was relatively low.Western blot analysis indicated the encoding protein could be detected in the soluble protein of adult worm rather than schistosomula.However,the real time-PCR revealed that the transcript levels did not express differentially in the adult worm and schistosomula.The immunolocalization showed the encoding protein located in the tegument,gut epithelial tissues,parenchyma and vitelline gland of adult worms,but the fluorescent signal was not detected in schistosomula.The findings provided the evidence for the known pharmacological effects of the drug.The results revealed the distribution of SjCavβvar may be target tissue that was firstly attacked by PZQ.Therefore, SjCavβvar played a role in drug action and may be the target for PZQ.Thus,the relatively low overall similarity to humanβ1-β4subunits(38.6%-41.4%) makes it a potential target for the development of new drugs.
4.Functional analysis onβinteraction domain of schistosome voltage-gated calcium channel variantβsubunit
Theβinteraction domain(BID) of schistosome voltage-gated calcium channel variantβsubunit is important to regulate sensitivity of voltage-gated calcium channel to drug.The recombinant BID protein(rSjccβkd) of schistosome voltage-gated calcium channel variantβsubunit was firstly expressed and refolded.The aims of study were(1) to detect the binding capacity of rSjccβkd with PZQ,(2) to observe effect of rSjccβkd to PZQ,(3) to investigate effect of antibody of rSjccβkd on aldult worms in vitro and(4) to examine the protective efficacy of rSjccβkd.The binding capacity of the rSjccβkd to PZQ was detected by radioactive counting(decay per minute,DPM).The worms were observed for contractility,motility,viability and the change in tugement was examined simultaneously after incubation with rSjccβkd protein and immune rabbit serum of rSjccβkd,respectively.The protective experiment of rSjccβkd was carried out in mice.The binding assay using ~3H-PZQ demonstrated specific binding of the PZQ to rSjccβkd.The DPM of refolded rSjccβkd binding to PZQ were almost 3 times higher than denatured rSjccβkd.The results implied that rSjccβkd have no effect on PZQ action on adult worms in vitro.When adult worms of Schistosoma japonicum were maintained in culture medium containing immune rabbit serum and exposed to PZQ,the number of died worms was 1/3 more than that only exposed to PZQ in the same observed period.The results revealed that rSjccβkd did not directly antagonize PZQ action,but the immune rabbit serum had synergetic effect to PZQ.The immunication test showed a certain extent protection with worm reduction rate of 24.7%and egg reduction rate of 16.7%.The radio-ligand receptor assays indicated that it was sample and effective method to screen drug target in vitro.
一、吡喹酮作用前后日本血吸虫蛋白质组的分离、鉴定与分析
利用二维-纳喷雾-液相色谱联用串联质谱技术对吡喹酮作用前后日本血吸虫的总蛋白质进行了分离和鉴定,构建了各自总蛋白信息数据库。结果表明,未经吡喹酮处理组(对照组)基于1431个肽段,鉴定到437种蛋白质,有明确功能注释的为278种;吡喹酮处理组基于2117个肽段,鉴定到73种蛋白质,有明确功能注释的为41种;其中,有16种功能明确的蛋白在两组中均能检测到。对比分析发现,吡喹酮处理组的蛋白种类明显少于正常对照组;在所有鉴定到的蛋白中,有16种发生明显上调(12种)或明显下调(4种)。参与代谢、DNA/RNA进程调节的蛋白明显下调。此外,尚有一些蛋白没有出现明显上调或明显下调,但存在差异性表达:上调蛋白主要是骨架蛋白、应激蛋白和分子伴侣、信号转导蛋白,下调蛋白主要是糖酵解和钙通路蛋白以及转录和翻译调节的蛋白质。根据蛋白在血吸虫组织中的定位分,体被蛋白在药物作用前后出现明显变化。实验结果表明参与细胞骨架构成分子、基因转录和翻译调控分子、应激反应的分子伴侣、代谢的酶类以及信息传导分子均呈现表达差异。因此,提示吡喹酮对日本血吸虫成虫的特定基因的表达具有促进或抑制作用。这些特定基因编码的蛋白与抗血吸虫药物的作用机制有关,是潜在的药物靶点,对研发新的抗血吸虫药物具有指导意义。
二、改良Drug-Western法筛选日本血吸虫cDNA文库的药靶基因
Drug-Western法是目前用于分离cDNA编码的药物靶标蛋白基因的一种便捷、有效的方法,即利用标记分子与药物结合作为探针,直接从cDNA表达文库筛选药物结合蛋白的基因,并利用二抗检测标记分子,获得阳性克隆,分离、测序,以获取目的蛋白进行结构和功能研究。本研究在文献报道Drug-Western法的基础上,结合吡喹酮自身的结构特点和性质,以~3H标记为探针标记吡喹酮,并与日本血吸虫成虫cDNA文库杂交,通过放射性X射线曝光检测探针放射性信号,获得与药物结合的阳性克隆。挑出阳性克隆,测序并对基因序列分析。结果显示通过筛选找到7个阳性克隆,测序结果表明这些阳性克隆分别代表5个基因。比对结果表明,其中一个阳性克隆为日本血吸虫细胞色素氧化酶,另一个克隆为日本血吸虫蛋白SJCHGC02820,其余为未知的新基因。提示利用改良Drug-Western法,获得与药物吡喹酮结合的融合表达蛋白。该改良Drug-Western法的建立为结构特殊的药物筛选药靶提供了新的方法。
三、日本血吸虫Ca~(2+)离子通道变异型β亚基基因的生物学特征
吡喹酮作用蛋白质组的信息以及血吸虫Ca~(2+)离子通道电生理学的研究结果提示日本血吸虫Ca~(2+)离子通道变异型β亚基(SjCavβvar)可能与吡喹酮的作用机制有关。本部分着重研究SjCavβvar在吡喹酮不同敏感期(成虫和童虫)的差异表达,以及Ca~(2+)离子通道β亚基基因在吡喹酮敏感性不同的物种间的差异。本研究分别利用系统进化树分析种间差异,Real time PCR定量检测转录水平的变化,Western blot分析蛋白水平差异,间接免疫荧光观察蛋白在组织中的定位。系统进化分析结果显示吡喹酮敏感性不同的生物之间的Ca~(2+)离子通道β亚基之间存在差异,相似性较低。该基因在成虫和童虫两个发育期的转录水平无明显差异,但相应的编码蛋白仅在成虫蛋白组中得到鉴定。SjCavβvar特异性分布在成虫体被和肠管,而在童虫中没有检测到荧光信号。因此,日本血吸虫Ca~(2+)离子通道变异型β亚基在吡喹酮敏感性发育期成虫有特异性表达,在组织中的分布位置可能是吡喹酮首先攻击的靶部位,而在童虫期低表达支持了已知的药物效应。因而,日本血吸虫Ca~(2+)离子通道变异型β亚基具备吡喹酮靶蛋白的特征,较低的相似性有可能使它成为新药潜在的药靶。
四、日本血吸虫Ca~(2+)离子通道变异型β亚基BID区域融合蛋白功能分析
日本血吸虫Ca~(2+)离子通道变异型β亚基BID区域对于调控门控通道的药物敏感性十分重要。本研究旨在分析日本血吸虫变异型β亚基BID区域融合表达蛋白(rSjccβkd)4个方面的功能,包括rSjccβkd与吡喹酮的结合力、rSjccβkd对吡喹酮的阻断作用、rSjccβkd抗血清对成虫的影响以及rSjccβkd免疫保护作用。利用放射性配基受体结合法,通过测定放射性计数(DPM,每分钟衰减率)确定变性及复性rSjccβkd与吡喹酮的结合力;体外培养体系中,观察分别加入rSjccβkd及其免疫血清后,对暴露于吡喹酮的成虫的挛缩、活动、死亡状态的影响及虫体体被的变化;对rSjccβkd蛋白免疫保护性进行分析。受体结合分析结果表明rSjccβkd可与吡喹酮特异性结合,复性蛋白显著高于变性蛋白3倍;rSjccβkd不能直接拮抗吡喹酮抗虫作用;暴露于rSjccβkd的免疫兔血清与吡喹酮组的死亡成虫数要比单独暴露于吡喹酮组的死亡数增加1/3;rSjccβkd的动物保护试验表明具有一定的免疫保护效果,减虫率为24.7%,减卵率为16.7%。结果提示放射性配基受体结合分析可以作为体外筛选药靶蛋白简便有效的方法;rSjccβkd的免疫血清对吡喹酮抗虫具有协同作用。
Schistosomiasis is recognized as one of the major global public health problems. Chemotherapy is an important measure for control the disease and reducing the prevalence of schistosomiasis.At present,praziquantel(PZQ) is the only drug for the treatment of schistosomiasis caused by five main human schistosome species.In spite of several studies have been undertaken on the mechanism of PZQ action,the molecular target of PZQ has not yet been defined.We intended to investigate the molecular target of PZQ and provide some clues as to finding new antischistosome drug.
1.Isolation,identification and analysis of differentially expressed proteins of Schistosoma japonicum proteomics between the treated group with PZQ and the untreated
At first,we performed the isolation and identification of differentially expressed proteins of Schistosoma japonicum proteomics from each group using two-dimensional-nano-liquid chromatography coupled by tandem mass spectrometry (2D-nano-LC-MS/MS).The database was established for each group.There 437 proteins based on 1431 peptides were identified and 253 proteins were annotated with known function in the control group.In the other group 73 proteins based on 2117 peptides were identified and 73 proteins were marked with function.There were 16 proteins found in both the control and the treated group.The number of total protein category of the treated group was significantly less than that of the control,in which a series of molecules involved in cellular metabolism,transcriptional/translational regulation were expressed differentially between the control and the treated.The statistics analysis showed there were 12 significantly up-regulated proteins and 4 significantly down-regulated proteins in the treated compared with the control.The former were cytoskeleton and motor proteins,response stress and chaperones, intracellular signal molecules,on the other hand,the latter were molecules of metabolism and regulation.In addition,the tegument proteins obviously changed in level and category between the control and the treated group.The result indicated there was significant difference in protein level between the two groups.It is suggested that PZQ can increased or inhabited the expression of certain genes of Schistosoma japonicum.The expressed differentially proteins may be related to the mode of PZQ action and provide some potential target for PZQ,and also permit the identification of protein candidates for the development of new targets for drug against schistosomiasis.
2.Screening the target-protein gene of PZQ antischistosoma using improved Drug-Western method from cDNA Library
Drug-Western method is a novel and convenient method to isolate genes of drug-binding proteins directly from a cDNA expression library.The combination of drug and marker molecule acted as probe,then the probe was detected using secondary antibody labeled.The positive clones obtained was separated,sequenced and expressed so as to study the function and structure of the gene.Based on structure and characteristics of PZQ,we improved the Drug-Western method:PZQ labeled ~3H was regarded as probe directly to screen cDNA expression library of schistosoma. After probing,the radioactive signal was detected by X-ray.The positive clones were obtained and the corresponding gene was sequenced and aligned.The results showed 7 positive clones belonged to 5 genes:one of them encodes cytochrome c oxidase, another was Schistosoma japonicum special protein with unknown function (SJCHGC02820),and the other three were new genes.The drug-binding proteins were gained by screening the genes of drug-binding proteins directly from a cDNA expression library of schistosoma using improved Drug-Western method.The improved method provides a new approach for screening drug target of the specific structure drug.
3.Biocharacteristics of schistosome voltage-gated calcium channel variantβsubunit
The result of PZQ proteomics analysis and the electrophysiological study suggested schistosome voltage-gated calcium channelβsubunit may be related to mode of PZQ.The expressed level was investigated in the PZQ-sensitive(adult worm) and PZQ-insensitive(schistosomula) stages.The sequence of theβsubunits were aligned in different species which are distinct in sensitivity to PZQ.The difference of the gene among species was analyzed using phylogenetic tree.We examined the transcript and protein levels of the gene by real time-PCR and Western blot analysis, and localized the encoding protein in the adult worm and schistosomula by indirect fluorescent-antibody assay.The phylogenetic analysis showed the variant and the conventionalβsubunits tended to separate,the former only was found in PZQ-sensitive parasites and the similarity was relatively low.Western blot analysis indicated the encoding protein could be detected in the soluble protein of adult worm rather than schistosomula.However,the real time-PCR revealed that the transcript levels did not express differentially in the adult worm and schistosomula.The immunolocalization showed the encoding protein located in the tegument,gut epithelial tissues,parenchyma and vitelline gland of adult worms,but the fluorescent signal was not detected in schistosomula.The findings provided the evidence for the known pharmacological effects of the drug.The results revealed the distribution of SjCavβvar may be target tissue that was firstly attacked by PZQ.Therefore, SjCavβvar played a role in drug action and may be the target for PZQ.Thus,the relatively low overall similarity to humanβ1-β4subunits(38.6%-41.4%) makes it a potential target for the development of new drugs.
4.Functional analysis onβinteraction domain of schistosome voltage-gated calcium channel variantβsubunit
Theβinteraction domain(BID) of schistosome voltage-gated calcium channel variantβsubunit is important to regulate sensitivity of voltage-gated calcium channel to drug.The recombinant BID protein(rSjccβkd) of schistosome voltage-gated calcium channel variantβsubunit was firstly expressed and refolded.The aims of study were(1) to detect the binding capacity of rSjccβkd with PZQ,(2) to observe effect of rSjccβkd to PZQ,(3) to investigate effect of antibody of rSjccβkd on aldult worms in vitro and(4) to examine the protective efficacy of rSjccβkd.The binding capacity of the rSjccβkd to PZQ was detected by radioactive counting(decay per minute,DPM).The worms were observed for contractility,motility,viability and the change in tugement was examined simultaneously after incubation with rSjccβkd protein and immune rabbit serum of rSjccβkd,respectively.The protective experiment of rSjccβkd was carried out in mice.The binding assay using ~3H-PZQ demonstrated specific binding of the PZQ to rSjccβkd.The DPM of refolded rSjccβkd binding to PZQ were almost 3 times higher than denatured rSjccβkd.The results implied that rSjccβkd have no effect on PZQ action on adult worms in vitro.When adult worms of Schistosoma japonicum were maintained in culture medium containing immune rabbit serum and exposed to PZQ,the number of died worms was 1/3 more than that only exposed to PZQ in the same observed period.The results revealed that rSjccβkd did not directly antagonize PZQ action,but the immune rabbit serum had synergetic effect to PZQ.The immunication test showed a certain extent protection with worm reduction rate of 24.7%and egg reduction rate of 16.7%.The radio-ligand receptor assays indicated that it was sample and effective method to screen drug target in vitro.
引文
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