CN104193809A - 一种凝血酶抑制及其制备方法、应用 - Google Patents
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Abstract
本发明涉及药物领域，具体涉及预防和治疗或预防动脉粥样硬化的多肽化合物。凝血酶抑制多肽1，其特征在于：其序列为ETARTPRADDGKLAAAACLEGNCAE。采用Fmoc保护的固相合成技术制备。可共价连接一个佐剂，佐剂是牛血清白蛋白，人血清白蛋白，或聚乙二醇。凝血酶抑制多肽1在治疗动脉粥样硬化相关疾病中的应用。所述的动脉粥样硬化相关疾病是心绞痛、心肌梗塞、心律失常、脑卒中、脑萎缩、顽固性高血压、肾功能不全等病变。可通过多种给药方式治疗动脉粥样硬化相关疾病，包括皮下或肌肉注射，静脉注射或者静脉滴注，口服给药如药丸、胶囊等，鼻喷剂等。本发明中的凝血酶抑制多肽1可以靶向抑制凝血酶，抑制凝血，达到预防或治疗动脉粥样硬化的作用。
Description
技术领域：
本发明涉及药物领域，具体涉及用于预防和治疗或预防动脉粥样硬化的多肽化合物。
背景技术：
动脉粥样硬化(Atherosclerosis)是由于脂肪、血栓、结缔组织和碳酸钙在血管(主要是动脉，但也包括静脉)沉积所造成的一种对人体有害的状态。其特点是动脉管壁增厚变硬、失去弹性和管腔缩小。动脉粥样硬化的症状主要决定于血管病变及受累器官的缺血程度，主动脉粥样硬化常无症状，冠状动脉粥样硬化者，若管径狭窄达75％以上,则可发生心绞痛、心肌梗塞、心律失常，甚至猝死。脑动脉硬化可引起脑缺血、脑萎缩，或造成脑血管破裂出血，肾动脉粥样硬化常引起夜尿、顽固性高血压、严重者可有肾功能不全。肠系膜动脉粥样硬化可表现为饱餐后腹痛便血等症状。下肢动脉粥样硬化引起血管腔严重狭窄者可出现间歇性跛行、足背动脉搏动消失，严重者甚至可发生坏疽。动脉粥样硬化是一组称为动脉硬化的血管病中最常见、最重要的一种。
目前预防和治疗动脉粥样硬化的药物，主要为针对控制易患因素。如患有糖尿病、应及时控制血糖，包括饮食控制。2型糖尿病的降糖药物应以不引起高胰岛素血症为宜如达美康等；如有高血压则应给降压药，使血压降至适当水平，如有血胆固醇增高，则应控制高胆固醇适当给予降脂药物。
凝血酶能使纤维蛋白原转化成纤维蛋白。血管内促进血栓的形成，引起动脉粥样硬化。我们的实验表明，采用凝血酶抑制剂可以控制血管内动脉粥样硬化血栓的形成，能有效抑制动脉粥样硬化斑块的形成。这是一个治疗动脉粥样硬化的新靶点。
现阶段，没有成熟开发的凝血酶抑制剂问世，用于治疗动脉粥样硬化。
发明内容：
本发明目的是针对现有治疗动脉粥样硬化药物的特点，设计一种多肽化合物，能有效治疗或预防动脉粥样硬化。
技术方案
凝血酶抑制多肽1，其特征在于：其序列为ETARTPRADDGKLAAAACLEGNCAE。采用Fmoc保护的固相合成技术制备。可共价连接一个佐剂，佐剂是牛血清白蛋白，人血清白蛋白，或聚乙二醇。凝血酶抑制多肽1在治疗动脉粥样硬化相关疾病中的应用。所述的动脉粥样硬化相关疾病是心绞痛、心肌梗塞、心律失常、脑卒中、脑萎缩、顽固性高血压、肾功能不全等病变。可通过多种给药方式治疗动脉粥样硬化相关疾病，包括皮下或肌肉注射，静脉注射或者静脉滴注，口服给药如药丸、胶囊等，鼻喷剂等。
有益结果：
本发明中的凝血酶抑制多肽1可以靶向抑制凝血酶，抑制凝血，达到预防或治疗动脉粥样硬化的作用。更优选是治疗动脉粥样硬化相关疾病药物中的用途。所述的脉粥样硬化相关疾病包括心绞痛、心肌梗塞、心律失常、脑卒中、脑萎缩、顽固性高血压、肾功能不全等病变。
具体实施方式
实施例1
多肽的化学合成方法
多肽1用Fmoc保护的固相合成技术制备。合成反应按照多肽1序列从C端向N端进行，Rink介质(可在Advanced Chem Tech公司购得)上有自由氨基。每一步连接过程中，氨基酸残基都要活化，活化混合物中有4倍于介质上自由氨基的HBTU，HOBt，DIEA和Fmoc-氨基酸。每次氨基酸的连接反应之后，都用一个吡啶/醋酸/N-甲基咪唑(4:1:0.5)的混合物来封闭未连接的自由氨基，封闭反应10分钟。每次氨基酸的连接反应之后，下一个氨基酸连接之前，都要把介质上的Fmoc-基团去掉，去Fmoc-基团使用含20％哌啶的二甲基甲酰胺，需15分钟。最后，当所有氨基酸残基顺序连接之后，多肽1用98％三氟乙酸从介质上切割下来，切割在室温下进行2小时。
应用上述化学条件可合成并获得多肽1，序列为ETARTPRADDGKLAAAACLEGNCAE，该序列为全新序列。
实施例2
凝血酶抑制多肽1对小鼠动脉粥样硬化模型的影响
建立小鼠动脉粥样硬化模型。雄性8周龄的C57BL/6J小鼠40只，随机分为4组，分别为：A组为空白对照组：普通饲料喂养；B组为模型对照组：造模+高脂饲料喂养；C组为药物干预组：造模+高脂饲料+凝血酶抑制多肽1(10mg/kg/d)；D为阳性药干预组：造模+高脂饲料+瑞舒伐他汀片(10mg/kg/d)。连续12周。A组小鼠饲料为普通饲料，B、C、D组小鼠用高脂高胆固醇饲料(含15％猪油+0.25％胆固醇)喂养，以加速动脉粥样硬化模型的形成。12周后，记录小鼠体重，检测多肽1对血清胆固醇的影响：血清总胆固醇(total cholesterol,TC)、甘油三酯(tryglyeride,TG)、高密度脂蛋白胆固醇(high density lipoproteincholesterol,HDL-C)和低密度脂蛋白胆固醇(low density lipoprotein cholesterol,HDL-C)的水平；，检测小鼠主动脉粥样硬化形成情况：对小鼠主动脉大体和主动脉根部冰冻切片行油红O染色，对动脉粥样斑块面积进行定量。
结果：各组实验小鼠实验期间体重都有增长趋势。随着喂养时间的变化，高脂饮食喂养组的体重增长较正常饮食组快(P<0.05，见表1)。多肽1组小鼠体重增长与正常饮食组相当(P>0.05)，与模型组相比体重较轻(P<0.05)。多肽1组与高脂高胆固醇喂养的模型小鼠组相比，TG、TC、HDL-C、LDL-C水平显著降低(P<0.01，见表2)，动脉粥样斑块面积显著性减小(P<0.01，见表3)，与模型对照组比较差异均有统计学意义。
表1 凝血酶抑制多肽1对小鼠动脉粥样硬化模型小鼠体重的影响
*p<0.05，**p<0.01与模型组相比
表2 凝血酶抑制多肽1对小鼠动脉粥样硬化模型小鼠胆固醇的影响
*p<0.05，**p<0.01与模型组相比
表3 凝血酶抑制多肽1对小鼠动脉粥样硬化模型小鼠动脉粥样硬化面积的影响
*p<0.05，**p<0.01与模型组相比
结论：凝血酶抑制多肽1对小鼠动脉粥样硬化具有治疗作用。
SEQUENCE LISTING
<110> 苏州普罗达生物科技有限公司
<120>一种凝血酶抑制及其制备方法、应用
<130>
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 25
<212> PRT
<213> 人工序列
<400> 1
Glu Thr Ala Arg Thr Pro Arg Ala Asp Asp Gly Lys Leu Ala Ala Ala
1 5 10 15
Ala Cys Leu Glu Gly Asn Cys Ala Glu
20 25
Claims (6)
1.一种凝血酶抑制多肽，其特征在于：其序列为ETARTPRADDGKLAAAACLEGNCAE。
2.一种权利要求1 所述多肽的制备方法，其特征在于：采用Fmoc 保护的固相合成技术制备。
3.根据权利要求2所述的多肽的制备方法，其特征在于：共价连接一个佐剂，佐剂是牛血清白蛋白，人血清白蛋白，或聚乙二醇。
4.一种权利要求1所述的多肽在制备治疗动脉粥样硬化相关疾病中药物的应用。
5.根据权利要求4的用途，其特征在于所述的动脉粥样硬化相关疾病是心绞痛、心肌梗塞、心律失常、脑卒中、脑萎缩、顽固性高血压、肾功能不全。
6.根据权利要求4所述的多肽1的用途，其特征在于：通过多种给药方式治疗动脉粥样硬化相关疾病，包括皮下或肌肉注射，静脉注射或者静脉滴注，口服给药如药丸、胶囊等，鼻喷剂。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105175505A (zh) * | 2015-09-08 | 2015-12-23 | 苏州普罗达生物科技有限公司 | 瘦素激动多肽及其应用 |
| CN105175504A (zh) * | 2015-09-08 | 2015-12-23 | 苏州普罗达生物科技有限公司 | 血管性血友病因子抑制多肽及其应用 |
| CN113773369A (zh) * | 2015-08-05 | 2021-12-10 | 陕西麦科奥特科技有限公司 | 有抗凝血和抗血小板活性的多靶点化合物及制法和用途 |
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| CN1050720A (zh) * | 1989-10-03 | 1991-04-17 | 默里尔多药物公司 | 抗凝血肽 |
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| CN1050720A (zh) * | 1989-10-03 | 1991-04-17 | 默里尔多药物公司 | 抗凝血肽 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113773369A (zh) * | 2015-08-05 | 2021-12-10 | 陕西麦科奥特科技有限公司 | 有抗凝血和抗血小板活性的多靶点化合物及制法和用途 |
| CN105175505A (zh) * | 2015-09-08 | 2015-12-23 | 苏州普罗达生物科技有限公司 | 瘦素激动多肽及其应用 |
| CN105175504A (zh) * | 2015-09-08 | 2015-12-23 | 苏州普罗达生物科技有限公司 | 血管性血友病因子抑制多肽及其应用 |
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