CN109206474A - 一种线性肽合成方法 - Google Patents
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Abstract
本发明公开了一种线性肽合成方法，将2‑Chlorotrityl Chloride树脂用二氯甲烷、N，N‑二甲基甲酰胺进行活化后采用固相合成方法得到直链肽，使用三氟乙酸、水、苯酚和三异丙基硅烷的混合溶液对树脂进行切割，旋蒸除去三氟乙酸，加入冰乙醚，有白色固体析出，离心后的固体加水溶解，使用冻干机对其冻干，得到固体粉末；构建其中的一对二硫键，7位，20位半胱氨酸选用的巯基保护基为三苯甲基。本发明的有益效果是在保持原本稳定性的基础上，显著提高生物活性，具备穿透细胞膜能力，抗肿瘤活性。
Description
技术领域
本发明属于线性肽合成技术领域，具体涉及一种由L型，D型氨基酸组成的具备了穿透细胞膜能力，抗肿瘤活性的线性肽。
背景技术
NC_HLHR_D1自然杂志(DOI:10.1038/nature19791)记载，具有明显的热，酶稳定性。无生物活性。自然界中，野生型多肽稳定性差。全新设计多肽稀缺，生物活性难以控制，穿透细胞膜能力差。
发明内容
本发明的目的在于提供一种线性肽合成方法，本发明的有益效果是在保持原本稳定性的基础上，显著提高生物活性，具备穿透细胞膜能力，抗肿瘤活性。
本发明所采用的技术方案是按照以下步骤进行：
步骤1：将2-Chlorotrityl Chloride树脂用二氯甲烷、N，N-二甲基甲酰胺进行活化，后遵循固相合成方法得到直链肽P*LLYWRCLQLrRRpraerkcrrrRRN；
步骤2：使用三氟乙酸、水、苯酚和三异丙基硅烷的混合溶液对树脂进行切割，旋蒸除去三氟乙酸，加入冰乙醚，有白色固体析出，离心后的固体加水溶解，使用冻干机对其冻干，得到固体粉末；
步骤3：构建其中的一对二硫键，7位，20位半胱氨酸选用的巯基保护基为三苯甲基。
进一步，步骤1中用1：1的二氯甲烷、N，N-二甲基甲酰胺对树脂进行活化。
进一步，步骤3中三氟乙酸：水：苯酚：三异丙基硅烷＝88：5：5：2。
进一步，步骤4中对7位20位的二硫键进行构建：采用空气氧化法，取50mg的固体粉末，以0.2mg/mL的浓度溶解在150mL 0.2M碳酸氢铵水溶液中，于250mL茄形瓶，电磁搅拌，室温条件下反应48h，使用冻干机得到白色固体粉末。
附图说明
图1是合成方法示意图；
图2是UPROL-10e与MDM2的大分子相互作用数据图；
图3是UPROL-10e对肿瘤细胞HCT116p53+/+作用的柱状图；
Nutlin-3为阳性对照，UPROL，UPROL-4e为阴性对照。
图4是UPROL-10e体外血清稳定性实验，经过4小时的酶解，还有50％的保留量，证明稳定性好
图5是UPROL-10e标记荧光基团后，进入细胞核的情况。
具体实施方式
下面结合具体实施方式对本发明进行详细说明。
本发明技术方案如图1所示的合成路线：
1、UPROL-10e的合成：选用2-Chlorotrityl Chloride树脂，用1：1的二氯甲烷、N，N-二甲基甲酰胺对树脂进行活化，后遵循固相合成方法得到直链肽P*LLYWRCLQLrRRpraerkcrrrRRN，其中的11个氨基酸采用D型氨基酸，15个氨基酸采用L型氨基酸。通过修改序列，设计出全新线性结构，不仅保留其稳定性，还具备了穿透细胞膜能力，抗肿瘤活性。NC_HLHR_D1序列为PELQRKCKELdTRpeaerkcreeSDN。(小写字母为D型氨基酸缩写，大写字母为L型氨基酸)改造后UPROL-10e的序列为P*LLYWRCLQLrRRpraerkcrrrRRN。P*为合成非天然氨基酸。
2、随后使用三氟乙酸(TFA)：水：苯酚：三异丙基硅烷＝88：5：5：2的20mL混合溶液对树脂进行切割，旋蒸除去三氟乙酸，加入冰乙醚，有白色固体析出，离心后的固体加水溶解，使用冻干机对其冻干，得到固体粉末。
3、然后开始构建其中的一对二硫键，7位，20位半胱氨酸选用的巯基保护基为三苯甲基(Trt)。对7位20位的二硫键进行构建：Trt保护基在切割过程中被同时脱去，因此采用空气氧化法，取50mg的固体粉末，以0.2mg/mL的浓度溶入150mL 0.2M碳酸氢铵水溶液，250mL茄形瓶，电磁搅拌，室温条件下反应48h，反应结束后进行HPLC分离分析，同时辅以ESI-MS检测，收集目标峰后，使用冻干机得到白色固体粉末。
实验方法：
借助Arrayit，SpotBot3针点平台中的SpotBot3Microarrayer控制软件将化合物至于生物芯片Graft-to-PCL表面，紫外光交联15min将化合物交联于芯片表面。蛋白的初始浓度为0.1-100μM。用PBS缓冲液，按照一定的比例进行稀释，配置不同浓度的蛋白进样检测。得到的数据根据PLEXERA SPR Date Analysis Module(DAM)分析软件进行数据分析与拟合，获得结合动力学常数。
缓冲液(buffer)：1×PBS
重生液：Gly-Hcl(PH＝2)
进样流速1μl/s，进样时间180s；
解离流速1μl/s，进样时间200s；
重生流速2μl/s，重生时间200s。
图2是UPROL-10e与MDM2的大分子相互作用数据图；图3是UPROL-10e对肿瘤细胞HCT116 p53+/+作用的柱状图；其中Nutlin-3为阳性对照，UPROL，UPROL-4e为阴性对照。图4是UPROL-10e体外血清稳定性实验，经过4小时的酶解，还有50％的保留量，证明稳定性好。图5是UPROL-10e标记荧光基团后，进入细胞核的情况。表1是UPROL-10e与MDM2蛋白结合动力学常数。
表1
| Samples | Ka(1/Ms) | Kd(1/s) | KD(M) |
| UPROL-10e-MDM2 | 5.19e4 | 6.38e-5 | 1.23e-9 |
UPROL-10e与p53的竞争性地与肿瘤细胞内的MDM2结合。起到抗肿瘤的作用。p53为肿瘤抑制蛋白(也称为p53蛋白或p53肿瘤蛋白)，属于最早发现的肿瘤抑制基因(或抑癌基因)之一。p53蛋白能调节细胞周期和避免细胞癌变发生。因此，p53蛋白被称为基因组守护者。总而言之，其角色为保持基因组的稳定性，避免突变发生。MDM2是一种人类中由MDM2基因编码的蛋白质。Mdm2是p53肿瘤抑制因子的重要负调节因子。Mdm2蛋白起到E3泛素连接酶的作用，其识别p53肿瘤抑制因子的N-末端反式激活结构域(TAD)和p53转录激活的抑制剂。UPROL-10e作为线性肽，合成产量大，合成难度小。UPROL-10e的KD达到1.23e-9，说明与MDM2有强结合力。
本发明的优点还在于：UPROL-10e仍保持着与NC_HLHR_D1相当的稳定性而其还具备了透膜能力，针对p53的抗肿瘤活性。
以上所述仅是对本发明的较佳实施方式而已，并非对本发明作任何形式上的限制，凡是依据本发明的技术实质对以上实施方式所做的任何简单修改，等同变化与修饰，均属于本发明技术方案的范围内。
Claims (4)
1.一种线性肽合成方法，其特征在于按照以下步骤进行：
步骤1：将2-Chlorotrityl Chloride树脂用二氯甲烷、N，N-二甲基甲酰胺进行活化，后遵循固相合成方法得到直链肽P*LLYWRCLQLrRRpraerkcrrrRRN；
步骤2：使用三氟乙酸、水、苯酚和三异丙基硅烷的混合溶液对树脂进行切割，旋蒸除去三氟乙酸，加入冰乙醚，有白色固体析出，离心后的固体加水溶解，使用冻干机对其冻干，得到固体粉末；
步骤3：构建其中的一对二硫键，7位，20位半胱氨酸选用的巯基保护基为三苯甲基。
2.按照权利要求1所述一种线性肽合成方法，其特征在于：所述步骤1中用1：1的二氯甲烷、N，N-二甲基甲酰胺对树脂进行活化。
3.按照权利要求1所述一种线性肽合成方法，其特征在于：所述步骤3中三氟乙酸：水：苯酚：三异丙基硅烷＝88：5：5：2。
4.按照权利要求1所述一种线性肽合成方法，其特征在于：所述步骤4中对7位20位的二硫键进行构建：采用空气氧化法，取50mg的固体粉末，以0.2mg/mL的浓度溶解在150mL 0.2M碳酸氢铵水溶液中，于250mL茄形瓶，电磁搅拌，室温条件下反应48h，使用冻干机得到白色固体粉末。
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| CN108623659A (zh) * | 2018-03-17 | 2018-10-09 | 中国海洋大学 | 一种氨基酸全部选用d型氨基酸的抗菌肽合成方法 |
| CN108640975A (zh) * | 2018-03-17 | 2018-10-12 | 中国海洋大学 | 一种n端乙酰化抗菌肽的合成方法 |
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