CN104415739A - 苯乙烯-二乙烯苯医用树脂的应用 - Google Patents
苯乙烯-二乙烯苯医用树脂的应用 Download PDFInfo
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Abstract
苯乙烯-二乙烯苯医用树脂的应用，其树脂球密布微孔，孔径范围在70-140纳米；树脂球比表面积大于1000平米／克；树脂球微孔孔容大于6.000e-01cc／克；其特征在于：以该树脂作为电子云场力、gp120、gp41氨基酸保守序列靶标位点吸附剂架构，树脂内部以孔径及附加电荷为主，形成电子云场力；树脂表面包覆蛋白膜，载入gp120、gp41氨基酸保守序列特异性氨基酸短肽作为靶点探针。
Description
技术领域
本发明属于医用高分子材料，具体是一种电子云场力干预HIV受体基团二维动态结构的靶向吸附大孔径树脂颗粒及吸附柱的制备与应用。
背景技术
人类免疫缺陷综合症是一种人类免疫缺陷病毒感染后导致的以免疫系统损害为主疾病，艾滋病是累及全身多器官系统的疾病，皮肤粘膜、淋巴结、眼部、呼吸系统、消化系统、神经系统、泌尿系统等。除免疫系统病变，还包括多系统机会性感染(如病毒、细菌、真菌和原虫)和恶性肿瘤(包括卡波氏肉瘤、恶性淋巴瘤和子宫颈癌)，构成了艾滋病复杂的临床病理变化。2010年WHO报告全世界存活HIV携带者及艾滋病患者共3400万，新感染270万，全年死亡180万人。每天有超过7000人新发感染，全世界各地区均有流行，但97％以上在中、低收入国家，尤以非洲为重。中国CDC估计，截止至2011年底，我国存活HIV携带者及艾滋病患者约78万人，全年新发感染者4.8万人，死亡2.8万人。疫情已覆盖全国所有省、自治区、直辖市，目前我国面临艾滋病发病和死亡的高峰期，且已由吸毒、暗娼等高危人群开始向一般人群扩散。
HIV属于逆转录病毒科慢病毒属中的人类慢病毒组，分为1型和2型，目前世界范围内主要流行HIV-1，HIV-1为20面体立体对称，直径约100～120nm球形颗粒，由核心和包膜两部分组成，核心包括两条单股RNA链、核心结构蛋白和病毒复制所必须的酶类，含有逆转录酶、整合酶和蛋白酶。HIV-1感染人体后，选择性的吸附于靶细胞的CD4受体上，在辅助受体的帮助下进入宿主细胞。经环化及整合、转录及翻译、装配、成熟及出芽，形成成熟的病毒颗粒。HIV需借助于易感细胞表面的受体进入细胞，包括第一受体和第二受体。HIV进入人体后，在24-48小时内到达局部淋巴结，约5天左右在外周血中可以检测到病毒成份。继而产生病毒血症，导致急性感染。由于人体免疫系统主要通过针对HIV蛋白的各种特异性抗体、特异性CD4+T淋巴细胞免疫反应和CTL直接或分泌各种细胞因子(如肿瘤坏死因子，干扰素等)，抑制病毒复制，但机体的免疫系统不能完全清除病毒，最终形成慢性感染，进入潜伏期。HIV病毒在人体内不断繁殖，病人CD4+T淋巴细胞计数明显下降，多＜200／mm3，HIV血浆病毒载量明显升高，表现为HIV相关症状、各种机会性感染及肿瘤，为感染HIV后的最终阶段。
HIV导致患者出现机体功能障碍，进展为AIDS主要免疫病理基础是CD4+T淋巴细胞数量减少。感染HIV后体内CD4+T淋巴细胞数量不断减少，分为3个阶段：①急性感染期：CD4+T淋巴细胞数量短期内一过性迅速减少，大多数感染者未经特殊治疗，CD4+T淋巴细胞数可自行恢复至正常水平或接近正常水平；②无症状感染期：CD4+T淋巴细胞数量持续缓慢减少，多在800～350／mm3之间，此期持续数月至十数年不等，平均持续约8年左右；③有症状期：CD4+T淋巴细胞再次较快速的减少，多在350／mm3以下，部分晚期病人降至200／mm3以下，并快速减少。T辅助细胞1(Th1)细胞被T辅助细胞2(Th2)细胞代替、抗原递呈细胞功能受损、白细胞介素-2产生减少和对抗原反应活化能力丧失，使HIV／AIDS病人易发生各种感染。
抗HIV治疗治疗目标：最大限度地抑制病毒的复制，保存和恢复免疫功能，降低病死率和HIV相关性疾病的发病率，提高患者的生活质量，减少艾滋病的传播。高效抗逆转录病毒治疗(Highly Active Antiretroviral Therapy，HAART)是艾滋病的最根本的治疗方法，需要终生服药。当前抗反转录病毒(ARV)药物有六大类30多种。核苷类反转录酶抑制剂(NRTIs)、非核苷类反转录酶抑制剂(NNRTIs)、蛋白酶抑制剂(Pls)、整合酶抑制剂(raltegravir)、融合酶抑制剂(FIs)及CCR5抑制齐(maraviroc)。
国内外有关艾滋病预防与治疗的研究在持续不断的进行，遗憾的是当前所有关于预防的治疗的均告失败，2007年默克公司宣布疫苗研制失败，2009年NIH宣告疫苗研究失败，一方面是疫苗研究的失败，另一方面是大量高危人群的暴露。同时随着抗病毒治疗的进行，大量耐药菌株出现，尤其是抗病毒治疗药物的毒副作用、经济因素、患者依从性下降及治疗的不规范，导致抗病毒失败、免疫失败到临床失败大量出现，系列治疗的失败引发功能性损伤，患者出现临床并发症，生活质量下降致病致残，造成大量的社会负担。
针对抗病毒治疗的失败，有考虑新的治疗方法，其中血液净化治疗不断尝试，但HIV病毒在人体环境内呈现高度变异，结构多变，单纯的吸附治疗难以有效清除病毒，尤其是与CD4结合病毒的清除难以实现，难以达到治疗效果，武汉大学2012.4.23申请的申请号为201210118840.9的专利，有提高亲和性吸附治疗HIV的设计，但，由于gp120高度变异性、功能基团多变，亲和抗体难以达到亲和效果，尤其是蛋白亲和抗体，在经过消毒、病原微生物灭活过程中，蛋白亲和受体非常容易灭活，少量残存受体，由于gp120受体各亚基之间分子动态结构转换需要动力，与保守位点亲和结合需要亚基基团暴露，也是单一亲和难以达到的。
发明内容
本发明目的在于克服现有艾滋病治疗的难点与不足，依据电子云场力、gp120受体、gp41受体基团的蛋白组学特征，针对gp120、gp41亚基氨基酸保守序列为靶点，设计高度特异性氨基酸探针，特异性结合HIV病毒，根据gp120、gp41亚基结合CD4受体后二维结构的动态转换特点，依据拉伸分子动力学模型检测出gp120特异性结合CD4时二维空间结构转换的力学范围，设计出一种特定范围的靶向结合的电子云场力干预HIV功能基团动态结构转换的乙烯-二乙烯苯材料大孔树脂微球，微球本身带有中空孔，特异性设计孔径大小，遇艾滋病患者内环境后产生虹吸力，此虹吸力可有效吸附人体内环境中HIV病毒颗粒，颗粒表面包裹蛋白包膜而不破坏人体正常结构，以此微球为基质材料制备吸附柱，口服颗粒清除艾滋病病毒，达到治疗的目的。
本发明医用大孔吸附树脂是以苯乙烯-二乙烯苯树脂球作为电子云场力、gp120、gp41氨基酸保守序列靶标位点吸附剂架构的医用吸附树脂，其树脂球密布微孔，孔径范围在70-140纳米；树脂球比表面积大于1000平米／克；树脂球微孔孔容大于6.000e-01cc／克；树脂树脂内部以孔径及附加电荷为主题，形成电子云场力，表面包覆蛋白膜，载入gp120、gp41氨基酸保守序列特异性氨基酸短肽作为靶点探针。树脂包膜根据需要可以处理带有极性，表现为负性，保持与V3区含较多带正电荷的氯基酸残基，减少病毒高突变区的变异，解决抗病毒治疗耐药HIV病毒株的清除。
研究发现：pl20分子结构特点及功能定位gpl20分子从蛋白质肽链的N端到C端可依次分为T细胞向性主要决定簇、单核细胞向性主要决定簇、V3环、CD4结合区、gpl20与gp41切割区、融合区以及跨膜区，gpl20上有2个具有强保守序列的结构域，发挥着覆盖和隐藏宿主细胞表面CD4／CCR5／CXCR4等受体的结合位点的作用；同时，gpl20的羧基端还有3个具有一定保守性但不连续的序列共同构成CD4分子的结合域，它们之间区段具有高突变频率的氨基酸序列分隔，从而使得机体免疫应答难以针对gpl20上的结合位点发挥有效的免疫清除作用；此外，gpl20表面存在着5个变异区(variable region，V区)，其中V3区是最为重要，研究发现HIV一1的中和抗原表位存在于V3环上，V3环是囊膜蛋白的重要功能区，同时也是HIV-I进入宿主细胞过程最重要的环节，V3环是不典型的环状结构，由大约35～36个氨基酸残基构成，两端各有一个半胱氯酸，彼此形成二硫键进行连接，其二级结构不规则。研究表明V3区含较多带正电荷的氯基酸残基，而其相对应的共受体CXCR4与CCR5含有较多的带负电荷的氨基酸残基，V3区中N一末端的精氨酸与靠近V3区顶端的疏水氨基酸苯丙氨酸的替换会影响与CCR5的相互作用。研究还表明V3区有6个氨基酸残基在gpl20与cCR5的相互作用过程中起着重要的作用，包括位于V3环的基部的精氨酸303～11丙氯酸333残基，和位于V3环两侧的D片层内的赖氨酸310，异亮氨酸312，精氨酸318和苯丙氨酸320t～。针对此相对保守序列，将只与gp120特异性结合的多肽与Fc片段或假单胞菌外毒素A进行融合，进而形成只针对gp120的特异性融合蛋白多肽，形成结合靶位，共价结合。形成树脂微球特异性吸附位点，为持续电子云场力干预gp120二维结构，破坏与CD4受体结合，降低淋巴细胞受攻击与损伤，保持HIV病毒游离状态，达到树脂高效清除的效果。
gp120-CD4与靶细胞表面的趋化因子CXCR4或CXCR5结合形成CD4-gp120-CXCR4／CXCR5三分子复合物，复合物形成后，gp41暴露，在其中起着桥的作用，利用自身的疏水作用介导病毒囊膜与细胞膜融合，最终造成细胞被破坏。制备抗HIV-1gp41合成多肽gp41-5的单克隆抗体(mAb)，得到的4株mAb能特异结合gp41核心结构的空间构象结构域新的靶向工具，形成二次靶向结合，清除gp120不能完全干预的HIV结构，形成清除HIV二重结构，这也是本发明的一个亮点，即可以清除与CD4细胞已经结合的HIV。
以gpl20功能结构与拉伸分子动力学为基础，检测gp120结合CD4细胞时空间二维结构转换的所需要动力大小，充分应用树脂微球自旋电子云场力，干预与改变gpl20二维结构，破坏gpl20与CD4受体结合能力，这也是本发明特异性和唯一性特征。
gpl20核心结构已经通过X射线晶体衍射技术对其与受体CD451]抗体17b的晶体复合物结构的解析得出，gpl20的核心包含内部结构域和外部结构域2个主要结构域和一个所谓的“桥片层”结构，在该晶体复合物中，gPl20核心结构不包含N一和C一末端、V1／V2以及V3和V4环结构，尽管如此，该复合物结构表明，来自gpl20内部结构域、外部结构域和桥片层的某些结构组分均与CD4分子发生相互作用，这些相互作用将gpl20分子稳定在CD4结合(CD4一bound)构象状态.同时，该复合物结构为分析gpl20抗原位点以及HIV感染机理提供了结构基础。
拉伸分子动力学基于gp120的主要运动模式，主要表现为内部结构域、外部结构域、桥片层以及V3环之间的旋转／扭曲、绕曲／关闭、延长／压缩运动或这些运动方式的组合，利用本质亚空间重叠算法评估gp120不同构象间的相互转换能力，结果表明，CD4结合前状态(unliganded)gp120向复合物状态(CD4-complexed)转化的能力强于向移除CD4复合物状态(CD4-free)转化的能力，而CD4-freegp120比CD4-complexed gp120具有更强的向结合前状态转化的能力.以gp120动态结构与功能的关系，计算出gp120不同动态结构转换需要的场力大小，决定树脂微球电子云场力范围，制约gp120动态结构转换能力，达到干预gp120二维空间转换效果，控制gp120与CD4结合。
Claims (2)
1.苯乙烯-二乙烯苯医用树脂的应用，其树脂球密布微孔，孔径范围在70-140纳米；树脂球比表面积大于1000平米／克；树脂球微孔孔容大于6.000e-01cc／克；其特征在于：
以该树脂作为电子云场力、gp120、gp41氨基酸保守序列靶标位点吸附剂架构，树脂内部以孔径及附加电荷为主，形成电子云场力；树脂表面包覆蛋白膜，载入gp120、gp41氨基酸保守序列特异性氨基酸短肽作为靶点探针。
2.如权利要求1所述的苯乙烯-二乙烯苯医用树脂，其特征在于：
所述的树脂包膜根据需要可以处理带有极性，表现为负性，保持与V3区含较多带正电荷的氯基酸残基，减少病毒高突变区的变异，解决抗病毒治疗耐药HIV病毒株的清除。
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