CN114452372B - 一种具有抗癌作用的多肽组合物及其应用 - Google Patents
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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Abstract
本发明提供了一种具有抗癌作用的多肽组合物及其应用，特别涉及药物制备领域。本发明提供了一种具有抗癌作用的多肽组合物，所述组合物包括多肽和/或所述多肽的药用盐；所述多肽包括靶向多肽。本发明所述组合物，能够结合BRD4ET结构域，还能够有效抑制癌细胞扩增，具有抗肿瘤的作用。
Description
技术领域
本发明涉及药物制备领域，特别是涉及一种具有抗癌作用的多肽组合物及其应用。
背景技术
BET家族中的蛋白有两个保守的结构域，一个是BRD4氨基段两个串联的bromodomains(BDI和BDII)，它能结合乙酰化的组蛋白；另一个是extrateminal(ET)结构域，ET结构域的功能目前研究并不多，研究认为该结构域主要通过招募转录因子参与基因转录。两个结构域互为补充，共同执行BRD4的生物功能。
目前，人们报道了BRD4 ET结构域的结合蛋白有JMJD6和NSD3等。其中，JMJD6是最为关键的结合蛋白之一。JMJD6与BRD4 ET结构域结合，形成的蛋白复合体能共同调节基因转录延伸，JMJD6与BRD4在基因转录过程中起协同作用，它们结合后介导的生物学过程是基因转录过程的关键一步。研究显示，在肿瘤细胞中，二者共同参与了癌基因的转录激活或者抑癌基因的转录抑制。此外，BRD4的ET结构域还和赖氨酸甲基转移酶NSD3结合，改变BRD4结合基因附近的染色质微环境参与基因转录调控。二者的结合对急性髓系白血病维持的至关重要。值得注意的是，JMJD6和NSD3等蛋白在BRD4ET结构域上的结合位点相同，因此一个可行的方案是阻断BRD4 ET结构域与以上蛋白的结合从而起到抑制肿瘤的效果。
事实上，BRD4在癌症中的功能研究表明该BRD4是一类新的抗肿瘤药物靶标，一些靶向BRD4 Bromodomain的小分子抑制剂已进入抗肿瘤临床研究，但尚未报道有抑制剂(包括有机小分子或短肽)能够抑制BRD4 ET结构域介导的生物功能。尽管人们报道了少数几个可以结合BRD4 ET结构域的短肽，但是并未对其生物功能和抗癌用途进行研究。
发明内容
为了解决上述问题，本发明提供了一种具有抗癌作用的多肽组合物及其应用。本发明提供的多肽组合物，能够结合BRD4 ET结构域，还能够有效抑制癌细胞扩增，具有抗肿瘤的作用。
为了实现上述目的，本发明提供如下技术方案：
本发明提供了一种具有抗癌作用的多肽组合物，所述多肽组合物包括多肽和/或所述多肽的药用盐；所述多肽包括靶向多肽。
优选的，所述靶向多肽包括P3和/或P4；所述P3的氨基酸序列如SEQ ID No.1所示；所述P4的氨基酸序列如SEQ ID No.2所示。
优选的，所述多肽还包括穿膜肽；所述穿膜肽的氨基酸序列如SEQ ID No.3或SEQID No.4所示。
优选的，所述药用盐包括将所述多肽与酸和/或与无机碱的酸式盐结合所形成的盐。
优选的，所述酸包括盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸；所述无机碱的酸式盐包括含有碱性金属阳离子的盐、含有碱土金属阳离子的盐或含有铵离子的盐。
本发明提供了上述多肽组合物在制备BRD4多肽抑制剂中的应用。
本发明提供了一种BRD4多肽抑制剂，所述多肽抑制剂的有效成分包括上述多肽组合物。
本发明提供了上述多肽组合物或上述多肽抑制剂在制备治疗癌症的药物中的应用。
本发明提供了一种治疗癌症的药物，所述药物的有效成分包括上述多肽组合物或上述多肽抑制剂。
优选的，所述癌症包括肝癌、肺腺癌、前列腺癌、乳腺癌、胰腺癌、结肠癌、口腔鳞状细胞癌、黑色素瘤、肾癌、胆管癌或胶质母细胞瘤。
有益效果：本发明提供了一种具有抗癌作用的多肽组合物，所述多肽组合物包括多肽和/或所述多肽的药用盐；所述多肽包括靶向多肽和/或穿膜肽。采用本发明提供的多肽组合物能够达到治疗肿瘤的效果。实验表明，本发明所述多肽组合物的Kd为194～995μm，能够结合BRD4 ET结构域，还能够有效抑制癌细胞扩增，具有抗肿瘤的作用。
具体实施方式
本发明提供了一种具有抗癌作用的多肽组合物，所述多肽组合物包括多肽和/或所述多肽的药用盐；所述多肽包括靶向多肽。在本发明中，所述靶向多肽优选包括P3和/或P4；所述P3的氨基酸序列优选如SEQ ID No.1所示：RNQKFKCGE；所述P4的氨基酸序列如SEQID No.2所示：GYSVKMKMK。
本发明所述多肽优选还包括穿膜肽；所述穿膜肽的氨基酸序列优选如SEQ IDNo.3所示：YGRKKRRQRRRRNQKFKCGE或SEQ ID No.4所示：YGRKKRRQRRRGYSVKMKMK，本发明所述序列优选均由金斯瑞生物科技(GenScript Biotech)合成。
本发明对多肽和穿膜肽的连接先后顺序没有特殊限定。
本发明所述药用盐优选包括将所述多肽与酸和/或与无机碱的酸式盐结合所形成的盐。本发明所述酸优选包括盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸，更优选包括盐酸。本发明所述无机碱的酸式盐优选包括含有碱性金属阳离子的盐、含有碱土金属阳离子的盐或含有铵离子的盐；所述碱性金属阳离子优选包括锂离子(Li+)、钠离子(Na+)、钾离子(K+)、铷离子(Rb+)、铯离子(Cs+)和钫离子(Fr+)。
本发明所述多肽组合物可用于制备BRD4多肽抑制剂，本发明所述多肽组合物能够竞争性的结合BRD4 ET结构域，从而发挥抑制BRD4的作用。
本发明提供了上述多肽组合物在制备BRD4多肽抑制剂中的应用。
本发明提供了一种BRD4多肽抑制剂，所述多肽抑制剂的有效成分包括上述多肽组合物。本发明所述多肽抑制剂还优选包括药学上可接受的辅料。本发明所述多肽组合物Kd为194～995μm，对乳腺癌的细胞系MCF7细胞增殖抑制的IC50为13.64～57.11，可见本发明所述多肽组合物能够结合BRD4 ET结构域的同时，还具有有效抑制癌细胞扩增的作用。
本发明提供了上述多肽组合物或上述多肽抑制剂在制备治疗癌症的药物中的应用。
本发明提供了一种治疗癌症的药物，所述药物的有效成分包括上述多肽组合物或上述多肽抑制剂。本发明所述药物优选还包括药学上可接受的辅料。本发明所述癌症优选包括肝癌、肺腺癌、前列腺癌、乳腺癌、胰腺癌、结肠癌、口腔鳞状细胞癌、黑色素瘤、肾癌、胆管癌或胶质母细胞瘤。在本发明实施例中，利用乳腺癌的细胞系MCF7表征所述药物对于乳腺癌的抑制效果，所述细胞系的来源优选为ATCC细胞库，本发明所述多肽组合物对乳腺癌的细胞系MCF7细胞增殖抑制的IC50为43.64～57.11，所以本发明所述药物具有显著的抑制癌细胞增殖的效果。
为了进一步说明本发明，下面结合实施例对本发明提供的一种具有抗癌作用的多肽组合物及其应用进行详细地描述，但不能将它们理解为对本发明保护范围的限定。
应用例1
采用Biacore表面等离子共振技术进行测试P3(SEQ ID No.1)对BRD4的结合能力。用PBS将BRD4 ET蛋白稀释到0.021μg/μL，pH值为7.4。用氨基偶联试剂盒将BRD4 ET固定到CM5芯片传感器上。
配制不同浓度梯度(500μM、250μM、125μM、62.5μM、31.25μM、15.625μM和0μM)的P3多肽，检测它们依次通过固化有BRD4 ET的芯片表面的相应值。用BIACORE T200evaluation software v3软件对数据进行分析，选择1：1Langmuir结合模式进行拟合曲线分析，从而获得亲和力常数Kd为194μM。
因此，P3具有明显的BRD4 ET结构域结合能力。由于BRD4在癌细胞生长增殖中具有关键作用，P3可用于预防或治疗与BRD4多肽有关的疾病的药物中，尤其是相关的治疗癌症的药物中的应用。
应用例2
将乳腺癌细胞系的细胞(MCF7)铺于96孔板中，铺板密度为20％。
24小时后，加入含有不同浓度P3多肽的溶液。测试药物P3多肽设立6个药物浓度梯度：100μM，30μM，10μM，3μM，1μM，0.3μM，同时设置空白对照组。每个浓度梯度的处理包括3个重复平行。加药之前细胞换液。加药48小时后，用CellTiterAQueous单溶液细胞增殖检测试剂盒)以比色法检测细胞毒性。CellTiter/>AQueous单溶液试剂包含3-(4,5-二甲基噻唑-2-基)-5-(3-羧甲氧基苯基)-2-(4-磺苯基)-2H-四唑[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophe nyl)-2H-tetrazolium,内盐；MTS]和一个电子耦合试剂(乙硫吩嗪，PES)。每100μl培养基加入20μl CellTiter/>AQueous溶液试剂，在37℃，5％CO2培养箱中培养1小时。加入25μl 10％SDS终止反应。使用ThermoMultiskan MK3微孔板酶标仪，记录在波长490nm处的吸光值数据。利用GraphPadPrism 6软件分析药物的IC50值。检测结果如表1所示。
表1细胞增殖抑制数据
| MCF7(IC50/μM) | |
| P3 | 43.64 |
| 空白对照 | - |
由表1可知，P3具有显著的抑制乳腺癌细胞增殖的技术效果。P3可用于预防或治疗与BRD4抑制剂有关的疾病的药物中，尤其是相关的治疗癌症的药物中的应用。
应用例3
采用Biacore表面等离子共振技术进行测试P4(SEQ ID No.2)对BRD4的结合能力。用PBS将BRD4 ET蛋白稀释到0.021μg/μL，pH值为7.4。用氨基偶联试剂盒将BRD4 ET固定到CM5芯片传感器上。配制不同浓度梯度(500μM、250μM、125μM、62.5μM、31.25μM、15.625μM和0μM)的P4多肽，检测它们依次通过固化有BRD4 ET的芯片表面的相应值。用BIACORE T200evaluation software v3软件对数据进行分析，选择1：1Langmuir结合模式进行拟合曲线分析，从而获得亲和力常数Kd为995μM。
因此，P4具有明显的BRD4 ET结构域结合能力。由于BRD4在癌细胞生长增殖中具有关键作用，P4可用于预防或治疗与BRD4多肽有关的疾病的药物中，尤其是相关的治疗癌症的药物中的应用。
应用例4
将乳腺癌细胞系的细胞(MCF7)铺于96孔板中，铺板密度为20％～30％。
24小时后，加入含有不同浓度P4多肽的溶液。测试药物P4设立6个药物浓度梯度：100μM、30μM、10μM、3μM、1μM和0.3μM，同时设置空白对照组。每个浓度梯度的处理包括3个重复平行。加药之前细胞换液。加药48小时后，用CellTiterAQueous单溶液细胞增殖检测试剂盒)以比色法检测细胞毒性。CellTiter/>AQueous单溶液试剂包含3-(4,5-二甲基噻唑-2-基)-5-(3-羧甲氧基苯基)-2-(4-磺苯基)-2H-四唑[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophe nyl)-2H-tetrazolium,内盐；MTS]和一个电子耦合试剂(乙硫吩嗪，PES)。每100μl培养基加入20μl CellTiter/>AQueous溶液试剂，在37℃，5％CO2培养箱中培养1小时。加入25μl 10％SDS终止反应。使用ThermoMultiskan MK3微孔板酶标仪，记录在波长490nm处的吸光值数据。整理数据，用GraphPadPrism 6软件分析药物的IC50值。检测结果如表2所示。
表2细胞增殖抑制数据
由表2可知，P4具有显著的抑制乳腺癌细胞增殖的技术效果。P4可用于预防或治疗与BRD4抑制剂有关的疾病的药物中，尤其是相关的治疗癌症的药物中的应用。
虽然本发明已以较佳的实施例公开如上，但其并非用以限定本发明，任何熟悉此技术的人，在不脱离本发明的精神和范围内，都可以做各种改动和修饰，因此本发明的保护范围应该以权利要求书所界定的为准。
序列表
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<120> 一种具有抗癌作用的多肽组合物及其应用
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Claims (3)
1.一种具有抗癌作用的多肽组合物，其特征在于，所述多肽组合物包括多肽；
所述多肽的氨基酸序列如SEQ ID No .3或SEQ ID No .4所示；所述多肽为穿膜肽和靶向多肽的融合；所述靶向多肽为P3或P4；所述P3的氨基酸序列如SEQ ID No .1所示；所述P4的氨基酸序列如SEQ ID No .2所示。
2.权利要求1所述多肽组合物在制备治疗乳腺癌的药物中的应用。
3.一种治疗乳腺癌的药物，其特征在于，所述药物的有效成分包括权利要求1所述多肽组合物。
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