CN104109193A - 一种抗癌活性肽变体及其应用 - Google Patents
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Abstract
本发明提供了一种抗癌活性肽变体，该蛋白变体相对于野生型具有更强的抑制肿瘤细胞生长的效果。这些变体蛋白质和它们的衍生物可以用于多种肿瘤的治疗。
Description
技术领域
本发明属于生物技术领域，具体地说，本发明涉及抗癌活性肽变体。
背景技术
多肽抗癌药物是近年来抗癌药物研发的热点。现有技术中，专利申请ZL200710035478.8从新疆穴居狼蛛粗毒中分离纯化获得的抗癌活性肽，为24肽。这种多肽能诱导细胞凋亡杀灭多种癌细胞，并能抑制癌细胞增殖，但对正常细胞和动物毒性较弱；同时还可抑制低氧诱导因子HIFα转录活性，从而抑制肿瘤组织血管再生，有效的抑制实体瘤生长；其抗癌活性具有高效低毒的特点，对于开发治疗肺癌、肝癌、子宫颈癌等实体瘤的药物有着较好的应用前景。
现有技术中，为了提高多肽的活性，针对多肽序列进行特异性的改变，从而寻找活性更高的变体是常规的做法。为了进一步提高该多肽的生物活性，申请人通过大量的实验，针对该申请获得的多肽进行了氨基酸的改变，从而获得了比原始多肽本身具有更高抑制活性的变体。
发明详述
本发明涉及的多肽，序列如下：
NB：RKGWFKAMKSIAKFIAKEKLKEHL；
(NB1)：RKGWFKAMKSTAKFIAKEKLKEHL；
(NB2)：RKGWFKAMKSTAKFIAKEKLKEHLS；
(NB3)：SRKGWFKAMKSTAKFIAKEKLKEHLSS；
(NB4)：SRKGWFKAMKSTAKFIAKEKEKEHLS；
(NB5)：SRKGWFKAMKSTAKFIAKEKSKEHLSS；
(NB6)：SRKGSFKAMKSTAKFIAKEKSKEHLS；
(NB7)：SRKGFKAMKSTAKFIAKEKSKEHLSS；
(NB8)：SRKGFKAMKSTAKFIAKEKSKEHLS；
(NB9)：RKGWAKAMKSTAKFIAKEKLKEHL；
(NB10)：RKGWAKAMKSFAKFIAKEKLKEHL；
(NB11)：RKGWIKAMKSFAKFIAKEKLKEHL；
(NB12)：RKGWIKAMKSFAKFIAKEKLKEHLS；
(NB13)：RKGWWKAMKSTAKFIAKEKLKEHLS；
(NB14)：RKGWWKAMKSTAKFIAKEKLKEHL；
对照1：RKGWFKAMKSWAKFIAKEKLKEHL；
对照2：RKGWSKAMKSIAKFIAKEKLKEHL。
本发明的多肽合成后，可以做成游离态形式，也可以做成阳离子盐，如：TFA盐(三氟乙酸盐)，HCl盐(盐酸盐)，醋酸盐形式。
本发明的多肽，可以选择和一种或多种药物载体组合，制成多种药物剂型，用于治疗。这些药物剂型涵盖：注射溶液、片剂、霜剂、胶囊、软膏、洗剂、舌含片等剂型局部或全身给药。剂量优选在10-5～10-2mg/kg体重的范围内，以0.1％-0.5％的较高浓度全身或局部给药。对于具体治疗的最佳剂量的确定是本领域技术人员熟知的。
具体实施方式
实施例1：本发明多肽的人工化学合成
通过常规的合成方法，合成了本发明多肽，经质谱鉴定显示纯度较高，与设定序列的多肽分子结构相同。
实施例2：多肽杀灭癌细胞实验
通过MTT分析法测定了本发明多肽对Hela、CNE1和JB63种细胞株的毒性。作用浓度为40微摩尔本发明多肽。为了进一步验证，采用溶血实验检测本发明多肽对于正常细胞的毒性，结果显示200微摩尔本发明多肽只能裂解约15％的红细胞，说明本发明多肽对于正常细胞毒性较弱。在整体动物水平，我们也检测了本发明多肽的毒性，以200毫克/kg体重皮下注射小鼠没有出现明显的毒性反应(48小时内)，表明本发明多肽毒性较低，对于癌细胞具有较强的选择性。
采用Annexin V-异硫氰酸荧光素/碘化丙啶双染法检测了本发明多肽杀灭癌细胞的机制，发现本发明多肽可诱导Hela细胞凋亡，未经药物处理的Hela细胞凋亡较少，说明本发明多肽通过诱导细胞凋亡杀灭癌细胞。
本发明多肽对3中细胞株的杀灭结果
| 多肽名称 | Hela(致死率) | CNE1(致死率) | 肺癌细胞株A549(致死率) |
| NB | 95％ | 55％ | 69％ |
| NB1 | 99％ | 78％ | 97％ |
| NB2 | 99％ | 77％ | 96％ |
| NB3 | 100％ | 79％ | 96％ |
| NB4 | 100％ | 79％ | 95％ |
| NB5 | 99％ | 77％ | 97％ |
| NB6 | 100％ | 77％ | 98％ |
| NB7 | 100％ | 78％ | 97％ |
| NB8 | 99％ | 78％ | 96％ |
| NB9 | 99％ | 77％ | 96％ |
| NB10 | 99％ | 77％ | 97％ |
| NB11 | 100％ | 79％ | 98％ |
| NB12 | 100％ | 78％ | 97％ |
| NB13 | 99％ | 78％ | 98％ |
| NB14 | 99％ | 79％ | 97％ |
| 对照1 | 23％ | 11％ | 15％ |
| 对照2 | 30％ | 13％ | 17％ |
实施例3本发明多肽抑制裸鼠荷瘤生长
上述实验表明本发明多肽具有较强的抑制癌细胞作用，但仍需要确定本发明多肽是否具有在体抗实体瘤的作用，采用裸鼠荷瘤模型开展研究。实验结果示本发明多肽可明显抑制实体瘤生长。在给药前(0天)，对照组(生理盐水)和给药组的实体瘤体积大小相似，而在药物干预的时间内，生理盐水对照组的肿瘤体积快速增大，表明其肿瘤持续生长，而给药组中NB和NB1-14的肿瘤体积没有明显变化，说明肿瘤生长被抑制。在第10天给药完成，对照组(生理盐水)的肿瘤体积是给药组的5倍，而给药为对照1和对照2的肽其肿瘤大小与给药为生理盐水的对照组结果相似，肿瘤大小相当。上述结果表明本发明多肽可有效的抑制肿瘤生长。
Claims (3)
1.一种抗癌活性肽，其氨基酸序列为SEQ ID NO：1-15所示。
2.如权利要求1所述的活性肽变体在制备抑制肿瘤药物中的用途。
3.一种抗肿瘤药物制剂，它含有权利要求1所述的活性肽变体以及药学上合适的载体。
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106589093A (zh) * | 2017-01-17 | 2017-04-26 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106589096A (zh) * | 2017-01-17 | 2017-04-26 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106589097A (zh) * | 2017-01-17 | 2017-04-26 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106589095A (zh) * | 2017-01-17 | 2017-04-26 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106589094A (zh) * | 2017-01-17 | 2017-04-26 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106632639A (zh) * | 2017-01-17 | 2017-05-10 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106632638A (zh) * | 2017-01-17 | 2017-05-10 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106699864A (zh) * | 2017-01-17 | 2017-05-24 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106699863A (zh) * | 2017-01-17 | 2017-05-24 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106699865A (zh) * | 2017-01-17 | 2017-05-24 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106749592A (zh) * | 2017-01-17 | 2017-05-31 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106831970A (zh) * | 2017-01-17 | 2017-06-13 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN109293759A (zh) * | 2017-01-17 | 2019-02-01 | 李露青 | 一种抗癌活性肽变体及其应用 |
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| CN101168563A (zh) * | 2007-07-31 | 2008-04-30 | 厦门北大之路生物工程有限公司 | 抗癌活性肽 |
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| CN106589093A (zh) * | 2017-01-17 | 2017-04-26 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106589096A (zh) * | 2017-01-17 | 2017-04-26 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106589097A (zh) * | 2017-01-17 | 2017-04-26 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106589095A (zh) * | 2017-01-17 | 2017-04-26 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106589094A (zh) * | 2017-01-17 | 2017-04-26 | 李露青 | 一种抗癌活性肽变体及其应用 |
| CN106632639A (zh) * | 2017-01-17 | 2017-05-10 | 李露青 | 一种抗癌活性肽变体及其应用 |
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| CN106699864A (zh) * | 2017-01-17 | 2017-05-24 | 李露青 | 一种抗癌活性肽变体及其应用 |
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| CN109293759A (zh) * | 2017-01-17 | 2019-02-01 | 李露青 | 一种抗癌活性肽变体及其应用 |
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