CN114585735A - ‘血管内血栓’溶解剂 - Google Patents
‘血管内血栓’溶解剂 Download PDFInfo
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- CN114585735A CN114585735A CN202080073980.1A CN202080073980A CN114585735A CN 114585735 A CN114585735 A CN 114585735A CN 202080073980 A CN202080073980 A CN 202080073980A CN 114585735 A CN114585735 A CN 114585735A
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Abstract
本发明涉及一种‘血管内血栓’的溶解剂,更具体地说,涉及一种由对于‘血管内血栓’的血栓识别结构域和血栓溶解结构域组成而具有溶解‘血管内血栓’功能的多肽、基因及含有其的药物组合物。本发明的识别‘血管内血栓’而溶解‘血管内血栓’的多肽,其特征在于,由包括被记载为序列号1或序列号2的氨基酸序列的血栓溶解结构域和包括被记载为序列号3或序列号4的氨基酸序列的血栓识别结构域组成。根据本发明的识别‘血管内血栓’而溶解血栓的多肽,由于通过没有严重出血副作用地溶解哺乳动物的血液内血栓而具有预防和治疗血栓症的效果,因此可以被广泛利用为血栓症和相关疾病的预防或治疗剂。
Description
技术领域
本发明涉及一种‘血管内血栓’的溶解剂,更具体地说,涉及一种由对于‘血管内血栓’的血栓识别结构域(thrombo-recognition domain)和血栓溶解结构域(thrombolyticdomain)组成而具有溶解‘血管内血栓’功能的多肽、基因及含有其的药物组合物。
背景技术
当血管组织受伤时,血液会流到血管外,因此在血管的伤口周围血管组织会形成用于防止出血的血液凝固块(blood clot)。仅限于伤口部位而防止出血的组织血栓是一种正常的伤口治愈过程,是包括人类在内的动物生存所必须的过程。与此不同,在血液流过的血管内存在非正常血液凝固块的情况被称为“血管内血栓(Intravascular thrombus)”。如果血管内血栓没有被清除,就会阻塞血液的流动而引起血栓症(thrombosis)。当血液的流动受阻时,会引起因缺氧(hypoxia)而引起组织坏死(necrosis)的诸如脑中风、肺梗塞及心肌梗塞的致命性血栓症(thrombosis)疾病。因此,如果发生血栓症,迫切需要立即治疗。
血栓症是一种非常严重的疾病且发病率也高,已经开发了各种治疗剂。血栓溶解剂(Thrombolytics)作为溶解血栓的直接治疗剂,代表性的有组织型纤溶酶原激活剂(tissue-type plasminogen activator:tPA)(US4766075、US5185259、US5587159、US5869314、US6274335)、尿激酶(urokinase)(US4259447、US4851345、US5055295、US6759042)、链激酶(streptokinase)(US3855065、US5011686、US7105327)。这些血栓溶解剂,即tPA(阿替普酶(alteplase),瑞替普酶(reteplase))、尿激酶(urokinase)、链激酶(streptokinase)等,均具有切断体内纤溶酶原(plasminogen)而激活成纤溶酶(plasmin),激活的纤溶酶分解血栓而治疗血栓症的效果。然而,激活的纤溶酶也分解用于防止受损血管出血的血栓,从而诱导伤口部位的严重出血。这是因为纤溶酶是一种不具有针对‘血管内血栓’的特异性的非特异性血栓溶解剂。由于纤溶酶的严重出血副作用,从而产生纤溶酶的血栓溶解剂,即tPA、尿激酶及链激酶,都非常受限制,仅在某些情况下才被使用。
由于血栓溶解剂的致命副作用,实际上在医院,给血栓症患者使用诸如肝素(heparin)、华法林(warfarin)、达比加群(davigatran)等抗凝剂(anticoagulant)或诸如阿司匹林等抗血小板剂(Antiplatelets)来代替血栓溶解剂。抗凝剂和抗血小板剂不会分解已经形成的血栓,而是会防止血管内形成额外的血栓。即,抗凝剂和抗血小板药物不具有血栓分解能力,因此致命的出血少,但是对血栓症的治疗没有大的效果。此外,由于抗凝剂和抗血小板剂会干扰血栓形成,因此阻碍伤口治愈,从而出血副作用也很严重。
因此,为了治疗血栓症,迫切需要开发一种对‘血管内血栓’具有特异性的溶解剂,该溶解剂能够仅对‘血管内血栓’进行准确地识别和分解且不干扰正常的伤口治愈而最小化出血副作用。
发明内容
要解决的技术问题
本发明的发明人在认识到不干扰血管组织中正常发生的血液凝固过程和伤口治愈而仅对引起血栓症的‘血管内血栓’进行准确溶解的‘血管内血栓’溶解剂是最理想的血栓症治疗剂之后,一直在锐意开发一种‘血管内血栓’溶解剂。因此,本发明的目的在于提供一种创新概念的‘血管内血栓’溶解剂作为血栓症治疗剂,所述‘血管内血栓’溶解剂通过仅对引起血栓症的‘血管内血栓’进行准确溶解而完全没有诸如全身出血的严重出血副作用。
解决问题的方案
为了实现上述目的,本发明提供一种多肽,所述多肽识别‘血管内血栓’而溶解‘血管内血栓’,其特征在于,由包括被记载为序列号1或序列号2的氨基酸序列的血栓溶解结构域和包括被记载为序列号3或序列号4的氨基酸序列的血栓识别结构域组成。
本发明还提供一种血栓溶解结构域基因,所述血栓溶解结构域基因编码具有被记载为序列号1或序列号2的氨基酸序列的血栓溶解结构域,其特征在于,具有被记载为序列号5或序列号6的碱基序列。
本发明还提供一种血栓识别结构域基因,所述血栓识别结构域基因编码具有被记载为序列号3或序列号4的氨基酸序列的血栓识别结构域,其特征在于,具有被记载为序列号7或序列号8的碱基序列。
本发明还提供一种用于治疗或预防血栓症和相关疾病的药物组合物,其特征在于,包括识别‘血管内血栓’而溶解血栓的多肽或编码其的基因作为有效成分。
发明的效果
根据本发明的识别‘血管内血栓’而溶解血栓的多肽,通过没有严重出血副作用地溶解哺乳动物的血液内血栓而具有预防和治疗血栓症的效果。
附图说明
图1是根据发明的实验例1对离体血栓用血栓溶解酶SK或HtrA1进行处理后确认血栓溶解能力的结果(a;溶解有血栓的图像(HA1)和未溶解血栓的血栓块图像(SK)、b;处理前的以%表示的血栓块溶解度、c;血栓分解物FDP(fibrin degradation products,纤维蛋白降解产物)、d;血栓分解物D-二聚体(D-dimer)的量(Ctrl:对照组、SK:链激酶、HA1;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA1)。
图2是根据发明的实验例1对离体血栓用血栓溶解酶SK或HtrA2进行处理后确认血栓溶解能力的结果(a;溶解有血栓的图像(HA2)和未溶解血栓的血栓块图像(SK)、b;处理前的以%表示的血栓块溶解度、c;血栓分解物FDP(fibrin degradation products,纤维蛋白降解产物)、d;血栓分解物D-二聚体(D-dimer)的量(Ctrl:对照组、SK:链激酶、HA2;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA2)。
图3是根据发明的实验例2确认‘血管内血栓’溶解多肽HtrA1的纤溶酶原活性性能的结果(a;由纤溶酶原的激活产生的纤溶酶降解的基质的荧光强度测量值、b;确认由纤溶酶原的激活产生的纤溶酶带的SDS-PAGE图像(Ctrl:对照组、PL:纤溶酶、SK:链激酶、UK;尿激酶、HA1;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA1)。
图4是根据发明的实验例2确认‘血管内血栓’溶解多肽HtrA2的纤溶酶原活性性能的结果(a;由纤溶酶原的激活产生的纤溶酶降解的基质的荧光强度测量值、b;确认由纤溶酶原的激活产生的纤溶酶带的SDS-PAGE图像(Ctrl:对照组、PL:纤溶酶、SK:链激酶、UK;尿激酶、HA2;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA2)。
图5是根据本发明实验例3为了评价本发明的血管内血栓溶解多肽是否具有血栓特异性而确认对伤口治愈过程中出现的纤溶成分(fibrinolysis components)是否具有活性的结果(a;对纤维蛋白原处理各血栓溶解酶之后由SDS-PAGE确认纤维蛋白原是否分解成纤维蛋白的图像、b;对细胞纤连蛋白(cellular fibronectin)处理各血栓溶解酶之后由免疫印迹(immuno-blot)确认纤连蛋白是否分解的图像、c;对血浆纤连蛋白(plasmafibronectin)处理各血栓溶解酶之后由免疫印迹确认纤连蛋白是否分解的图像(Ctrl:对照组、PL:纤溶酶、SK:链激酶、UK;尿激酶、HA1;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA1)。
图6是根据本发明实施例1利用动物模型在尾巴血栓症小鼠中确认本发明的‘血管内血栓’溶解多肽对血栓症的治疗效果的血栓症尾部图像结果(Ctrl:对照组、PL:纤溶酶、SK:链激酶、UK;尿激酶、tPA;组织纤溶酶原激活剂(tissue plasminogen activator)、HA1;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA1、HA2;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA2)。
图7是根据本发明实施例1利用动物模型在尾巴血栓症小鼠中确认本发明的‘血管内血栓’溶解多肽对血栓症的治疗效果的血栓症尾部组织的H&E染色图像结果(Ctrl:对照组、PL:纤溶酶、SK:链激酶、UK;尿激酶、tPA;组织纤溶酶原激活剂、HA1;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA1、HA2;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA2)
图8是根据本发明实施例3利用创伤动物模型确认本发明的‘血管内血栓’溶解多肽对伤口治愈的影响的出血图像结果(Ctrl:对照组、PL:纤溶酶、SK:链激酶、UK;尿激酶、tPA;组织纤溶酶原激活剂、HA1;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA1、HA2;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA2)。
图9是根据本发明实施例3利用创伤动物模型确认本发明的‘血管内血栓’溶解多肽HtrA1对伤口治愈的影响的出血试验结果。a;出血时间测量值、b;出血量测量值、c;出血液中血红蛋白含量测量值、d;伤口治愈和血液凝固所需时间测量值(Ctrl:对照组、PL:纤溶酶、SK:链激酶、UK;尿激酶、HA1;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA1)。
图10是根据本发明实施例3利用创伤动物模型确认本发明的‘血管内血栓’溶解多肽HtrA2对伤口治愈的影响的出血试验结果。a;出血时间测量值、b;出血量测量值、c;出血液中血红蛋白含量测量值、d;伤口治愈和血液凝固所需时间测量值(Ctrl:对照组、PL:纤溶酶、SK:链激酶、tPA;组织纤溶酶原激活剂(tissue plasminogen activator)、HA2;本发明的识别‘血管内血栓’而溶解血栓的多肽HtrA2)。
最佳实施方式
为了去除血栓,已经开发了各种药物,但是现有血栓溶解剂都有严重的出血副作用,难以有效地治疗血栓症和相关疾病。此外,这些治疗方法不能提前预防血栓症。
本发明人们着眼于‘血管内血栓’是一种蛋白质聚集体(protein aggregate)的点及降解聚集蛋白质的质量控制蛋白质(Quality control protein)是生物生存所必须的点,试图确认在体内存在具有识别错误折叠/聚集蛋白质(misfolded/aggregatedprotein)的结构域及分解错误折叠/聚集蛋白质而进行去除的结构域的内源性蛋白酶(endogenous proteinase),且该内源性蛋白酶可以分解血管内血栓。
因此,在本发明中,探索了识别错误折叠/聚集蛋白质的结构域、分解错误折叠/聚集蛋白质而进行去除的结构域及包括这些结构域的质量控制蛋白质。其结果,包括血栓识别结构域和血栓溶解结构域的多肽通过特异性地识别‘血管内血栓’并分解后去除,从而可以确认识别‘血管内血栓’而溶解血栓的多肽可以没有严重出血副作用地治疗血栓症。
即,在本发明中,可以确认通过识别包括血管内血栓识别结构域和血栓溶解结构域的‘血管内血栓’而溶解血栓的多肽(1)具有优异的血栓溶解能力,(2)与现有血栓溶解剂不同,由于不会将纤溶酶原激活成纤溶酶,因此不会有因纤溶酶的产生而导致出血风险,(3)与现有血栓溶解剂不同,由于不会分解对伤口治愈重要的纤维蛋白原(fibrinogen)、c-纤连蛋白(c-fibronectin)及p-纤连蛋白(p-fibronectin),因此不会干扰伤口治愈,(4)在体内动物模型中有效地治疗血栓症,(5)与现有血栓溶解剂不同,在体内动物模型中血栓栓塞症的治疗后痊愈存活率达到100%,(6)与现有血栓溶解剂不同,在体内出血动物实验中不干扰血液凝固和伤口治愈,因此没有出血副作用。
即,在本发明的一实施例中,在小鼠尾部血栓症模型中确认治疗效果的结果,确认了,与现有血栓溶解剂不同,本发明的识别‘血管内血栓’而溶解的多肽具有对血栓症的痊愈效果。
在作为本发明的另一实施例的肺血栓栓塞症的小鼠模型中,虽然在现有血栓溶解剂处理组中可以确认个体死亡,但是在识别‘血管内血栓’而溶解血栓的多肽治疗组中,存活率为100%,从而确认了本发明的识别‘血管内血栓’而溶解血栓的多肽完美地治疗致命的血栓栓塞症。
此外,在小鼠尾部出血实验中确认伤口治愈能力的结果,确认了本发明的识别‘血管内血栓’而溶解血栓的多肽处理组的伤口部位出血时间、出血量、损失的血红蛋白量、血液凝固时间等优异至未处理对照组的水平,从而与现有血栓溶解剂不同,具有完美的伤口治愈效果而完全没有出血副作用。
因此,一方面,本发明涉及一种识别‘血管内血栓’而溶解血栓的多肽,其特征在于,由包括被记载为序列号1或序列号2的氨基酸序列的血栓溶解结构域和包括被记载为序列号3或序列号4的氨基酸序列的血栓识别结构域组成。
在本发明中,所述多肽可以由包括被记载为序列号1的氨基酸序列的血栓溶解结构域和包括被记载为序列号3的氨基酸序列的血栓识别结构域组成,或可以由包括被记载为序列号2的氨基酸序列的血栓溶解结构域和包括被记载为序列号4的氨基酸序列的血栓识别结构域组成。
本发明中,所述识别‘血管内血栓’而溶解血栓的多肽,其特征在于,优选属于作为胰蛋白酶样多肽(trypsin-like polypeptide)的丝氨酸蛋白酶(serine protease)的高温要求(Htr)家族(High Temperature Requirement(Htr)family),更优选包括HtrA1、HtrA2。
所述血栓溶解结构域,其特征在于,可以是与序列号1或序列号2的氨基酸序列具有50%以上、优选80%以上、更优选90%以上类似性(homology)的结构域,所述血栓溶解结构域的特征在于,包括GNSGGPL肽或类似肽而赋予丝氨酸蛋白酶活性的结构域。
此外,所述血栓识别结构域,其特征在于,可以是与序列号3或序列号4的氨基酸序列具有50%以上、优选80%以上、更优选90%以上类似性(homology)的结构域。所述血栓识别结构域,其特征在于,具有由β-折叠链(beta-strand)和α-螺旋(alpha-helix)的多个组合组成的拓扑(topology)结构。即,所述血栓识别结构域可以是具有识别‘血管内血栓’和调节溶解酶活性功能的PDZ结构域或PDZ样结构域。
另一方面,本发明涉及一种血栓溶解结构域基因,所述血栓溶解结构域基因编码具有被记载为所述序列号1或序列号2的氨基酸序列的血栓溶解结构域,其特征在于,具有被记载为序列号5或序列号6的碱基序列。
所述血栓溶解结构域基因,其特征在于,与序列号5或序列号6的碱基序列具有50%以上、优选80%以上、更优选90%以上的类似性(homology)。
另一方面,本发明涉及一种血栓识别结构域基因,所述血栓识别结构域基因编码具有被记载为序列号3或序列号4的氨基酸序列的血栓识别结构域,其特征在于,具有被记载为序列号7或序列号8的碱基序列。
所述血栓识别结构域基因,其特征在于,与序列号7或序列号8的碱基序列具有50%以上、优选80%以上、更优选90%以上的类似性(homology)。
另一方面,本发明涉及一种用于治疗或预防血栓症和相关疾病的药物组合物,其特征在于,包括识别‘血管内血栓’而溶解血栓的多肽或编码其的基因作为有效成分。
本发明的药物组合物可以包括制剂时通常利用的药学上可接受的载体,可以举出乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯树胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油等,但不限于此。
本发明的药物组合物除了上述成分以外,还可以包括润滑剂、润湿剂、甜味剂、香味剂、乳化剂、悬浮剂、防腐剂等。适宜的药学上可接受的载体和制剂详细记载于雷明顿制药科学(Remington's Pharmaceutical Sciences)(第19版,1995年)。
本发明的药物组合物可以口服或非口服给药,优选非口服给药,在非口服给药的情况下,可以通过肌肉注射、静脉注射、皮下注射、腹腔注射、局部给药、经皮给药等方式给药。
本发明药物组合物的适宜给药量可根据制剂化方法、给药方式、患者的年龄、体重、性别、病理状况、食物、给药时间、给药途径、排泄速度及反应敏感性等因素以多种方式开处方。另一方面,本发明的药物组合物的优选给药量为每天0.0001-1000μg。
本发明的药物组合物按照本领域普通技术人员容易实施的方法通过利用药学上可接受的载体和/或赋形剂来制剂化,从而可以以单位剂量形式制备或通过封装在多剂量容器内制备。此时,制剂可以是在油或水性介质中的溶液、悬浮液或乳液的形态,或可以是提取物、粉末剂、颗粒剂、片剂或胶囊剂的形态,还可以包括分散剂或稳定剂。
根据本发明的用于治疗或预防血栓症和相关疾病的药物组合物,在对哺乳动物给药时,具有溶解‘血管内血栓’和最小化出血副作用的效果。
在本发明中,所述血栓症及相关疾病优选为选自血栓症(Thrombosis)、栓塞症(Embolism)、血栓栓塞症(Thromboembolism)、动脉血栓栓塞症(ArterialThromboembolism)、静脉血栓栓塞症(Venous Thromboembolism,VTE)、心血管疾病(cardiovascular disease)、脑血管疾病(cerebrovascular disease)、缺血性疾病(Ischemic disease)等由‘血管内血栓’引起的疾病组成的组中的任一个,但不限于此。作为具体的例子,优选选自深静脉血栓症(Deep Vein Thrombosis,DVT)、肺梗塞症(Pulmonary Embolism,PE)、缺血性脑中风(ischemic stroke)、中风、脑出血、脑梗塞、心肌梗塞、心脏麻痹及不稳定型心绞痛(unstable angina)组成的组中的任一个,但不限于此。
具体实施方式
以下,通过具体实施例更详细地说明本发明。然而,这些实施例仅用于更详细地说明本发明,本发明的范围不受这些实施例的限制。
实验例1:离体血栓溶解能力评价
作为识别‘血管内血栓’而溶解血栓的多肽的HtrA1和HtrA2被制备成重组蛋白。为此,利用正向引物(5'-AATTCATATGCAAGGGCAGGAAGATCCCA-3')(序列号11)和反向引物(5'-TATCTCGAGCTATGGGTCAATTTCTTCGGG-3')(序列号12)用PCR扩增相当于将血管内血栓结构域和血栓溶解结构域都包括的HtrA1氨基酸序列(序列号9)的157-480的cDNA。PCR条件是在95℃初始变性(initial denaturation)5分钟,然后将扩增(在95℃执行30秒,在63℃执行1分钟,在72℃执行2分钟)过程重复34次,然后在72℃执行10分钟。将其亚克隆到作为表达载体的pET28a+表达载体(Novagen,USA)的NdeI/XhoI位点。将获得的HtrA1重组质粒(recombinant plasmid)在大肠杆菌(E.coli)BL21(DE3)pLysS(Stratagene,USA)中电穿孔(electroporation)后在培养的情形下添加IPTG以表达HtrA1。重组大肠杆菌培养液经超声处理而制备细胞裂解液(cell lysate),使其通过econo-pac层析柱(Bio-Rad)进行分离,然后通过PD-10柱(Amersham,US)纯化,从而得到重组蛋白HtrA1。在HtrA2的情况下,利用正向引物(5'-GTCCTCGCCCATATGGCCGTCCCTAGCC-3')(序列号13)和反向引物(5'-GGCTCTCTCGAGTCATTCTGTGACCTCAGGG-3')(序列号14)用PCR扩增相当于HtrA2氨基酸序列(序列号10)的134-458的cDNA。PCR条件是在95℃初始变性5分钟,然后将扩增(在95℃执行30秒,在65℃执行45秒,在72℃执行1分钟)过程重复34次后在72℃执行10分钟。获得其后,以与HtrA1相同的方式,亚克隆到pET28a+表达载体(Novagen,USA)之后进行表达,从而获得重组蛋白HtrA2。
将准备好的重组蛋白HtrA1和HtrA2对离体血栓进行处理的情形下,确认了血栓溶解活性。利用血小板丰富的血液形成血栓,并在37℃下将对照组或各血栓溶解酶(2mg/ml)与50mM的三羟甲基氨基甲烷盐酸盐(Tris-HCl)一同处理24小时。在处理各酶后测量血栓的重量,并以处理前的%来表示。此外,对因组成血栓的纤维蛋白聚合物的(fibrin polymer)分解而产生的纤维蛋白降解产物(fibrin degradation products,FDP)和D-二聚体的量进行量化。
在图1中,与现有血栓溶解酶进行相比时,HtrA1的血栓溶解能力(图1的a、b)和纤维蛋白的分解能力(图1的c、d)最优异。在图2中,在HtrA2的情况下,仍然显示出比现有血栓溶解酶优异的血栓溶解能力(图2的a、b)和纤维蛋白分解能力(图2中的c、d)。
实验例2:纤溶酶产生能力的评价(血栓溶解机理)
目前血栓溶解剂的血栓溶解机理是通过将纤溶酶原激活为纤溶酶而发生纤溶酶依赖性纤维蛋白溶解的作用机理。为了与现有血栓溶解酶相比来确认作用机理,首先将各血栓溶解酶(0.1mg/ml)添加到纤溶酶原(1.23μM)和纤溶酶特异性荧光基质Boc-Glu-Lys-Lys-MCA(100μM)中,然后进行培养。通过测量被纤溶酶溶解的基质的荧光强度来确认了纤溶酶原对纤溶酶的激活。在由纤溶酶原(5.14μM)处理各酶(0.15mg/ml)之后,通过SDS-PAGE确认实际由纤溶酶原的激活而产生的纤溶酶带。
与现有血栓溶解酶相比时,HtrA1完全没有纤溶酶原的激活效果(图3的a),当然也没有产生纤溶酶(图3的b)。同样地,HtrA2也没有纤溶酶原的激活效果(图4的a),其结果,也没有纤溶酶产生(图4的b)。
实验例3:血栓特异性评价
为了评价HtrA1的血栓特异性,确认了对伤口治愈过程中出现的纤溶成分是否具有活性。为此,将纤维蛋白原与凝血酶(thrombin)进行反应而获得的纤维蛋白凝块(fibrinclot)与50mM的Tris-HCl对照组或血栓溶解酶(2mg/ml)在37℃下培养24小时。使用分光光度计在415nm波长测量纤维蛋白凝块的溶解。为了观察HtrA1对纤维蛋白原的活性,将纤维蛋白原(5μM)与50mM的Tris-HCl对照组或各血栓溶解酶(0.15mg/ml)在37℃下培养3小时,然后用SDS-PAGE确认了纤维蛋白原是否分解。为了观察HtrA1对纤连蛋白的活性,将纤连蛋白(1.52μM)与各血栓溶解酶(0.15mg/ml)一同在37℃下培养3小时,然后在4-12%的SDS凝胶进行分离,并用抗-cFN(anti-cFN)或抗-pFN(anti-pFN)抗体进行免疫染色。
如表1所示,HtrA1和HtrA2的情况下,与未处理的对照组相比时,不仅显示出了统计学上的显着差异,而且对于作为现有血栓溶解酶的链激酶的吸光度也显示出了统计学上的显着差异。就对纤维蛋白凝块的溶解性能而言,HtrA1最优异,其次优异的是HtrA2。
[表1]
组 | A415 |
对照 | 1.870±0.05 |
链激酶 | 1.335±0.07<sup>a</sup> |
尿激酶 | 1.047±0.06<sup>a</sup> |
HtrA1 | 1.055±0.10<sup>a,b</sup> |
HtrA2 | 1.002±0.09<sup>a,b</sup> |
a p<0.05与对照组的显着差异
b p<0.01与链激酶组的显着差异
然而,与现有血栓溶解酶不同,HtrA1显示出没有分解对伤口部位止血作用重要的纤维蛋白原(图5的a),也没有分解对伤口治愈重要的细胞纤连蛋白(cellularfibronectin)(图5的b)和血浆纤连蛋白(plasma fibr onectin)(图5的c)而保存。
最后,为了观察HtrA1对伤口治愈过程的活性,制作了将BALB/c小鼠尾部皮肤从外部切开的伤口(~30mm2)。将切下的伤口碎片与对照组50mM的Tris-HCl或各血栓溶解酶(2mg/ml)一同在37℃下培养72小时。通过观察装有伤口碎片的液体及测量550nm吸光度来判断伤口是否治愈。如上所述,在使用实际动物的创伤组织实验中,由于在现有血栓溶解酶处理时创伤组织的伤口没有治愈,因此可以确认因出血引起的吸光度数值,但是在HtrA1或HtrA2处理的情况下,由于吸光度低至与对照组相似的水平,因此可以确认发生了正常的伤口治愈(表2)。
[表2]
组 | A550 |
对照 | 0.235±0.031 |
链激酶 | 0.471±0.018<sup>a</sup> |
尿激酶 | 0.404±0.037<sup>a</sup> |
HtrA1 | 0.203±0.028<sup>a,b</sup> |
HtrA2 | 0.247±0.033<sup>a,b</sup> |
a p<0.05与对照组的显着差异
b p<0.01与链激酶组的显着差异
实施例1:血栓症的治疗效果
为了评价由本发明的成果物的血栓症治疗效果,进行了利用尾部血栓症模型的动物实验。在15周龄的雌性BALB/c小鼠中建立κ-角叉菜胶(κ-carrageenan)诱导的尾部血栓症模型。对具有尾部血栓症的各组(n=8)将生理盐水(对照组)或各血栓溶解酶注射至腹腔内,24小时后测量血栓症部位的长度和比率,将其结果示于表3和表4。
[表3]
a p<0.001与HtrA1(40mg/kg)组的显着差异
b p<0.01与HtrA1(40mg/kg)组的显着差异
如表3所示,在小鼠尾部血栓症模型中,与现有血栓溶解酶相比时,在HtrA1处理组的情况下,确认到能够观察到在尾部血栓症尾部长度和频率显着降低,这种血栓溶解效果与容量成比例地增加。即,在HtrA1的情况下,确认到即使是与现有血栓溶解酶相比,也具有统计学上显着水平的血栓症治疗效果。
[表4]
a p<0.001与HtrA2(40mg/kg)组的显着差异
b p<0.01与HtrA2(40mg/kg)组的显着差异
此外,如表4所示,在小鼠尾部血栓症模型中,与现有血栓溶解酶相比时,在HtrA2处理组的情况下,确认到也能够见到在尾部血栓症尾部长度和频率显着降低,且这种血栓溶解效果与容量成比例地增加。在HtrA2的情况下,不仅是与未处理组相比而且与现有溶栓酶相比,也具有统计学上显着水平的血栓症治疗效果。
在图7中,对血栓症尾部组织进行H&E染色而观察的结果,与上述血栓症尾部结果一样,直接确认血栓块和血栓溶解程度的结果,在HtrA1和HtrA2治疗组的情况下,完全没有发现血栓块,且在与现有血栓溶解酶相比时,也表现出优异的血栓症治疗。
实施例2:肺血栓栓塞症的治疗效果
接着,为了评价血栓栓塞症的预防和治疗效果,进行了利用肺血栓栓塞症模型的动物实验。在15周龄的雌性C57BL/6小鼠中建立由5'-二磷酸腺苷(Adenosine 5'-diphosphate,ADP)诱导的肺血栓栓塞症模型。对肺血栓栓塞症小鼠的各组(n=8)禁食12小时以上,然后以40mg/kg的剂量静脉注射生理盐水(对照组)或血栓溶解酶。30分钟后,给小鼠注射AD P(150mg/kg)诱导肺血栓栓塞症,然后确认死亡与否,将其结果示于表5和表6。
[表5]
组 | 剂量(mg/kg) | 致死数/总数 | 保护率(%) |
对照 | - | 6/6 | 0 |
纤溶酶 | 40 | 3/6 | 50 |
链激酶 | 40 | 4/6 | 33 |
尿激酶 | 40 | 2/6 | 67 |
HtrA1 | 40 | 0/6 | 100 |
从表5来看,在肺血栓栓塞症小鼠模型中,纤溶酶、链激酶、尿激酶处理组的情况下,表现出的存活率分别为50%、33%、66%,而HtrA1处理组表现出的存活率为100%,据此,可知本发明的HtrA1对致死性肺血栓栓塞症具有完美的治疗和预防效果。
[表6]
组 | 剂量(mg/kg) | 致死数/总数 | 保护率(%) |
对照 | - | 5/5 | 0 |
纤溶酶 | 40 | 2/5 | 60 |
链激酶 | 40 | 4/5 | 20 |
tPA | 40 | 3/5 | 40 |
HtrA2 | 40 | 0/5 | 100 |
从表6来看,在肺血栓栓塞症小鼠模型中,纤溶酶、链激酶、tPA处理组的情况下,表现出的存活率分别为60%、20%、40%,而HtrA2处理组表现出的存活率为100%,据此,可知本发明的HtrA2也对致死性肺血栓栓塞症具有完美的治疗和预防效果。
实施例3:消除体内出血风险的效果
当血栓溶解蛋白HtrA1给药时,为了确定创伤治愈期间是否存在体内出血风险,利用15周龄的C57BL/6雌性小鼠进行尾部出血检查。将生理盐水(对照组)或各血栓溶解酶以40mg/kg的剂量静脉内注射到小鼠组(n=5)。30分钟后,从麻醉的小鼠切下尾巴,采血直至出血停止,记录出血时间和出血量,测量采集的血液中的血红蛋白含量。此外,记录在鼠的断尾静脉中血液凝固所需的时间。
如图8所示,在小鼠尾部出血实验中,确认了HtrA1和HtrA2的出血与其他血栓溶解酶相比显着减少。在HtrA1处理组的情况下,测量实际出血时间(图9的a)、出血量(图9的b)、损失的血红蛋白量(图9的c)、止血所用时间(图9的d)的结果,确认到出血副作用无法与现有血栓溶解酶相比地减少,处于与对照组类似的水平。
在HtrA2处理组的情况下,也测量了实际出血时间(图10的a)、出血量(图10的b)、损失的血红蛋白量(图10的c)、止血所用时间(图10的d)的结果,确认到出血副作用无法与现有血栓溶解酶相比地减少,处于与对照组类似的水平。HtrA1和HtrA2不干扰作为伤口治愈过程的一部分的止血过程,从而完美地降低出血风险,因此可知可以用作显着减少出血副作用的血栓症治疗剂。
产业上的使用可能性
根据本发明的识别‘血管内血栓’而溶解血栓的多肽,由于通过没有严重出血副作用地溶解哺乳动物的血液内血栓而具有预防和治疗血栓症的效果,因此可以被广泛利用为血栓症和相关疾病的预防或治疗剂。
<110> 株式会社 JINIS
<120> 用于血管内血栓的溶栓剂
<130> OPP20020-PCT
<150> KR 2019-0131585
<151> 2019-10-22
<160> 14
<170> KoPatentIn 3.0
<210> 1
<211> 161
<212> PRT
<213> 人工序列
<220>
<223> HtrA1的溶栓结构域氨基酸序列 (HtrA1 as1)
<400> 1
Gly Ser Gly Phe Ile Val Ser Glu Asp Gly Leu Ile Val Thr Asn Ala
1 5 10 15
His Val Val Thr Asn Lys His Arg Val Lys Val Glu Leu Lys Asn Gly
20 25 30
Ala Thr Tyr Glu Ala Lys Ile Lys Asp Val Asp Glu Lys Ala Asp Ile
35 40 45
Ala Leu Ile Lys Ile Asp His Gln Gly Lys Leu Pro Val Leu Leu Leu
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Gly Arg Ser Ser Glu Leu Arg Pro Gly Glu Phe Val Val Ala Ile Gly
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Ser Pro Phe Ser Leu Gln Asn Thr Val Thr Thr Gly Ile Val Ser Thr
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Thr Gln Arg Gly Gly Lys Glu Leu Gly Leu Arg Asn Ser Asp Met Asp
100 105 110
Tyr Ile Gln Thr Asp Ala Ile Ile Asn Tyr Gly Asn Ser Gly Gly Pro
115 120 125
Leu Val Asn Leu Asp Gly Glu Val Ile Gly Ile Asn Thr Leu Lys Val
130 135 140
Thr Ala Gly Ile Ser Phe Ala Ile Pro Ser Asp Lys Ile Lys Lys Phe
145 150 155 160
Leu
<210> 2
<211> 177
<212> PRT
<213> 人工序列
<220>
<223> HtrA2的溶栓结构域的氨基酸序列 (HtrA2 as1)
<400> 2
Ile Leu Asp Arg His Pro Phe Leu Gly Arg Glu Val Pro Ile Ser Asn
1 5 10 15
Gly Ser Gly Phe Val Val Ala Ala Asp Gly Leu Ile Val Thr Asn Ala
20 25 30
His Val Val Ala Asp Arg Arg Arg Val Arg Val Arg Leu Leu Ser Gly
35 40 45
Asp Thr Tyr Glu Ala Val Val Thr Ala Val Asp Pro Val Ala Asp Ile
50 55 60
Ala Thr Leu Arg Ile Gln Thr Lys Glu Pro Leu Pro Thr Leu Pro Leu
65 70 75 80
Gly Arg Ser Ala Asp Val Arg Gln Gly Glu Phe Val Val Ala Met Gly
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Ser Pro Phe Ala Leu Gln Asn Thr Ile Thr Ser Gly Ile Val Ser Ser
100 105 110
Ala Gln Arg Pro Ala Arg Asp Leu Gly Leu Pro Gln Thr Asn Val Glu
115 120 125
Tyr Ile Gln Thr Asp Ala Ala Ile Asp Phe Gly Asn Ser Gly Gly Pro
130 135 140
Leu Val Asn Leu Asp Gly Glu Val Ile Gly Val Asn Thr Met Lys Val
145 150 155 160
Thr Ala Gly Ile Ser Phe Ala Ile Pro Ser Asp Arg Leu Arg Glu Phe
165 170 175
Leu
<210> 3
<211> 103
<212> PRT
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<220>
<223> HtrA1的血栓识别结构域的氨基酸序列 (HtrA1 as2)
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Thr Glu Ser His Asp Arg Gln Ala Lys Gly Lys Ala Ile Thr Lys Lys
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Lys Tyr Ile Gly Ile Arg Met Met Ser Leu Thr Ser Ser Lys Ala Lys
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Glu Leu Lys Asp Arg His Arg Asp Phe Pro Asp Val Ile Ser Gly Ala
35 40 45
Tyr Ile Ile Glu Val Ile Pro Asp Thr Pro Ala Glu Ala Gly Gly Leu
50 55 60
Lys Glu Asn Asp Val Ile Ile Ser Ile Asn Gly Gln Ser Val Val Ser
65 70 75 80
Ala Asn Asp Val Ser Asp Val Ile Lys Arg Glu Ser Thr Leu Asn Met
85 90 95
Val Val Arg Arg Gly Asn Glu
100
<210> 4
<211> 82
<212> PRT
<213> 人工序列
<220>
<223> HtrA2的血栓认知结构域的氨基酸序列 (HtrA2 as2)
<400> 4
Val Met Met Leu Thr Leu Ser Pro Ser Ile Leu Ala Glu Leu Gln Leu
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Arg Glu Pro Ser Phe Pro Asp Val Gln His Gly Val Leu Ile His Lys
20 25 30
Val Ile Leu Gly Ser Pro Ala His Arg Ala Gly Leu Arg Pro Gly Asp
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Val Ile Leu Ala Ile Gly Glu Gln Met Val Gln Asn Ala Glu Asp Val
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Tyr Glu Ala Val Arg Thr Gln Ser Gln Leu Ala Val Gln Ile Arg Arg
65 70 75 80
Gly Arg
<210> 5
<211> 483
<212> DNA
<213> 人工序列
<220>
<223> HtrA1的溶栓结构域的碱基序列 (HtrA1 bs1)
<400> 5
gggtctgggt ttattgtgtc ggaagatgga ctgatcgtga caaatgccca cgtggtgacc 60
aacaagcacc gggtcaaagt tgagctgaag aacggtgcca cttacgaagc caaaatcaag 120
gatgtggatg agaaagcaga catcgcactc atcaaaattg accaccaggg caagctgcct 180
gtcctgctgc ttggccgctc ctcagagctg cggccgggag agttcgtggt cgccatcgga 240
agcccgtttt cccttcaaaa cacagtcacc accgggatcg tgagcaccac ccagcgaggc 300
ggcaaagagc tggggctccg caactcagac atggactaca tccagaccga cgccatcatc 360
aactatggaa actcgggagg cccgttagta aacctggacg gtgaagtgat tggaattaac 420
actttgaaag tgacagctgg aatctccttt gcaatcccat ctgataagat taaaaagttc 480
ctc 483
<210> 6
<211> 531
<212> DNA
<213> 人工序列
<220>
<223> HtrA2的溶栓结构域的碱基序列 (HtrA2 bs1)
<400> 6
atcctggacc ggcacccttt cttgggccgc gaggtcccta tctcgaacgg ctcaggattc 60
gtggtggctg ccgatgggct cattgtcacc aacgcccatg tggtggctga tcggcgcaga 120
gtccgtgtga gactgctaag cggcgacacg tatgaggccg tggtcacagc tgtggatccc 180
gtggcagaca tcgcaacgct gaggattcag actaaggagc ctctccccac gctgcctctg 240
ggacgctcag ctgatgtccg gcaaggggag tttgttgttg ccatgggaag tccctttgca 300
ctgcagaaca cgatcacatc cggcattgtt agctctgctc agcgtccagc cagagacctg 360
ggactccccc aaaccaatgt ggaatacatt caaactgatg cagctattga ttttggaaac 420
tctggaggtc ccctggttaa cctggatggg gaggtgattg gagtgaacac catgaaggtc 480
acagctggaa tctcctttgc catcccttct gatcgtcttc gagagtttct g 531
<210> 7
<211> 309
<212> DNA
<213> 人工序列
<220>
<223> HtrA1的血栓识别域碱基序列 (HtrA1 bs2)
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acggagtccc atgaccgaca ggccaaagga aaagccatca ccaagaagaa gtatattggt 60
atccgaatga tgtcactcac gtccagcaaa gccaaagagc tgaaggaccg gcaccgggac 120
ttcccagacg tgatctcagg agcgtatata attgaagtaa ttcctgatac cccagcagaa 180
gctggtggtc tcaaggaaaa cgacgtcata atcagcatca atggacagtc cgtggtctcc 240
gccaatgatg tcagcgacgt cattaaaagg gaaagcaccc tgaacatggt ggtccgcagg 300
ggtaatgaa 309
<210> 8
<211> 246
<212> DNA
<213> 人工序列
<220>
<223> HtrA2的血栓识别域碱基序列 (HtrA2 bs2)
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gtgatgatgc tgaccctgag tcccagcatc cttgctgaac tacagcttcg agaaccaagc 60
tttcccgatg ttcagcatgg tgtactcatc cataaagtca tcctgggctc ccctgcacac 120
cgggctggtc tgcggcctgg tgatgtgatt ttggccattg gggagcagat ggtacaaaat 180
gctgaagatg tttatgaagc tgttcgaacc caatcccagt tggcagtgca gatccggcgg 240
ggacga 246
<210> 9
<211> 480
<212> PRT
<213> 人工序列
<220>
<223> HtrA1的氨基酸序列 (HtrA1)
<400> 9
Met Gln Ile Pro Arg Ala Ala Leu Leu Pro Leu Leu Leu Leu Leu Leu
1 5 10 15
Ala Ala Pro Ala Ser Ala Gln Leu Ser Arg Ala Gly Arg Ser Ala Pro
20 25 30
Leu Ala Ala Gly Cys Pro Asp Arg Cys Glu Pro Ala Arg Cys Pro Pro
35 40 45
Gln Pro Glu His Cys Glu Gly Gly Arg Ala Arg Asp Ala Cys Gly Cys
50 55 60
Cys Glu Val Cys Gly Ala Pro Glu Gly Ala Ala Cys Gly Leu Gln Glu
65 70 75 80
Gly Pro Cys Gly Glu Gly Leu Gln Cys Val Val Pro Phe Gly Val Pro
85 90 95
Ala Ser Ala Thr Val Arg Arg Arg Ala Gln Ala Gly Leu Cys Val Cys
100 105 110
Ala Ser Ser Glu Pro Val Cys Gly Ser Asp Ala Asn Thr Tyr Ala Asn
115 120 125
Leu Cys Gln Leu Arg Ala Ala Ser Arg Arg Ser Glu Arg Leu His Arg
130 135 140
Pro Pro Val Ile Val Leu Gln Arg Gly Ala Cys Gly Gln Gly Gln Glu
145 150 155 160
Asp Pro Asn Ser Leu Arg His Lys Tyr Asn Phe Ile Ala Asp Val Val
165 170 175
Glu Lys Ile Ala Pro Ala Val Val His Ile Glu Leu Phe Arg Lys Leu
180 185 190
Pro Phe Ser Lys Arg Glu Val Pro Val Ala Ser Gly Ser Gly Phe Ile
195 200 205
Val Ser Glu Asp Gly Leu Ile Val Thr Asn Ala His Val Val Thr Asn
210 215 220
Lys His Arg Val Lys Val Glu Leu Lys Asn Gly Ala Thr Tyr Glu Ala
225 230 235 240
Lys Ile Lys Asp Val Asp Glu Lys Ala Asp Ile Ala Leu Ile Lys Ile
245 250 255
Asp His Gln Gly Lys Leu Pro Val Leu Leu Leu Gly Arg Ser Ser Glu
260 265 270
Leu Arg Pro Gly Glu Phe Val Val Ala Ile Gly Ser Pro Phe Ser Leu
275 280 285
Gln Asn Thr Val Thr Thr Gly Ile Val Ser Thr Thr Gln Arg Gly Gly
290 295 300
Lys Glu Leu Gly Leu Arg Asn Ser Asp Met Asp Tyr Ile Gln Thr Asp
305 310 315 320
Ala Ile Ile Asn Tyr Gly Asn Ser Gly Gly Pro Leu Val Asn Leu Asp
325 330 335
Gly Glu Val Ile Gly Ile Asn Thr Leu Lys Val Thr Ala Gly Ile Ser
340 345 350
Phe Ala Ile Pro Ser Asp Lys Ile Lys Lys Phe Leu Thr Glu Ser His
355 360 365
Asp Arg Gln Ala Lys Gly Lys Ala Ile Thr Lys Lys Lys Tyr Ile Gly
370 375 380
Ile Arg Met Met Ser Leu Thr Ser Ser Lys Ala Lys Glu Leu Lys Asp
385 390 395 400
Arg His Arg Asp Phe Pro Asp Val Ile Ser Gly Ala Tyr Ile Ile Glu
405 410 415
Val Ile Pro Asp Thr Pro Ala Glu Ala Gly Gly Leu Lys Glu Asn Asp
420 425 430
Val Ile Ile Ser Ile Asn Gly Gln Ser Val Val Ser Ala Asn Asp Val
435 440 445
Ser Asp Val Ile Lys Arg Glu Ser Thr Leu Asn Met Val Val Arg Arg
450 455 460
Gly Asn Glu Asp Ile Met Ile Thr Val Ile Pro Glu Glu Ile Asp Pro
465 470 475 480
<210> 10
<211> 458
<212> PRT
<213> 人工序列
<220>
<223> HtrA2的氨基酸序列 (HtrA2)
<400> 10
Met Ala Ala Pro Arg Ala Gly Arg Gly Ala Gly Trp Ser Leu Arg Ala
1 5 10 15
Trp Arg Ala Leu Gly Gly Ile Arg Trp Gly Arg Arg Pro Arg Leu Thr
20 25 30
Pro Asp Leu Arg Ala Leu Leu Thr Ser Gly Thr Ser Asp Pro Arg Ala
35 40 45
Arg Val Thr Tyr Gly Thr Pro Ser Leu Trp Ala Arg Leu Ser Val Gly
50 55 60
Val Thr Glu Pro Arg Ala Cys Leu Thr Ser Gly Thr Pro Gly Pro Arg
65 70 75 80
Ala Gln Leu Thr Ala Val Thr Pro Asp Thr Arg Thr Arg Glu Ala Ser
85 90 95
Glu Asn Ser Gly Thr Arg Ser Arg Ala Trp Leu Ala Val Ala Leu Gly
100 105 110
Ala Gly Gly Ala Val Leu Leu Leu Leu Trp Gly Gly Gly Arg Gly Pro
115 120 125
Pro Ala Val Leu Ala Ala Val Pro Ser Pro Pro Pro Ala Ser Pro Arg
130 135 140
Ser Gln Tyr Asn Phe Ile Ala Asp Val Val Glu Lys Thr Ala Pro Ala
145 150 155 160
Val Val Tyr Ile Glu Ile Leu Asp Arg His Pro Phe Leu Gly Arg Glu
165 170 175
Val Pro Ile Ser Asn Gly Ser Gly Phe Val Val Ala Ala Asp Gly Leu
180 185 190
Ile Val Thr Asn Ala His Val Val Ala Asp Arg Arg Arg Val Arg Val
195 200 205
Arg Leu Leu Ser Gly Asp Thr Tyr Glu Ala Val Val Thr Ala Val Asp
210 215 220
Pro Val Ala Asp Ile Ala Thr Leu Arg Ile Gln Thr Lys Glu Pro Leu
225 230 235 240
Pro Thr Leu Pro Leu Gly Arg Ser Ala Asp Val Arg Gln Gly Glu Phe
245 250 255
Val Val Ala Met Gly Ser Pro Phe Ala Leu Gln Asn Thr Ile Thr Ser
260 265 270
Gly Ile Val Ser Ser Ala Gln Arg Pro Ala Arg Asp Leu Gly Leu Pro
275 280 285
Gln Thr Asn Val Glu Tyr Ile Gln Thr Asp Ala Ala Ile Asp Phe Gly
290 295 300
Asn Ser Gly Gly Pro Leu Val Asn Leu Asp Gly Glu Val Ile Gly Val
305 310 315 320
Asn Thr Met Lys Val Thr Ala Gly Ile Ser Phe Ala Ile Pro Ser Asp
325 330 335
Arg Leu Arg Glu Phe Leu His Arg Gly Glu Lys Lys Asn Ser Ser Ser
340 345 350
Gly Ile Ser Gly Ser Gln Arg Arg Tyr Ile Gly Val Met Met Leu Thr
355 360 365
Leu Ser Pro Ser Ile Leu Ala Glu Leu Gln Leu Arg Glu Pro Ser Phe
370 375 380
Pro Asp Val Gln His Gly Val Leu Ile His Lys Val Ile Leu Gly Ser
385 390 395 400
Pro Ala His Arg Ala Gly Leu Arg Pro Gly Asp Val Ile Leu Ala Ile
405 410 415
Gly Glu Gln Met Val Gln Asn Ala Glu Asp Val Tyr Glu Ala Val Arg
420 425 430
Thr Gln Ser Gln Leu Ala Val Gln Ile Arg Arg Gly Arg Glu Thr Leu
435 440 445
Thr Leu Tyr Val Thr Pro Glu Val Thr Glu
450 455
<210> 11
<211> 29
<212> DNA
<213> 人工序列
<220>
<223> HtrA1正向引物
<400> 11
aattcatatg caagggcagg aagatccca 29
<210> 12
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> HtrA1反向引物
<400> 12
tatctcgagc tatgggtcaa tttcttcggg 30
<210> 13
<211> 28
<212> DNA
<213> 人工序列
<220>
<223> HtrA2正向引物
<400> 13
gtcctcgccc atatggccgt ccctagcc 28
<210> 14
<211> 29
<212> DNA
<213> 人工序列
<220>
<223> HtrA2反向引物
<400> 14
ggctctcgag tcattctgtg acctcaggg 29
Claims (13)
1.一种识别‘血管内血栓’而溶解血栓的多肽,其特征在于,
所述多肽由包括被记载为序列号1或序列号2的氨基酸序列的血栓溶解结构域和包括被记载为序列号3或序列号4的氨基酸序列的血栓识别结构域组成。
2.根据权利要求1所述的识别‘血管内血栓’而溶解血栓的多肽,其特征在于,
所述多肽由包括被记载为序列号1的氨基酸序列的血栓溶解结构域和包括被记载为序列号3的氨基酸序列的血栓识别结构域组成。
3.根据权利要求1所述的识别‘血管内血栓’而溶解血栓的多肽,其特征在于,
所述多肽由包括被记载为序列号2的氨基酸序列的血栓溶解结构域和包括被记载为序列号4的氨基酸序列的血栓识别结构域组成。
4.根据权利要求1所述的识别‘血管内血栓’而溶解血栓的多肽,其特征在于,
所述血栓溶解结构域是与序列号1或序列号2的氨基酸序列具有50%以上类似性的结构域。
5.根据权利要求1所述的识别‘血管内血栓’而溶解血栓的多肽,其特征在于,
所述血栓溶解结构域是包括GNSGGPL肽或类似肽而赋予丝氨酸蛋白酶活性的结构域。
6.根据权利要求1所述的识别‘血管内血栓’而溶解血栓的多肽,其特征在于,
所述血栓识别结构域是与序列号3或序列号4的氨基酸序列具有50%以上类似性的结构域。
7.根据权利要求1所述的识别‘血管内血栓’而溶解血栓的多肽,其特征在于,
所述血栓识别结构域具有由β-折叠链和α-螺旋的多个组合组成的拓扑结构。
8.根据权利要求1所述的识别‘血管内血栓’而溶解血栓的多肽,其特征在于,
所述血栓识别结构域为识别血管内血栓和调节溶解酶活性功能的PDZ结构域或PDZ样结构域。
9.一种血栓溶解结构域基因,其特征在于,所述血栓溶解结构域基因编码具有权利要求1的被记载为序列号1或序列号2的氨基酸序列的血栓溶解结构域,具有被记载为序列号5或序列号6的碱基序列。
10.根据权利要求9所述的血栓溶解结构域基因,其特征在于,
所述血栓溶解结构域基因是与序列号5或序列号6的碱基序列具有50%以上类似性的基因。
11.一种血栓识别结构域基因,其特征在于,所述血栓识别结构域基因编码具有权利要求1的被记载为序列号3或序列号4的氨基酸序列的血栓识别结构域,具有被记载为序列号7或序列号8的碱基序列。
12.根据权利要求11所述的血栓识别结构域基因,其特征在于,
所述血栓识别结构域基因是与序列号7或序列号8的碱基序列具有50%以上类似性的基因。
13.一种用于治疗或预防血栓症和相关疾病的药物组合物,其特征在于,
包括识别权利要求1的‘血管内血栓’而溶解血栓的多肽或编码所述多肽的基因作为有效成分。
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KR1020190131585A KR102277471B1 (ko) | 2019-10-22 | 2019-10-22 | '혈관내 혈전' 용해제 |
PCT/KR2020/014217 WO2021080262A1 (ko) | 2019-10-22 | 2020-10-19 | '혈관내 혈전' 용해제 |
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US20220362355A1 (en) | 2022-11-17 |
JP2022551936A (ja) | 2022-12-14 |
MX2022004698A (es) | 2022-08-04 |
JP7427084B2 (ja) | 2024-02-02 |
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