CN114457052B - 一种抗肿瘤的多肽组合物及其应用 - Google Patents
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Abstract
本发明提供了一种抗肿瘤的多肽组合物及其应用，特别涉及抗癌药物领域。本发明提供了一种抗肿瘤的多肽组合物，所述多肽组合物包括WLP靶向肽；所述WLP靶向肽的氨基酸序列如SEQ ID No.1所示。本发明所述多肽组合物能够有效抑制癌细胞的增殖，从而达到治疗癌症的目的。
Description
技术领域
本发明涉及抗癌药物领域，特别是涉及一种抗肿瘤的多肽组合物及其应用。
背景技术
癌症已成为死亡率最高的疾病之一，癌症的发病率也在逐年增长，同时癌症的发病年龄也逐渐呈年轻化。因此寻找对癌症发生发展起关键作用的调控因子，并以此为药物靶点而设计出有效而特异的短肽抑制剂，具有重要的学术价值和社会效益。
CARM1(精氨酸甲基转移酶4(Protein Argine Methyltransferase4，PRMT4)又被称为共激活因子相关的精氨酸甲基转移酶1 (Coactivitor-Associated ArginineMethyltransferase1))，作为表观遗传调控子具有多种生物功能。精氨酸甲基化作用在癌症中的功能研究中表明，该表观遗传调控子是潜在抗肿瘤药物靶标。近一年，人们陆续报道了CARM1的小分子抑制剂，具有一定的抗肿瘤作用。此外，有报道发现CARM1底物蛋白PABP1肽序列与AdoMet辅助因子中的腺苷部分共价连接产生的肽类似物可以与酶形成稳定的复合物，也是有效的CARM1抑制剂，但体内抗肿瘤生物活性未见报道。除此之外，尚未有能够独立抑制CARM1酶活性的多肽报道。
发明内容
为了解决上述问题，本发明提供了一种抗肿瘤的多肽组合物及其应用。本发明所述多肽组合物能够有效抑制癌细胞的增殖，从而达到治疗癌症的目的。
为了实现上述目的，本发明提供如下技术方案：
本发明提供了一种抗肿瘤的多肽组合物，所述多肽组合物包括 WLP靶向肽；所述WLP靶向肽的氨基酸序列如SEQ ID No.1所示。
优选的，所述多肽组合物还包括穿膜肽。
优选的，在所述WLP靶向肽上还包括化学修饰。
优选的，所述化学修饰包括非天然氨基酸修饰、伪肽化策略、逆肽策略、环化策略、末端结构修饰、高级脂肪酸修饰、聚乙二醇修饰、蛋白融合策略或胆固醇修饰。
优选的，所述穿膜肽包括TAT、Antp-(43/58)、果蝇的触角足突变蛋白、小寡聚精氨酸、小寡聚赖氨酸、支多抗原肽(MAP)及它的类似物或转运素。
本发明提供了上述多肽组合物在制备CARM1短肽类抑制剂中的应用。
本发明提供了一种CARM1短肽类抑制剂，所述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抑制剂。
优选的，所述癌症包括乳腺癌、结直肠癌、肺癌、肝癌、卵巢癌、前列腺癌、口腔癌、骨肉瘤和急性髓细胞白血病。
有益效果：本发明提供了一种包含WLP靶向肽和/或穿膜肽的抗肿瘤多肽组合物，所述WLP靶向肽的氨基酸序列如SEQ ID No.1所示。本发明所述多肽组合物可用于预防或治疗与CARM1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。
同时本发明所述抗肿瘤多肽组合物是通过靶向精氨酸甲基转移酶，从而达到抑制癌细胞活性的效果，本发明具体实施例部分验证得到采用本发明所述抗肿瘤多肽组合物能够显著抑制乳腺癌和肝癌细胞的活性；本发明所述抗肿瘤多肽组合物是基于CARM1的底物结合区域的氨基酸序列设计的，CARM1相比较其他PRMT识别的底物氨基酸序列具有高度特异性；而免疫原性低主要是因为多肽抑制剂的氨基酸序列接近体内底物蛋白自身序列，不易引起机体免疫反应；因此本发明所述抗肿瘤多肽组合物相比较已知的靶向CARM1小分子药物存在分子量小、抗肿瘤特异性高、免疫原性低、并且易于合成和改造等优势。
具体实施方式
本发明提供了一种抗肿瘤的多肽组合物，所述多肽组合物包括 WLP靶向肽；所述WLP靶向肽的氨基酸序列如SEQ ID No.1所示： FSLNWRPPCLF。本发明在所述WLP靶向肽上优选还包括化学修饰；所述化学修饰优选包括非天然氨基酸修饰、伪肽化策略、逆肽策略、环化策略、末端结构修饰、高级脂肪酸修饰、聚乙二醇修饰、蛋白融合策略或胆固醇修饰。
在本发明中，所述非天然氨基酸修饰为β氨基酸或D型氨基酸，用它替换活性肽中的特定氨基酸，可以使活性肽在体内不易被蛋白酶识别水解；所述伪肽化策略优选为通过模拟多肽水解的过渡态，利用生物电子等排原理对易水解的酰胺键进行替换，使多肽免于蛋白酶的水解切割从而保留甚至提高肽类化合物的药理活性，用于替换结构有羟基亚甲基和缩硅酮片段等；所述逆肽策略为改变肽键方向的多肽结构修饰策略，相关的肽称为逆肽或逆反肽，肽键方向的改变同样可以改变蛋白酶对底物的识别作用，从而达到抗降解的作用。而且这种修饰可以在一定程度上提高化合物的代谢稳定性；所述环化策略优选为侧链-侧链式、终端-侧链式、终端-终端式(头尾相连式)；其中侧链 -侧链式环化最常见类型是半胱氨酸残基间的二硫桥接，引入这种环化的方法是通过一对半胱氨酸残基脱保护然后氧化构成二硫键，通过选择性地移除巯基保护基可以实现多环的合成；终端-侧链式环化通常涉及C末端与赖氨酸或鸟氨酸侧链的氨基，或者N末端与门冬氨酸或谷氨酸侧链，还有一些多肽环化是通过末端C与丝氨酸或苏氨酸侧链形成醚键而构成，链状多肽可以在溶剂中环化或者固定在树脂上通过侧链环化，头尾相连式合成环状多肽的产率取决于链状多肽的序列，因此，在大规模制备环状多肽前，首先应该创建可能的链状先导多肽库，然后进行环化以寻找能达到最佳结果的序列；所述末端结构修饰优选为N-端甲基化和N-端烷基化，N-端乙酰化和烷基化的酰胺键，往往可以改变肽类分子内或分子间的氢键相互作用，从而影响肽类分子的空间结构进而改变其物理化学性质，提高肽类分子的细胞渗透性；所述高级脂肪酸修饰可以改变肽类化合物的性质，提高肽类化合物的透膜性。如豆蔻酰化和棕榈酰化，用脂肪酸酰化N末端可以让多肽或蛋白质与细胞膜结合。利用标准的偶联反应即可将豆蔻酸连接到树脂-多肽的N末端，生成的脂肽可在标准条件下解离并通过 RP-HPLC纯化；所述聚乙二醇修饰(PEG修饰)可以改善肽类分子的稳定性、减少蛋白酶的降解、不易被肾小球滤过，从而提高多肽药物的稳定性，延长药物的半衰期。聚乙二醇即PEG活化成聚乙二醇二酸活化酯PEG-DA-NHS，PEG分子量选用4000～10000， PEG-DA-NHS与抗肿瘤寡肽反应是PEG-DA-NHS连接到抗肿瘤寡肽 N-末端的游离氨基上，1分子PEG通过共价结合2分子抗肿瘤寡肽，形成一个共价修饰物PEG-抗肿瘤寡肽；所述蛋白融合策略是指利用基因工程技术，将蛋白或多肽分子与免疫球蛋白Fc片段或血清白蛋白HSA融合而产生新型分子的修饰策略。融合Fc或HSA片段之后的多肽分子，分子尺寸显著增大，降低了肾对多肽药物的清除率，从而延长多肽药物的半衰期；所述胆固醇修饰中胆固醇的引入常常可以在提高其在体内半衰期的同时增强多肽的药理活性，一般是在C端外侧链接胆固醇分子。本发明这些化学修饰的目的是提高多肽抑制剂在体内的稳定性，延长在血清中的半衰期，从而提高改造后的多肽的成药性。
本发明所述多肽组合物优选还包括穿膜肽；所述穿膜肽包括 TAT、Antp-(43/58)、果蝇的触角足突变蛋白 (RQLKIWFQNRRMKWKK，SEQ ID No.4)、小寡聚精氨酸((R) n)、小寡聚赖氨酸((K)n)、支多抗原肽(MAP，KLALKALKALKAALKLA，SEQ ID No.5)及它的类似物或转运素 (GWTLNSAGYLLGKINLKALAALAKKIL，SEQ ID No.6)；所述 TAT的氨基酸序列优选如SEQID No.2所示：YGRKKRRQRRR，所述Antp-(43/58)的氨基酸序列优选如SEQ ID No.3所示：RQIKIYFQNRRMKWKK。
在本发明中，当多肽组合物包括WLP靶向肽和穿膜肽时，所述穿膜肽优选为TAT；所述多肽组合物的氨基酸序列优选为 FSLNWRPPCLF-YGRKKRRQRRR(SEQ ID NO.1接SEQ IDNo.2)，即TAT-WLP，或YGRKKRRQRRR-FSLNWRPPCLF(SEQ ID NO.2接SEQ ID No.1)，即WLP-TAT。本发明对所述组合的合成没有任何限定，优选由GenScript公司合成。
本发明所述多肽组合物通过靶向精氨酸甲基转移酶，抑制了癌细胞活性，进而达到了抗肿瘤的技术效果，因此可用于制备CARM1短肽类抑制剂。CARM1底物上甲基化位点所在的短肽序列与CARM1 的竞争性结合会影响CARM1酶活性，本发明此为基础利用计算机辅助筛选所有底物甲基化位点序列与CARM1的结合力，以结合力排序，合成了排名较前的七条短肽，并通过对癌细胞抑制活性的检测，确定了对癌细胞生长抑制效果最好的一条短肽，为潜在的CARM1的酶活性抑制剂。
本发明提供了上述多肽组合物在制备CARM1短肽类抑制剂中的应用。
本发明提供了一种CARM1短肽类抑制剂，所述抑制剂的有效成分包括上述多肽组合物。本发明所述多肽组合物对乳腺癌细胞系和肝癌细胞系的增殖抑制的IC50为7.69～20.3，能够显著地抑制乳腺癌细胞和肝癌细胞增殖，可用于制备预防和/或治疗与CARM1抑制剂有关的疾病的药物中。
本发明提供了上述多肽组合物或上述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抑制剂；在本发明中，所述癌症包括乳腺癌、结直肠癌、肺癌、肝癌、卵巢癌、前列腺癌、口腔癌、骨肉瘤和急性髓细胞白血病。在本发明实施例中，利用乳腺癌的细胞系MCF7、T47D和MDA-MB-231和肝癌的细胞系H1299和HepG2表征所述药物对于乳腺癌和肝癌的抑制效果，且上述细胞系的来源为ATCC细胞库，本发明所述多肽组合物对乳腺癌的细胞系MCF7、T47D和 MDA-MB-231和肝癌的细胞系H1299和HepG2细胞增殖抑制的IC50为7.69～20.3，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抗肿瘤的多肽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
将不同的乳腺癌细胞系(MCF7、T47D、MDA-MB-231)和肝癌细胞系(H1299、HepG2)的细胞铺于96孔板中，铺板密度为 20％～30％。
24小时后，加入含有不同浓度TAT-WLP(即， FSLNWRPPCLF-YGRKKRRQRRR，SEQ IDNO.1接SEQ ID No.2， GenScript公司合成)的水溶液。测试药物(TAT-WLP)设立12个药物浓度梯度：400μM、200μM、100μM、50μM、25μM、12.5μM、6.25μM、 3.125μM、1.5625μM和0μM(空白组，只添加DMSO)和对照组为穿膜肽TAT的短肽，其氨基酸序列为SQQTPRFNPIM(SEQ IDNo.7)。每个浓度梯度包括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单溶液试剂包含一种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 Thermo Multiskan 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1所示。
表1细胞增殖抑制数据
由表1可知，空白组和对照组均对细胞没有抑制作用，TAT-WLP 具有显著的抑制乳腺癌细胞和肝癌细胞增殖的效果，可用于制备预防和/或治疗与CARM1活性异常有关的疾病的药物中，尤其是制备治疗癌症的相关药物中的应用。
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。
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Claims (3)
1.一种抗肿瘤的多肽组合物，其特征在于，所述多肽组合物为由WLP靶向肽和穿膜肽连接形成的短肽TAT-WLP；所述WLP靶向肽的氨基酸序列如SEQ ID No.1所示；
所述穿膜肽为TAT，所述TAT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癌症的药物中的应用；所述癌症为乳腺癌或肝癌。
3.一种治疗癌症的药物，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；所述癌症为乳腺癌或肝癌。
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| Cancer-cell-secreted CXCL11 promoted CD8+ T cells infiltration through docetaxel-induced-release of HMGB1 in NSCLC;Qun Gao;J Immunother Cancer;第7卷(第1期);全文 * |
| 组蛋白甲基化的研究进展;梁琳;现代生物医学进展;第9卷(第10期);全文 * |
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