CN105777877B - 登革病毒e蛋白阻断肽p4及其应用 - Google Patents
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Abstract
本发明涉及登革病毒E蛋白阻断肽P4及其应用。本发明通过对登革病毒感染宿主的关键E蛋白进行生物信息学分析，针对其关键区域ED‑III设计合成小分子肽P4，然后结合动力学实验和细胞实验，研究其与受体之间的亲和力，进而通过细胞学实验研究其在阻断病毒进入宿主细胞方面的作用。结果表明，小分子肽P4与受体整合素β3有较强亲和力，可显著抑制登革病毒感染宿主细胞，从而达到阻断登革病毒感染的目的。利用所述小分子肽P4制备抗登革病毒感染的药物及登革疫苗，可实现登革病毒的有效防治。
Description
技术领域
本发明涉及生物医药工程领域，具体地说，涉及一种登革病毒E蛋白阻断肽P4及其应用。
背景技术
登革病毒(DENV)属于黄病毒科黄病毒属的单股正链RNA病毒，包括四种血清型DENV1-4，DENV基因组约11kb，由1个开放读码框编码包膜糖蛋白(E)、膜蛋白(M)和衣壳蛋白(C)三种结构蛋白以及NS1、NS2a、NS2b、NS3、NS4a、NS4b和NS5七种非结构蛋白(KuadkitkanA,Wikan N,Fongsaran C,Smith DR:Identification and characterization ofprohibitin as a receptor protein mediating DENV-2entry into insectcells.Virology 2010,406(1):149-161)。病毒表面的包膜蛋白E蛋白是DENV病毒体上的包膜糖蛋白和最大的结构蛋白，在病毒吸附、与宿主细胞膜融合以及病毒组装过程中具有重要的作用，是DENV吸附于靶细胞与受体相互作用的病毒表面特异性吸附蛋白(Miller JL,de Wet BJ,Martinez-Pomares L,Radcliffe CM,Dwek RA,Rudd PM,Gordon S:Themannose receptor mediates dengue virus infection of macrophages.PLoS Pathog2008,4(2):e17.)。DENV包膜糖蛋白E是由495～501个氨基酸残基组成的、分子量约为55～60kDa的糖蛋白，其结构分为三个功能区即E蛋白Domain-I、II和III(ED-I、II和III)。DENV糖蛋白E能够介导病毒与受体的结合及膜融合，同时含有诱发中和抗体的抗原决定簇，因而在DENV感染过程中发挥着重要作用。
目前关于E蛋白的研究主要集中于疫苗的研发，由登革病毒所致的登革热和重症登革热临床上还只能对症治疗，尚无特异性的抗病毒药物。
发明内容
本发明的目的是提供登革病毒E蛋白阻断肽P4及其应用。
本发明基于以下构思：病毒进入宿主细胞是其复制周期开始的第一步，也是决定病毒致病性的关键因素。研究发现，整合素β3可能是登革病毒感染的重要受体。通过开发特异性阻断肽或化合物，与DENV竞争结合受体整合素β3，进而阻断病毒进入细胞，从而达到抑制病毒感染的目的。
本发明人首次利用登革病毒感染宿主的关键E蛋白，通过生物信息学分析针对其关键区域ED-III设计合成小分子肽P4，然后结合动力学实验和细胞实验，研究其与受体之间的亲和力，进而通过细胞学实验研究其在阻断病毒进入宿主细胞方面的作用。结果表明，该小分子肽与受体整合素β3有较强亲和力，可显著抑制登革病毒感染宿主细胞，例如HUVEC(人脐静脉内皮细胞)。
为了实现本发明目的，本发明提供的登革病毒E蛋白阻断肽P4，所述阻断肽P4的氨基酸序列如SEQ ID NO:1所示，或该序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列。
本发明还提供所述阻断肽P4在制备抗登革病毒感染的药物及登革疫苗中的应用。
本发明还提供一种抗登革病毒感染的药物或药物组合物，其有效成分为所述阻断肽P4。
所述药物或药物组合物中还包括药学上可接受的载体或稀释剂。
本发明还提供一种登革疫苗或疫苗组合物，其有效成分为所述阻断肽P4。
所述疫苗或疫苗组合物中还包括药学上可接受的载体或稀释剂。
本发明进一步提供所述阻断肽P4在预防及治疗登革热和重症登革热中的应用。
将本发明的阻断肽P4在登革病毒感染前2小时与宿主细胞预孵育，可大大降低病毒的感染率，因此对于登革热流行区的人群，如提前服用由阻断肽P4制备的药物可大大降低登革病毒的感染的机率。
本发明提供的阻断肽P4，可通过与登革病毒受体整合素β3的结合，进而阻断登革病毒与宿主细胞的作用位点，从而达到抑制登革病毒感染的目的。小分子肽P4对细胞均无毒副作用，可用于登革病毒的防治。
附图说明
图1为本发明实施例1中SPR法研究小分子肽P4与登革病毒的受体整合素β3亲和力结果。
图2为本发明实施例2中利用MTT法测定小分子肽P4的细胞毒性结果。
图3为本发明实施例3中采用空斑试验测定胞内病毒滴度的结果。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段，所用原料均为市售商品。
以下实施例中小分子肽P4(SEQ ID NO:1)由上海强耀生物科技有限公司合成。
实施例1小分子肽P4与登革病毒的受体整合素β3亲和力研究
本实施例中采用SPR法研究小分子肽与登革病毒的受体整合素β3亲和力。用磷酸缓冲液(PBS，pH7.4)将小分子肽P4配制成一定浓度溶液。用磷酸缓冲液将整合素ανβ3(货号：RD 3050-av-050)缓冲液置换后配制成所需浓度。将整合素ανβ3高偶联到CM5芯片(货号：GE 29104988)上，小分子肽P4作为流动相进行亲和力测定。利用Biacore T200进行亲和力分析，结果表明，小分子肽P4与整合素β3的解离常数为9.09E-5，说明它与整合素β3具有较强亲和力(图1)。
实施例2小分子肽P4的细胞毒性实验
本实施例中采用MTT法测定小分子肽的细胞毒性。
用细胞培养基(含2％血清的DMEM，11965092,GIBCO)稀释小分子肽P4配制成一定浓度溶液。MTT(3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide)购自Sigma公司(货号：SIGMA M5655)。所用细胞为HUVEC(人脐静脉内皮细胞)。
具体步骤如下:待HUVEC细胞长至80％～90％时，弃掉原培养基，换成加入药物的维持液每孔200μl。两种药物均设6个梯度，即5μM、10μM、20μM、40μM、80μM和100μM,37℃5％CO2培养24h。24h后，弃掉含药物的维持液，换为含有10％MTT的维持液，每孔200μl，37℃5％CO2，避光孵育4h。4h后，800g离心10min，弃掉孔中的MTT维持液，加入200μl的DMSO，37℃100g转速摇床孵育10min促进细胞溶解。待细胞溶解后，使用酶标仪检测在570nm波长下的吸光度。结果显示，所有浓度的小分子肽均未见对细胞的毒性作用(图2)。
实施例3小分子肽P4对登革病毒感染的抑制实验
用细胞培养基(含2％血清的DMEM，11965092,GIBCO)稀释小分子肽P4配制成一定浓度溶液。所用细胞为HUVEC(人脐静脉内皮细胞)。
具体步骤如下:将HUVEC细胞，接种入48孔板，每孔约5×104个细胞。37℃5％CO2培养16h。弃去培养基，用PBS洗涤一遍，用含2％FBS的1640培养基稀释小肽，分别稀释至梯度为40μM、20μM、10μM、5μM、2.5μM、1.25μM和0.3μM。每孔100μl，设空白对照和阳性对照，37℃5％CO2培养2h。2h后，每孔加10μl病毒液(MOI＝2)，37℃5％CO2培养1h。1h后分别收集上清和细胞(用3M的甘氨酸除去胞外病毒)，放入-80℃冰箱冻存。采用空斑试验(Plaque法)测定胞内病毒滴度。结果显示，小分子肽P4可显著抑制登革病毒进入宿主细胞(图3)。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
Claims (4)
1.登革病毒E蛋白阻断肽P4，其特征在于，所述阻断肽P4的氨基酸序列如SEQ ID NO:1所示。
2.权利要求1所述阻断肽P4在制备抗登革病毒感染的药物中的应用。
3.一种抗登革病毒感染的药物或药物组合物，其特征在于，其有效成分为权利要求1所述的阻断肽P4。
4.根据权利要求3所述的药物或药物组合物，其特征在于，还包括药学上可接受的载体或稀释剂。
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