CN114656521B - 抑制新型冠状病毒刺突蛋白与ace2结合的化合物及其应用 - Google Patents
抑制新型冠状病毒刺突蛋白与ace2结合的化合物及其应用 Download PDFInfo
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Abstract
本发明公开了一种抑制新型冠状病毒刺突蛋白与ACE2结合的化合物，所述化合物为化合物A或化合物B，并且所述化合物A抑制ACE2的IC50值小于50uM，所述化合物B抑制ACE2的IC50值小于1uM；所述化合物A为二肽或三肽，并且所述化合物A的C端存在疏水性氨基酸残基，所述疏水性氨基酸残基包括脯氨酸、酪氨酸、苯丙氨酸和色氨酸中任意一种的残基；所述化合物B为含有化合物A结构的普利类药物，所述普利类药物包括但不限于卡托普利、依那普利、赖诺普利、福辛普利、培哚普利、贝那普利、依普利酮；上述化合物能够与新冠病毒S蛋白的RBD区域结合，竞争性的阻断RBD区域与ACE2受体结合，对于预防新型冠状病毒SARS‑CoV‑2具有积极的作用。
Description
技术领域
本发明属于生物医药技术领域，具体涉及一种抑制新型冠状病毒刺突蛋白与ACE2结合的化合物及其应用。
背景技术
新型冠状病毒的刺突（Spike）蛋白有助于病毒识别并进入靶细胞。许多研究小组表明，利用SARS-CoV-2突刺（Spike）蛋白通过其受体结合结构域（RBD）与ACE2结合。而受体ACE2是一种细胞外皮细胞上的二肽羧肽酶，该酶的特点是能够与细胞融合，从而携带病毒进入到细胞中，病毒进入细胞后通过表达使得人体细胞感染。所以医学上治疗病毒感染的关键途径之一是阻断病毒进入细胞。所以抑制SARS-CoV-2突刺蛋白和人类ACE2受体之间的相互作用目前被认为是一种关键的冠状病毒感染治疗策略，研发预防性的药物及化合物对于阻止新冠病毒的感染具有重要意义。
目前尚无专门用于预防和治疗新冠病毒的药物，但是肽类化合物抑制SARS-CoV-2突刺蛋白和人类ACE2受体之间相互作用的效果已经有所报道，如申请公开号为CN111825750A的中国专利申请在针对RBD的氨基酸结构设计了一系列蛋白多肽的基础上对该类多肽的氨基酸结构进行了修饰，并且通过分子、细胞及动物水平检验了这类肽对RBD与ACE2的结合具有阻断作用；授权公告号为CN 111349150B的中国专利根据新型冠状病毒S蛋白的HR2区设计了一种特异性结合的多肽，可以阻挡病毒与细胞的融合，可以有效的阻止病毒的感染；授权公告号为CN 112079901B的中国专利根据新型冠状病毒病毒S蛋白RBD区域的结构，合成了一类拮抗多肽，能够与RBD竞争性的与受体ACE2结合，从而阻止了新冠病毒进入细胞，对肾脏上皮细胞起到了保护作用。但是上述合成的肽类化合物仍然存在工作量大、数量少、链长太长、对人体的吸收利用率不高的问题。
发明内容
针对上述不问题，本发明公开了一种抑制新型冠状病毒刺突蛋白与ACE2结合的化合物，其具有来源广泛、合成技术成熟、易于人体吸收并且没有毒副作用的优点，对于制备治疗或预防冠状病毒感染药物具有重意义。
本发明是采用如下技术方案实现的：
一种抑制新型冠状病毒刺突蛋白与ACE2结合的化合物，所述化合物为化合物A或化合物B，并且所述化合物A抑制ACE2的IC50值小于50uM，所述化合物B抑制ACE2的IC50值小于1uM；
所述化合物A为二肽或三肽，并且所述化合物A的C端存在疏水性氨基酸残基，所述疏水性氨基酸残基包括脯氨酸（Pro）、酪氨酸（Tyr）、苯丙氨酸（Phe）和色氨酸（Trp）中任意一种的残基；
所述化合物B为含有化合物A结构的普利类药物，所述普利类药物包括但不限于卡托普利、依那普利、赖诺普利、福辛普利、培哚普利、贝那普利、依普利酮。
本发明利用所述化合物与新冠病毒S蛋白的RBD区域结合（RBD是新型冠状病毒S蛋白受体的结合区域），从而竞争性的阻断RBD区域与ACE2受体结合，同时还能促使结合在RBD区域的S蛋白-ACE2复合物的解离，进而对人体形成一个防御保护区，在细胞水平上可有效抑制新型冠状病毒SARS-CoV-2入侵，从而降低SARS-CoV-2感染的风险，对于预防新型冠状病毒SARS-CoV-2具有积极的作用；由于血管紧张素转换酶ACE1的结构与新型冠状病毒S蛋白受体ACE2结构具有近70%同源性，所以本发明所述化合物也能够结合在血管紧张素转换酶ACE1活性位点或活性位点附近从而抑制其活性，起到降低血压的作用。
进一步的，所述疏水性氨基酸残基优选脯氨酸残基。
进一步的，所述化合物A为食源蛋白中乳源蛋白、鱼类（包括海水鱼和淡水鱼）及其他动植物蛋白经蛋白酶解或微生物发酵的产物。
上述抑制新型冠状病毒刺突蛋白与ACE2结合的化合物的应用，将所述化合物A或化合物B用于制备预防或治疗新型冠状病毒肺炎、高血压的药物或功能食品。
进一步的，所述预防或治疗新型冠状病毒肺炎、高血压的药物为口服的喷剂、胶囊、片剂以及非口服的鼻腔喷剂中的任意一种。
本技术方案与现有技术相比较具有以下有益效果：
本发明所述化合物抑制ACE2的IC50值可以达到50uM以下，其一类为从海洋生物、鸡蛋、牛奶等物质中提取得到的二肽或三肽，另一类含有该二肽或三肽结构的普利类药物，所述二肽和三肽均属于食源蛋白提取物，具有来源广泛、合成技术成熟、易于人体吸收并且没有毒副作用的优点，同时所述化合物的肽链长度小，提取或制备的工艺简单，操作方便，对于制备治疗或预防冠状病毒感染以及缓解高血压的药物或功能食品具有重意义。
附图说明
图1是实施例1的步骤（1）中添加有CAP时，使用分子固化仪检测结果的示意图，其中曲线1表示未添加CAP的对照组溶液，曲线2表示CAP添加量为100nM的实验组溶液。
图2是实施例1的步骤（1）中添加有IPP时，使用分子固化仪检测结果的示意图，其中曲线1表示未添加IPP的对照组溶液，曲线2表示IPP添加量为100nM的实验组溶液。
图3是实施例1的步骤（2）中，使用分子相互作用仪测定的CAP抑制ACE2一半活性的浓度（IC50）的示意图。
图4是实施例1的步骤（2）中，使用分子相互作用仪测定的IPP抑制ACE2一半活性的浓度（IC50）的示意图。
图5是实施例1的步骤（3）中未添加CAP或IPP时，使用等温滴定量热仪测定结果的示意图。
图6是实施例1的步骤（3）中添加有CAP时，使用等温滴定量热仪测定结果的示意图。
图7是实施例1的步骤（3）中添加有IPP时，使用等温滴定量热仪测定结果的示意图。
图8是实施例1的步骤（4）中通过Vakser Lab模拟了RBD与ACE2的结合的示意图。
图9是实施例1的步骤（4）中通过Vakser Lab模拟了IPP与ACE2复合后再与RBD结合的示意图。
图10是实施例1的步骤（4）中通过Vakser Lab模拟了CAP与ACE2复合后再与RBD结合的示意图。
图11是实施例1的步骤（4）中通过分子对接模拟了CAP与ACE2结合的示意图。
图12是实施例1的步骤（4）中通过分子对接模拟了IPP与ACE2结合的示意图。
图13是实施例1的步骤（4）中通过分子对接模拟了CAP与RBD结合的示意图。
图14是实施例1的步骤（4）中通过分子对接模拟了IPP与RBD结合的示意图。
图15是实施例1中所述IPP的分子结构示意图。
图16是实施例1中所述CAP的分子结构示意图。
具体实施方式
以下通过实施例进一步说明本发明，但不作为对本发明的限制。下列实施例中未注明的具体实验条件和方法，所采用的技术手段通常为本领域技术人员所熟知的常规手段。
实施例1：
本发明人通过从食源蛋白中乳源蛋白、鱼类（包括海水鱼和淡水鱼）及其他动植物蛋白经蛋白酶解或微生物发酵得到若干个二肽或三肽产物（具体见表1），同时通过人工合成的方式获得若干个普利类化合物（具体见表2），然后对上述化合物与新冠病毒S蛋白的RBD区域结合效果的验证，以三肽IPP和卡托普利（CAP）为例，所述验证的方法包括以下步骤：
（1）用瑞士乳酸杆菌菌株发酵奶制品得到发酵产物，再利用超滤及高效液相色谱分离纯化发酵产物得到三肽IPP，并且通过人工合成得到卡托普利（CAP），同时取SARS-CoV-2刺突蛋白（RBD）和血管紧张素转化酶2（ACE2），并且配制磷酸盐缓冲溶液（PBS，PH=7.4）保存在低温冰箱中备用；接着通过分子固化仪（BLI）测定IPP或CAP抑制RBD与ACE2结合的效果。实验分为两组，分别是对照组和实验组。对照组为PBS、RBD和ACE2配制的溶液，实验组为在对照组溶液的基础上加入三肽IPP或卡托普利（CAP）；将对照组和实验组的溶液依次放置在分子相互作用仪中进行测试，其中使用带有HIS1K标签的传感器，并且应将传感器放置在装有PBS缓冲溶液的容器中提前润湿。
测试结果如图1和图2所示，未加入IPP或CAP的样品，RBD在传感器上固定后，RBD与ACE2发生了结合，使得传感器的厚度增加，而加入IPP或CAP的样品，传感器的厚度几乎保持不变，说明ACE2与RBD的结合被抑制，而且在解离的阶段，也未有明显的解离效果，由此可见，RBD与ACE2具有较强的结合能力，但是IPP或CAP能够明显的抑制RBD与ACE2的结合；
（2）ACE抑制活性的计算（IC50值的计算）
通过分子相互作用仪测试抑制肽在不完全抑制RBD与ACE2结合的浓度范围内，选取了三个浓度梯度，将RBD与ACE2的结合光程值（A0）的大小与不加抑制肽时RBD与ACE2结合的光程值（A1）的大小比较，通过公式1计算得到对应抑制肽浓度下的抑制率，再将浓度梯度下的抑制率与对应的浓度通过方程拟合之后计算得到IC50值。
公式1为：
按照上述方法，分别对三肽IPP、三肽VAP、三肽GRP、三肽FQP、卡托普利（CAP）、五肽RVCLP等抑制ACE2的IC50值进行计算，具体结果见图3～4和表3。
（3）通过等温滴定量热仪测定步骤（1）中所述IPP或CAP对RBD与ACE2结合的热力学情况影响，可以采用等温滴定量热仪（ITC）来研究IPP或CAP对RBD与ACE2结合的热量变化影响；首先，取步骤（1）中配制的PBS缓冲液，然后用0.22uM微孔膜过滤，再真空脱气10分钟后备用；实验分为三个平行组，分别是RBD滴定ACE2，RBD滴定ACE2与IPP的混合液以及RBD滴定ACE2与CAP的混合液。实验开始前，需取50uLRBD装入滴定针中，然后分别取250uL的 ACE2、ACE2与IPP混合液、ACE2与CAP的混合液装入样品池中，PBS溶液装入参比池中进行测定，所述等温滴定量热仪的实验条件为：搅拌速度250rpm，每次滴定2.5uL，间隔300s，自平衡1800s，此外可以用相同的条件用RBD滴定PBS，以消除背景热。实验结束后用LaunchNanoAnalyze软件对结果进行分析，从而得到热力学参数和拟合平衡线。
实验结果如图5～7所示，未加入IPP或CAP时，RBD与ACE2滴定过程中具有较大的热量变化，结合的亲和力为：3.32×109 M-1，证明了RBD与ACE2之间确实具有较强的结合能力，同时结合的热力学常数分别为：T∆S=2053KJ/mol、∆H =1999KJ/mol、∆G=-54.22KJ/mol，表示RBD与ACE2结合的作用力主要是疏水作用力，而且|∆H|<|-T∆S|，说明二者结合过程主要以熵驱动为主。当加入IPP或CAP后，滴定的热量曲线值均小于0.2uJ/s，表示RBD与ACE2之间几乎没有相互作用，所以说明IPP和CAP均具有抑制RBD与ACE2结合的能力；
（4）通过从分子水平研究IPP、CAP与RBD、ACE2结合及构象变化的情况；根据测定得到的IPP、CAP的结构数据，再由Chemdraw绘出其二级结构，并由Chem3D能量最小化后转化为PDB文件，其中RBD、ACE2的结构文件可以在RSBD数据库中下载；小分子与蛋白质大分子的对接由Autodock完成，蛋白质与蛋白质的对接由在线服务器（Vakser Lab）完成，接的结构由VMD和Pymol两个软件进行分析；
实验的结果如图8～16所示，与初始的RBD-ACE2复合物相比，将IPP或CAP加入到ACE2中后，RBD与新复合物再结合时构象发生了明显的变化，并且IPP或CAP与RBD的结合作用力比与ACE2的结合作用更强，所以表明IPP和CAP能够与ACE2受体竞争性的结合RBD，从而影响了了RBD与ACE2的结合；
综上所述，本实施1中所述的二肽和三肽以及普利类化合物可以按上述方法进行验证，经过验证可得到本发明所述的化合物均能够与RBD结合，从而影响了RBD与ACE2的结合方式，由此能够阻止SARS-CoV-2-S刺突蛋白进入人体细胞的能力，阻断了病毒的感染。
表1本实施例中所述二肽和三肽
表2本实施例中所述普利类化合物
表3 本实施例中部分化合物的IC50值
此外，应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施例中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。
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Claims (2)
1.一种抑制新型冠状病毒刺突蛋白与ACE2结合的化合物的应用，其特征在于：所述化合物是序列为RVCLP的五肽且所述化合物抑制ACE2的IC50值小于50uM，将所述化合物用于制备预防或治疗新型冠状病毒肺炎的药物。
2.根据权利要求1所述抑制新型冠状病毒刺突蛋白与ACE2结合的化合物的应用，其特征在于：所述预防或治疗新型冠状病毒肺炎的药物为口服的喷剂、胶囊、片剂以及非口服的鼻腔喷剂中的任意一种。
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