CN110215458A - 矢车菊素-3-O-葡萄糖苷在制备α-突触核蛋白聚集抑制剂中的用途 - Google Patents
矢车菊素-3-O-葡萄糖苷在制备α-突触核蛋白聚集抑制剂中的用途 Download PDFInfo
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Abstract
本发明提出矢车菊素‑3‑O‑葡萄糖苷制备α‑突触核蛋白聚集抑制剂中的用途,属于医药、保健品或食品技术领域。矢车菊素‑3‑O‑葡萄糖苷在制备用于预防和/或治疗以α‑突触核蛋白的聚集沉淀为特征的疾病的药物、保健品或食品中的用途。本发明提出的矢车菊素‑3‑O‑葡萄糖苷在抑制α‑突触核蛋白聚集中的用途,可有效抑制了α‑突触核蛋白聚集,有效预防PD的发生和延缓PD的发展。并且有效抑制了α‑突触核蛋白聚集体对细胞产生的毒性,抑制α‑突触核蛋白的聚集及其构象变化过程,是治疗和预防帕金森的理想药物。
Description
技术领域
本发明属于医药、保健品或食品技术领域,尤其涉及矢车菊素-3-O-葡萄糖苷在制备α-突触核蛋白聚集抑制剂中的用途。
背景技术
帕金森综合症(Parkinson’s disease,PD)为一种常见的中老年人神经系统变性疾病。主要临床特征为肌肉震颤、肌强直及运动迟缓。研究发现,大部分PD患者主要病变发生在中脑黑质和纹状体中,其内存在路易小体Lewy体(LB)或路易轴突Lewy轴突(LN) 的细胞内包涵体。而正常人体内易于聚集的α-突触核蛋白(α-Syn)发生聚集形成的LB 或LN,从而产生的基因点突变和扩增,是导致家族性帕金森综合症发生的主要原因。
越来越多的研究表明α-Syn单体没有毒性,但其聚集体通过多种作用方式产生细胞毒性,引起神经元变性甚至凋亡,脑内胶质细胞活性增高,从而激发体内炎症反应。有研究表明,这些症状的出现均先于淀粉样斑块的形成,与病人体内的可溶性寡聚体的浓度密切相关。因此,目前将α-Syn聚集以及可溶性寡聚体的形成视为研究重点。
由于α-Syn的聚集沉淀与PD密切相关,如何阻止α-Syn的聚集沉淀就成为当前研究者关注的热点问题。从α-Syn的生成和构象转换角度可以采用以下三种方法和手段来治疗PD:1)稳定淀粉样蛋白的天然单体状态;2)靶向淀粉样蛋白通路上的不同中间体并阻断其转化为原纤维;3)改变聚集途径,促进非淀粉样蛋白聚集体的生成。由于α-Syn 自身具有生物体所必需的生理功能,所以目前最安全和可靠的治疗PD的方法就是稳定α-Syn初始结构及抑制其聚集。
现有的聚集抑制剂主要分为有机小分子类、多肽类、蛋白及酶类、抗体类、纳米颗粒类和金属鳌合剂类等。近年来,随着PD研究的深入,由于天然产物小分子,具有丰富来源,副作用小,适合长期服用等特点,逐渐得到研究人员关注。因此,从天然产物中筛选有效的α-Syn聚集抑制剂,是开发PD新药的有效途径。
发明内容
本发明提出矢车菊素-3-O-葡萄糖苷在制备α-突触核蛋白聚集抑制剂中的用途,并将其用于治疗疾病的使用,有效防止PD的发生。
本发明提出矢车菊素-3-O-葡萄糖苷在制备α-突触核蛋白聚集抑制剂中的用途。
进一步地,矢车菊素-3-O-葡萄糖苷在制备用于预防和/或治疗以α-突触核蛋白的聚集沉淀为特征的疾病的药物、保健品或食品中的用途。
进一步地,疾病为帕金森综合症。
进一步地,矢车菊素-3-O-葡萄糖苷以水分散体系存在。
进一步地,矢车菊素-3-O-葡萄糖苷以浓度为2.5-100μM的矢车菊素-3-O-葡萄糖苷水分散体系存在。
进一步地,矢车菊素-3-O-葡萄糖苷以浓度为5-50μM的矢车菊素-3-O-葡萄糖苷水分散体系存在。
本发明的矢车菊素-3-O-葡萄糖苷在制备α-突触核蛋白聚集抑制剂中具有以下优势:
本发明提出的矢车菊素-3-O-葡萄糖苷作为天然产物小分子,毒副作用小,是理想的聚集抑制剂,可抑制α-突触核蛋白聚集,有效防止PD的发生或延缓PD的发展。可用于制备预防和/或治疗以α-突触核蛋白的聚集沉淀为特征的疾病的药物、保健品或食品。在一定浓度范围内,随着矢车菊素-3-O-葡萄糖苷浓度增加,抑制效果越好;并且有效抑制了α-突触核蛋白聚集体对细胞产生的毒性;抑制蛋白向二级结构的β-折叠结构转换;改变了纤维聚集体的形貌。
附图说明
构成本发明的一部分的附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。在附图中:
图1为实施例1中不同浓度矢车菊素-3-O-葡萄糖苷与α-Syn共培养不同时间后培养物的ThT荧光图;
图2为实施例2中不同浓度矢车菊素-3-O-葡萄糖苷与α-Syn共培养9d后培养物对PC12的MTT细胞毒性图;
图3为实施例3中不同浓度矢车菊素-3-O-葡萄糖苷与α-Syn共培养9d后培养物的二级结构变化图;
图4为实施例1中100μΜ矢车菊素-3-O-葡萄糖苷与α-Syn共培养10d后培养物的原子力显微镜(AFM)图。
具体实施方式
需要说明的是,在不冲突的情况下,本发明中的实施例及实施例中的特征可以相互组合。
本发明实施例提出矢车菊素-3-O-葡萄糖苷在抑制α-突触核蛋白聚集中的用途。
矢车菊素-3-O-葡萄糖苷结构式如下:
矢车菊素-3-O-葡萄糖苷是花色苷类的一种,主要存在于黑米,黑豆,紫薯等植物中,可用于抑制体内外肺癌生长。而本申请提出矢车菊素-3-O-葡萄糖苷在抑制α-突触核蛋白 (α-Syn)聚集中的用途。能够有效抑制α-Syn的聚集,为α-Syn聚集抑制剂的研究提供了新思路。
α-Syn是一种丰富的突触前蛋白,它由高度可溶性的140个氨基酸构成,分子量为19kDa。包括三个结构域:N端结构域(残基1-60),NAC结构域(残基61-95)和C 端结构域(残基96-140)。
其中,N端结构域(残基1-60)可获得α-螺旋结构,易形成两性α-螺旋类似载脂蛋白的脂质结合区域,是介导α-Syn与细胞脂质膜结合的区域;NAC结构域的非淀粉样成分(残基61-95)具有高度疏水性,主要参与α-Syn聚集;C端结构域(残基96-140)具有高度酸性且无特定结构。
由于α-Syn含有氨基酸数目较多,聚集过程复杂且缓慢,需要一周甚至几周才能达到稳定的平台期,最终形成空间结构复杂多变的“U”型二级结构,并在脑内发生沉积。
而矢车菊素-3-O-葡萄糖苷主要用于抑制α-Syn聚集,破坏蛋白质的“U”型二级结构,但是由于矢车菊素-3-O-葡萄糖苷的分子结构相对较小,所以容易进入U型结构的内腔和外部中,与不同的氨基酸结合,从而达到较好的抑制效果。
矢车菊素-3-O-葡萄糖苷与α-Syn相互作用的的关键残基是疏水残基,其侧链也与矢车菊素-3-O-葡萄糖苷发生疏水作用形成氢键,可以在一定程度上扰乱α-Syn的盐桥,同时形成氢键,导致蛋白质构象的内部作用力减弱,结构变得不稳定,链与链之间的间隙变大,聚集性开始降低。这两种相互作用的协同效应对矢车菊素-3-O-葡萄糖苷与α-Syn的结合起到了很大作用。
本发明实施例中,α-Syn通常定位于神经元突触前端,在中枢神经系统中表达。
本发明一实施例中,矢车菊素-3-O-葡萄糖苷在制备用于预防和/或治疗以α-突触核蛋白的聚集沉淀为特征的疾病的药物、保健品或食品中的用途。本发明充分利用矢车菊素 -3-O-葡萄糖苷作为天然小分子,具有丰富来源,毒副作用小,适合长期服用等特点,将其作为α-突触核蛋白聚集抑制剂分别用于药物、保健品或食品的新开发。
本发明一优选实施例中,矢车菊素-3-O-葡萄糖苷作为α-突触核蛋白聚集抑制剂在制备药物中的用途。由于矢车菊素-3-O-葡萄糖苷毒副作用小,将其用于药物的开发,患者能够更快的适应,副作用较低。
进一步地,矢车菊素-3-O-葡萄糖苷作为α-突触核蛋白聚集抑制剂在制备预防和/或治疗帕金森综合症(PD)的药物中的用途。大部分PD患者是由于中脑黑质和纹状体中内路易小体Lewy体(LB)或路易轴突Lewy轴突(LN)的细胞内包涵体,而α-Syn发生聚集形成的LB或LN,为中脑黑质神经元死亡。可见,本发明实施例提供的用途进一步促进了治疗帕金森综合症的研究进展。
具体而言,矢车菊素-3-O-葡萄糖苷可以以水分散体系存在。换言之,矢车菊素-3-O- 葡萄糖苷可以以水分散体系的形式服用,如针剂、注射液、软胶囊、饮料、口服液等形式。
具体而言,矢车菊素-3-O-葡萄糖苷以浓度为2.5-100μM的矢车菊素-3-O-葡萄糖苷水分散体系存在。优选的,矢车菊素-3-O-葡萄糖苷以浓度为5-50μM的矢车菊素-3-O-葡萄糖苷水分散体系存在。具体可以为2.5μM、5μM、20μM、25μM、40μM,50μM、80μM、 100μM等。
本发明一优选实施例中,矢车菊素-3-O-葡萄糖苷作为α-突触核蛋白聚集抑制剂在制备保健品或食品中的用途。优选的,矢车菊素-3-O-葡萄糖苷作为α-突触核蛋白聚集抑制剂在制备预防帕金森综合症的保健品或食品中的用途。保健品和食品对人体的毒副作用相对较小,将其用于预防PD具有良好效果。
下面参照具体实施例进一步阐述矢车菊素-3-O-葡萄糖苷在抑制α-突触核蛋白聚集中的用途。
实施例1不同浓度矢车菊素-3-O-葡萄糖苷与α-Syn共培养不同时间后培养物的ThT 荧光强度变化
首先,重组α-Syn蛋白大肠杆菌菌株由课题组前期构建,经诱导表达、纯化,最终获得纯度达95%以上的α-Syn蛋白,冻干后置于-20℃储存,得纯化冻干的α-Syn。然后纯化冻干的α-Syn中加入TBS缓冲溶液,超声10min使之充分溶解,16000g离心20min 去除已经发生聚集的蛋白质,然后取上清的75%,测定蛋白浓度。
称取16mgThT溶于50mL Tris-HCl缓冲液(TBS,Tris Buffered Saline,PH=7.4,其中Tris buffer浓度为20mM,NaCl浓度为150mM)配制1mM ThT母液。
称取0.4mg矢车菊素-3-O-葡萄糖苷溶于1mL过膜水中获得浓度为1mM的矢车菊素-3-O-葡萄糖苷母液,避光保存。
将α-Syn母液与矢车菊素-3-O-葡萄糖苷按梯度稀释,获得矢车菊素-3-O-葡萄糖苷终浓度分别为0μM,25μM,50μM,100μMα-Syn溶液(此时溶液中的α-Syn的浓度为50 μM,ThT的浓度为250μM)。将四种溶液在37℃进行原位培养。
测定其在440nm处激发波长和480nm处发射波长下的荧光强度,激发和发射缝宽均为5nm,扫描速度为100nm/min,扫描结果均为3次平均值。将480nm处的荧光强度对时间作图,结果如图1所示。
由图1可知,α-Syn的ThT荧光图为“S”形曲线,存在滞后期(0~144h),快速增长期(144h~216h)和稳定平台期(216h~)。加入矢车菊素-3-O-葡萄糖苷后α-Syn的ThT 荧光强度明显下降,且ThT荧光下降程度与加入的矢车菊素-3-O-葡萄糖苷的浓度呈正比,加入矢车菊素-3-O-葡萄糖苷的浓度越大,荧光抑制效果越强,说明矢车菊素-3-O-葡萄糖苷有效抑制了α-Syn的聚集。
实施例2用MTT方法检测不同浓度的矢车菊素-3-O-葡萄糖苷与α-Syn共培养9d后培养物对PC12的细胞毒性
细胞毒性实验中使用的细胞为鼠肾上腺嗜铬瘤细胞株(PC12)。
首先,取低分化细胞,用含有10%胎牛血清和1%青霉素-链霉素的RPMI-1640培养基进行培养,5%CO2,37℃培养。观察到PC12细胞在NGF诱导下长出较长的突起,成为高分化细胞后向培养瓶中加入含有0.25%胰酶的溶液对高分化细胞进行消化,再用含有10%胎牛血清和1%青霉素一链霉素的RPMI-1640培养基以适当浓度稀释细胞,以 5×104cell/孔的细胞浓度加入到96孔板,每孔90μL。5%CO2,37℃培养24h。
配制浓度为50μMα-Syn和矢车菊素-3-O-葡萄糖苷终浓度分别为5μM,10μM,50μM的α-Syn溶液(此时溶液中的α-Syn的浓度均为50μM),其中α-Syn的处理方法与实施例1相同,37℃培养9d。
将上述老化好的α-Syn和加入不同浓度的矢车菊素-3-O-葡萄糖苷的α-Syn溶液加入到已经培养24h的含有PC12的96孔板中,10μL/孔。空白对照孔中不加矢车菊素-3-O- 葡萄糖苷和α-Syn溶液,而加入PBS缓冲液10μL/孔。最终使加药孔每孔中矢车菊素-3-O- 葡萄糖苷终浓度为2.5μM,5μM,10μM,α-Syn的终浓度为5μM。细胞在培养箱中以5% CO2,37℃培养48h后,加入10μL/孔的MTT溶液,使得培养基中的MTT终浓度为0.5 mg/mL。5%CO2,37℃条件继续培养4h。
移除96孔板中溶液,每孔加入100μL的DMSO 37℃培养10min,检测570nm处吸光值。将培养基中不含α-Syn和矢车菊素-3-O-葡萄糖苷孔作为空白对照组,记为细胞活性为100%,然后将其作为对照计算加药组的细胞存活率(图2)。实验中每个矢车菊素 -3-O-葡萄糖苷浓度梯度设置6个复孔。由图2可知当只有α-Syn单独存在时,细胞存活率为45%。而加入不同浓度的矢车菊素-3-O-葡萄糖苷(2.5μM,5μM,10μM)后细胞存活率提高到48%、60%、78%,加入的矢车菊素-3-O-葡萄糖苷的浓度越大,毒性缓解作用越强,说明矢车菊素-3-O-葡萄糖苷能够有效抑制α-Syn产生的细胞毒性。
实施例3不同浓度矢车菊素-3-O-葡萄糖苷与α-Syn共培养9d后培养物的二级结构变化
配制矢车菊素-3-O-葡萄糖苷终浓度分别为0μΜ,50μM,100μM的α-Syn溶液500μL(此时溶液中的α-Syn的浓度均为50μM),其中α-Syn的处理方法与实施例1相同,37℃培养9d。
取500μL培养液加入光程0.1mm的CD检测池中进行检测,波长扫描范围是 190~260nm,带宽2nm,扫描速度是100nm/min,实验结果为三次扫描平均值,结果如图 3所示。由图3可得,当蛋白培养9d以后,只有蛋白的对照组形成明显的β-sheet结构,加入50μΜ的矢车菊素-3-O-葡萄糖苷以后,蛋白的β-sheet程度发生明显的降低;加入 100μM的矢车菊素-3-O-葡萄糖苷以后蛋白由β-sheet结构向α-螺旋转变。说明矢车菊素 -3-O-葡萄糖苷可以抑制蛋白的结构转变,抑制蛋白的聚集,并且抑制作用为浓度依赖性。
实施例4实施例1中100μΜ矢车菊素-3-O-葡萄糖苷与α-Syn共培养9d后培养物的AFM图
按照与实施例1相同的方法处理α-Syn分子,并配制含有浓度为100μΜ矢车菊素 -3-O-葡萄糖苷的α-Syn溶液,溶液中α-Syn的终浓度为50μM。将上述溶液于37℃,180 rpm条件下进行培养。
在不同培养时间下,取100μLα-Syn培养液,超声10min,在干净的培养皿中用双面胶固定好圆形铁片,再在圆形铁片上用双面胶固定好云母片,然后用透明胶带连续将云母片粘三次,去掉云母片的不干净层数。后用20μL的移液枪,取20μL超声好的样品滴在云母片上,待15min后,再用移液枪取1mL过膜水缓慢冲洗,后自然晾干。然后用原子力显微镜进行观察,检测电压为100KV,选取放大尺度为2μm的图像进行观察,结果如图4所示。
由图4可知,加入矢车菊素-3-O-葡萄糖苷后α-Syn聚集的速度和聚集体的形貌发生了变化。当培养时间为9d到达稳定平台期时,α-Syn单独培养组,出现了大量纤维聚集体(图A);加入100μM矢车菊素-3-O-葡萄糖苷组,则以小的寡聚体为主,并伴有小的短棒状聚集体(图B)。这说明矢车菊素-3-O-葡萄糖苷的存在改变了α-Syn聚集体的形貌,阻止了其向纤维的转化。
实施例5:矢车菊素-3-O-葡萄糖苷用于保健品的制备
重量份组成为(每份为0.01g):矢车菊素-3-O-葡萄糖苷1份、维生素C 10份、维生素H 10份、硫酸亚铁5份、氧化锌1份。
引用时加水1L冲服。
使用该保健品与α-Syn的制得的混合溶液进行荧光强度测试,与对照组(未添加矢车菊素-3-O-葡萄糖苷的保健品与α-Syn形成的溶液)进行比较,加入矢车菊素-3-O-葡萄糖苷后α-Syn的荧光强度明显下降,说明矢车菊素-3-O-葡萄糖苷有效抑制了α-Syn的聚集。
实施例6:矢车菊素-3-O-葡萄糖苷用于饮料的制备
重量份数为:矢车菊素-3-O-葡萄糖苷0.01份、柠檬酸50份、葡萄糖25份、水1000份。
通过溶解活性组分,混合,在85℃下搅拌1h,过滤,然后将所有组分填装进瓶中进行灭菌制得健康饮料。
使用该饮品与α-Syn的混合溶液进行荧光强度测试,与未添加矢车菊素-3-O-葡萄糖苷与α-Syn形成的溶液进行比较,加入矢车菊素-3-O-葡萄糖苷后α-Syn溶液的荧光强度明显下降,说明矢车菊素-3-O-葡萄糖苷有效抑制了α-Syn的聚集。
α-Syn聚集抑制剂是PD治疗新药开发的主要热点,通过抑制α-Syn聚集,从而预防或治疗PD的产生,并且相关文献(Entacapone and Tolcapone,Two CatecholO-Methyltransferase Inhibitors,Block Fibril Formation of-Synuclein andβ-Amyloidand Protect against Amyloid-induced Toxicity,THE JOURNAL OF BIOLOGICALCHEMISTRY,VOL.285,NO.20,pp.14941–14954,May 14,2010)中也曾报道α-Syn聚集抑制剂对治疗或预防PD有重要影响。本发明提出了矢车菊素-3-O-葡萄糖苷在制备抑制α- 突触核蛋白聚集的药物的用途,并将其应用于α-Syn聚集和细胞毒性抑制实验,已通过现场较佳实施例子进行了描述,相关技术人员明显能在不脱离本发明内容、精神和范围内对本文的方法进行改动或适当变更与组合,来实现本发明技术。
特别需要指出的是,所有相类似的替代和改动对本领域技术人员来说是显而易见的,他们都被视为包括在本发明精神、范围和内容中。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (6)
1.矢车菊素-3-O-葡萄糖苷在制备α-突触核蛋白聚集抑制剂中的用途。
2.根据权利要求1所述的用途,其特征在于,所述矢车菊素-3-O-葡萄糖苷在制备用于预防和/或治疗以α-突触核蛋白的聚集沉淀为特征的疾病的药物、保健品或食品中的用途。
3.根据权利要求1所述的用途,其特征在于,所述疾病为帕金森综合症。
4.根据权利要求1所述的用途,其特征在于,所述矢车菊素-3-O-葡萄糖苷以水分散体系存在。
5.根据权利要求1所述的用途,其特征在于,所述矢车菊素-3-O-葡萄糖苷以浓度为2.5-100μM的矢车菊素-3-O-葡萄糖苷水分散体系存在。
6.根据权利要求1所述的用途,其特征在于,所述矢车菊素-3-O-葡萄糖苷以浓度为5-50μM的矢车菊素-3-O-葡萄糖苷水分散体系存在。
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