CN116496410B - 一种多肽衍生物及用途 - Google Patents
一种多肽衍生物及用途 Download PDFInfo
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- CN116496410B CN116496410B CN202310292726.6A CN202310292726A CN116496410B CN 116496410 B CN116496410 B CN 116496410B CN 202310292726 A CN202310292726 A CN 202310292726A CN 116496410 B CN116496410 B CN 116496410B
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Classifications
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
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Abstract
本申请属于生物领域，公开了一种多肽衍生物，包括具有自组装功能的多肽和连接在多肽上的单糖；所述多肽具有在溶酶体内富集的功能；所述富集是指多肽进入溶酶体的数量多于多肽从溶酶体内逃逸和降解的数量，该多肽衍生物通过细胞表面相应的受体协同进入细胞，提高了细胞摄取效率，同时，本申请中的多肽衍生物可以选择性的在溶酶体内富集并破坏溶酶体，且该多肽衍生物具有良好的生物相容性，能自组装形成水凝胶，提高了多肽的稳定性，持续的发挥抗肿瘤作用。
Description
技术领域
本发明涉及生物领域，尤其涉及一种多肽衍生物及用途。
背景技术
癌症是现代社会的一个主要健康问题，2018年导致全球960万人死亡，5年的患病率估计为4380万人。限制现有治疗方法疗效的原因主要有两个，其一是癌细胞巨大的复杂性和对癌细胞的理解有限，其二是当前化疗药物毒副作用大，对肿瘤细胞缺少靶向性导致其对目前使用的治疗方法产生耐药性，靶向抗肿瘤疗效也有限。尽管通过多种药物联合使用提高治疗的效率，从而避免化疗耐药，但到目前为止，结果没有达到所需的疗效。例如，三阴性乳腺癌(TNBC)是一种致命的乳腺癌形式，由于化疗耐药性的发展，影响了超过30％的患者。在此，迫切需要探索出减少耐药和抗肿瘤的新途径。
以肿瘤代谢为关注点探索抗肿瘤治疗新途径具有较大的潜力，其中代谢适应是肿瘤发生所固有的，以满足恶性肿瘤细胞对能量、生物合成增加需求。有氧糖酵解率的增加是许多癌细胞常见的代谢特征，而且一些肿瘤细胞中葡萄糖转运体1(GLUT1，由SLC2A1编码，葡萄糖摄取的关键速率限制因子)的表达升高和相关的代谢依赖性，并且作为癌症的治疗重点已得到广泛的研究；糖基化是一种常见的蛋白质翻译后修饰，增加了血清和内部分子的稳定性，并且多肽的糖基化可能会影响肽在癌细胞中的摄取效率。具体来说，所有糖肽的半抑制浓度值都低于没有糖基化修饰的相应肽，以及糖基化之后可以提高多肽进入细胞的效率，因此提高功能性多肽进入肿瘤细胞可能在决定最终的抗癌活性中起关键作用。
中国专利201710035869.3公开了一种可在肿瘤细胞溶酶体内发生形貌转换的多肽脂质体，该多肽脂质体由多肽自组装组成，所述多肽的主体为6个丙氨酸形成的肽链，所述肽链的N端修时有一个含苯环的基团，所述肽链的C端连接有RGD多肽序列，所述含苯环的基团为苯甲酸。
该方案在弱碱性生理PH下，该多肽可自组装形成类似脂质体的结构，在被肿瘤细胞识别通过内吞作用进入溶酶体后，多肽响应溶酶体内的酸性PH，自组装形貌脂质体结构变换成为纳米纤维，这些纳米纤维引起了溶酶体膜的透化作用，使得更多的组织蛋白酶被释放到了细胞质中。抑制溶酶体自修复作用的分子HsP 70抑制剂可被包载到多肽脂质体的亲水内腔中，在多肽自组装体形貌转换的同时释放药物，抑制溶酶体自修复，增强组织蛋白酶的作用。
中国专利202110068300.3公开了一种能够透过生物屏障且聚集核周的动力蛋白结合肽及其应用，该蛋白结合肽自N端到C端依次由核心区(具有动力蛋白结合能力)和穿膜肽组成，穿膜肽具体由8个连续的精氨酸残基(R)组成，该方案能够实现细胞内核周递送，具有生物屏障透过性，能够改善大分子药物(例如多肽、DNA、RNA等)和/或纳米载体的胞内转运能力，改善细胞内作用药物的效应强度，能够降低或改善多药耐药性。
本方案需要解决的问题：如何提供一种新的方式，使得多肽衍生物穿过细胞膜并在溶酶体处聚集。
发明内容
本发明的目的是提供一种多肽衍生物，该多肽衍生物能够富集于溶酶体内，并在溶酶体内自组装，破坏溶酶体。
其具体的机理来说，通过单糖和细胞表面的受体(GLUT1，葡萄糖单向转运蛋白)相互作用，含有多肽、单糖的多肽衍生物会进入细胞，多肽衍生物进入细胞中后，有部分多肽衍生物会进入到溶酶体内，本发明选择能够在溶酶体内富集的多肽，当溶酶体内的多肽浓度越来越高，多肽就会开始自组装形成凝胶，破坏溶酶体膜通透性，释放水解酶；进一步导致溶酶体功能紊乱，致使整个细胞被消化、死亡。
本发明之所以能够作为抗肿瘤药物使用，其原因之一在于，正常细胞表面的GLUT1受体会明显少于肿瘤细胞表面的GLUT1受体，因此肿瘤细胞会首先被杀死；即只需要控制药物浓度阈值，即可达到抗肿瘤的目的。
为实现上述目的，本申请公开了一种多肽衍生物，包括具有自组装功能的多肽和连接在多肽上的单糖；所述多肽具有在溶酶体内富集的功能；所述富集是指多肽进入溶酶体的数量多于多肽从溶酶体内逃逸和降解的数量。
根据本发明的实验，具有富集功能、自组装功能的多肽为自组装多肽；
或，
所述多肽由自组装多肽和穿膜肽连接形成。
优选地，所述自组装多肽、穿膜肽中具有至少一个带有正电荷的氨基酸。
在实际应用过程中，所述带正电荷的氨基酸包括赖氨酸、组氨酸和精氨酸。
自组装多肽、穿膜肽中任一者具有带正电荷的氨基酸的原因在于：细胞表面多为负电荷，通过带正电荷的氨基酸可提高多肽和细胞膜的结合概率、可靠性等；
优选地，所述自组装多肽、穿膜肽中具有至少一个D型氨基酸。
选择D型氨基酸的原因为：L型氨基酸大多为天然氨基酸，D型氨基酸大多为非天然氨基酸，所以D型氨基酸聚集在溶酶体中更不容易被酶所降解，能够进一步提高富集程度。
所述自组装多肽选自氨基酸序列SEQ ID No.2～3中任一种，或，所述自组装多肽的氨基酸序列为GFF或WYF；所述穿膜肽选自氨基酸序列SEQ ID No.4～7中任一种；
在一些实施案例中，具有以上功能的多肽为氨基酸序列SEQ ID No.2～3中任一种，或氨基酸序列为GFF或WYF的多肽；
在一些实施案例中，具有以上功能的多肽为氨基酸序列SEQ ID No.2～3中任一种、氨基酸序列SEQ ID No.4～7中任一种组成的多肽；
自组装多肽分别为FFKLV、FFVLK、GFF、WYF；
穿膜肽分别为RRVR、RRGK、RRVK、RRLR；
在一些实施案例中，所述多肽的氨基酸序列如SEQ ID No.1所示。
优选地，上述氨基酸序列SEQ ID No.1～7中，至少有一个氨基酸为带正电荷的氨基酸；
优选地，上述氨基酸序列SEQ ID No.1～7中，至少有一个氨基酸为D型氨基酸；
优选地，上述氨基酸序列SEQ ID No.1～7中，所有氨基酸均为D型氨基酸；
在本发明的一个具体的实施案例中，SEQ ID No.1中所有的氨基酸都为L型氨基酸，但是根据现有的实验结果来看，采用D型氨基酸更佳。
作为本领域的常规技术，在多肽上还可以连接封端基团，所述封端基团的加入为了消除端基的活性，防止在适宜的官能团存在时，肽链端的继续反应，使得肽链增长；在实际应用过程中，可供选择作为封端基团的单官能团化合物包括药物小分子但不限于：喜树碱、10-羟基喜树碱、阿霉素、萘普生、芘丁酸；更为优选地，所述封端基团为萘乙酸。
需要进一步说明的是：根据合理性推论，在本领域中一些药物多肽在其端部加上单糖一样可以实现穿膜目的，实现在溶酶体或细胞内发挥药物的功能，进而达到破坏溶酶体或细胞的目的。可以列举的，药物多肽可选择为：利拉鲁肽、奥曲肽、兰瑞肽；当然，这只是本发明的思路的另外一个方向的发散。
优选地，所述单糖为醛糖或酮糖，当单糖醛糖时，所述单糖选自葡萄糖、木糖、阿拉伯糖中的至少一种；
当单糖为酮糖时，所述单糖选自半乳糖、甘露糖、果糖中的至少一种。优选地，所述单糖为酮糖，所述单糖选自半乳糖、甘露糖中的至少一种。
此外，本申请还公开了上述的多肽衍生物，用作抑制肿瘤细胞生长药物的活性成分的用途。
本申请的有益效果是：
该多肽衍生物通过细胞表面相应的受体协同进入细胞，提高了细胞摄取效率，同时，本申请中的多肽衍生物可以选择性的在溶酶体内富集并破坏溶酶体，且该多肽衍生物具有良好的生物活性，能自组装形成水凝胶，提高了多肽的稳定性，持续的发挥抗肿瘤作用。
其中，通过单糖和细胞表面的受体(GLUT1，葡萄糖单向转运蛋白)相互作用，含有多肽、单糖的多肽衍生物会进入细胞，多肽衍生物进入细胞中后，有部分多肽衍生物会进入到溶酶体内，本发明选择能够在溶酶体内富集的多肽，当溶酶体内的多肽浓度越来越高，多肽就会开始自组装形成凝胶，破坏溶酶体；并且，溶酶体破损后会释放出水解酶，致使溶酶体功能紊乱，导致整个细胞死亡。
附图说明
图1为序列为NapFFKLV-RRVR(命名为P)、NapFFKLV-RRVR-甘露糖(命名为PG)的多肽结构式；
图2A为实施例2的多肽P的水凝胶的透射电子显微镜照片；
图2B为实施例2的多肽PG的水凝胶的透射电子显微镜照片；
图3为实施例3的不同多肽在不同频率下的储能模量和损耗模量图表；
图4A为实施例4的多肽P处理72h后的细胞毒性实验结果图；
图4B为实施例4的多肽PG处理72h后的细胞毒性实验结果图；
图5A为实施例5的细胞摄取流式图；
图5B为实施例5的多肽进入细胞后在细胞内分布的照片；
图5C为实施例5的糖基化多肽与D-甘露糖胺共孵育后的细胞摄取流式图；
图5D为实施例5的糖基化多肽与GLUT1抑制剂共孵育后的细胞摄取流式图；
图6A为实施例6的多肽处理后使用吖啶橙染色后的效果图；
图6B为实施例6的多肽处理后使用Magic Red染色后的效果图；
图7为抗肿瘤疗效图。
具体实施方式
下面将结合本发明的实施例，对本发明进行清楚、完整地描述，在本发明的描述中，需要说明的是，实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
实施例1
通过固相合成法合成多肽药物分子，氨基酸序列为分别为NapFFKLV-RRVR(简称P)和NapFFKLV-RRVR-甘露糖(简称PG)(附图1)。
利用二氯树脂为载体进行合成，将所需的氨基酸计算称量溶解后放入合成瓶，按照全自动合成仪器的操作进行设置合成，取出树脂切割、沉淀后得到多肽粗品。糖基化多肽通过HBTU、DIPEA和固相反应一样的条件反应得到，最后可以通过高效液相色谱仪进行纯化及冻干即可得到相应的多肽药物冻干粉。
该多肽中单糖为关键基团，能够促进多肽进入细胞，穿膜肽(RRVR)能够进一步提高进入细胞的速度，从而更好的发挥抗肿瘤作用，其中单糖通过细胞表面的受体进入细胞，上述的自组装多肽(FFKLV)能选择性在溶酶体中富集，并且破坏溶酶体，缺少单糖，进入细胞的效率大大下降，可见糖基化多肽具有潜在的应用价值。
实施例2
制备多肽水凝胶及其表征的方法
称取2mg的如实施例1所示的多肽成品(P和PG)，分别加入100μL的纯水，得到多肽水溶液，再加入100μL的PBS(2X)，放于37℃即可形成水凝胶，此为2wt％的水凝胶；分为水凝胶1(含P)和水凝胶2(含PG)。
将形成的水凝胶利用透射电子显微镜(Transmission Electron Microscopy,TEM)检测，结果表明其是一种纳米级的纤维结构(附图2A代表P，图2B代表PG)，多肽修饰单糖之后纳米纤维的直径由11nm(P)增加到17nm(PG)。
实施例3
利用流变仪进行时间扫描，验证其稳定性。称量4mg的多肽冻干粉(P和PG)，加入100μL的纯水(2wt％)，进行超声溶解，得到多肽水溶液；冰浴30min后再加入100μL的PBS，混合均匀后，迅速转移到流变仪的平台。设定参数：平台温度设定在37℃，间隙为0.5mm，时间一般设定为3h，频率为6rad/s，应变为0.2％，横坐标为时间，纵坐标G’为储能模量和G”损耗模量，结果表明二者均能形成稳定的水凝胶(附图3，(G’代表储存模量，G”代表损耗模量))。
实施例4
细胞毒性的测定：将多肽P和PG配置成40mM的母液，对其进行梯度稀释后，加入到提前铺好HCT116，HeLa，A549，HepG2细胞的96孔板中，每孔100μL，每个浓度三个复孔,处理时间分别是3天，然后用MTT在572nm处测定OD值，得出的数值经过计算。
结果发现多肽糖基化处理后，对肿瘤细胞的毒性显著增加(附图4，CellViability代表细胞存活率，Concentration代表多肽浓度)。
实施例5
细胞摄取率的测定：通过共聚焦荧光显微镜对细胞摄取进行定性分析，将多肽(P)和糖基化多肽(PG)进行荧光标记，使荧光肽和细胞孵育不同的时间，通过流式细胞仪进行定性分析发现糖基化多肽能显著增加其细胞摄取率，1h时糖基化多肽的细胞摄取率是普通多肽的6.2倍，并且随着时间增加，发现24h后糖基化多肽的细胞摄取率是普通多肽的16.2倍(附图5A，Normalized Mean Fl.代表以P进行归一化后的平均荧光强度)，这一结果证实了糖基化多肽可以增加其细胞摄取率。我们使用多肽与细胞共孵育，然后对细胞核和溶酶体进行染色，通过共定位发现，糖基化多肽在细胞的溶酶体中富集，而普通多肽没有发现这个现象(附图5B)。
细胞摄取机制的探索：
糖基化多肽PG的细胞摄取率较高可能和细胞表面的受体(GLUT1)有关，通过将糖基化多肽和甘露糖胺与细胞共同孵育一段时间，然后通过流式细胞仪进行监测发现摄取量明显减少，说明PG是通过GLUT1介导促进细胞摄取的(附图5C，Normalized Mean Fl.代表以control进行归一化后的平均荧光强度)。
通过GLUT1受体抑制剂处理，发现糖基化多肽的细胞摄取率显著降低(附图5D，Normalized Mean Fl.代表以control进行归一化后的平均荧光强度)。以上结果进一步说明通过GLUT1介导的促进细胞对多肽的吸收。
实施例6
糖基化多肽抗肿瘤机理的验证：
通过吖啶橙染料(AO)验证多肽对肿瘤细胞的溶酶体膜通透性破坏的能力，将多肽和糖基化多肽的提高到200μM和400μM处理细胞4h后，对溶酶体进行染色，发现200μM的糖基化多肽能在溶酶体内富集并且破坏溶酶体的膜通透性，而200μM的非糖基化多肽对溶酶体的影响显著降低(附图6A)。用同样的方法，使用Cathepsin B试剂盒(Magic Red)进行染色，结果表明糖基化修饰的多肽可以在200μM时破坏溶酶体，导致溶酶体内的酶释放到细胞质中，造成溶酶体功能紊乱而杀死细胞(附图6B)。
实施例7
糖基化多肽对肿瘤模型裸鼠的疗效：
将HCT-116肿瘤细胞皮下注射于裸鼠体内，肿瘤长到一定大小后，在裸鼠瘤周注射不同的溶液，溶液分为多肽药物PG两组(10mg/kg和20mg/kg组)，抗癌药物紫杉醇组，PBS组，两天给药一次，每次100μL，每组6只鼠，两天测量一次裸鼠体重以及利用游标卡尺测量裸鼠肿瘤体积大小，10天后处死裸鼠(附图7，第一行为PBS组，第二行为10mg/kgPG组；第三行为20mg/kgPG组，第四行为紫杉醇组)。
结果可知，药物组能减缓肿瘤的生长，和化疗药物紫杉醇具有相似的疗效，具有一定的研究价值。
Claims (2)
1.一种多肽衍生物，其特征在于，所述多肽衍生物的结构为NapFFKLV-RRVR-甘露糖。
2.采用如权利要求1所述的多肽衍生物制作抑制肿瘤细胞生长药物的用途，所述抑制肿瘤细胞生长药物用于抑制HCT-116肿瘤细胞、A549肿瘤细胞、HeLa肿瘤细胞或HepG2肿瘤细胞的生长。
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