CN114010765A - 一种长效人生长激素 - Google Patents
一种长效人生长激素 Download PDFInfo
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- CN114010765A CN114010765A CN202111004740.9A CN202111004740A CN114010765A CN 114010765 A CN114010765 A CN 114010765A CN 202111004740 A CN202111004740 A CN 202111004740A CN 114010765 A CN114010765 A CN 114010765A
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- growth hormone
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Abstract
本发明提出了一种长效人生长激素,含有碳水化合物肽序列的生长激素嵌合基因;其中碳水化合物肽包含一个或多个N‑连接寡糖识别位点;一个或者多个碳水化合物肽的序列将被连接到生长激素cDNA编码序列的N端和/或C端。多个碳水化合物肽到生长激素cDNA编码序列的N端和/或C端。本发明旨在通过将人类生长激素的编码序列与含有一个或多个N‑连接寡糖识别位点的碳水化合物肽连接,开发一种长效人类生长激素(记为GH‑LA)。在生长激素的主干中添加N‑连接寡糖将增加其循环的稳定性,从而增加其半衰期。增加生长激素的半衰期将使每周注射一次的治疗方案成为可能,而不是每天注射野生型。
Description
技术领域
本发明涉及一种长效人生长激素,具体是治疗生长激素缺乏症进行开发研究的。此长效生长激素的优点是可以仅需每周注射一次,而不是像野生型生长激素那样每天注射一次。
背景技术
人类生长激素(生长激素)是一个来自包含催乳素和胎盘乳素的高度相近的激素族的重要一员。生长激素调节多种生理过程,包括肌肉、骨骼和软骨细胞的生长和分化。生长激素由垂体前叶的生长激素细胞分泌,作用于各种组织,促进生长和影响代谢。
人类生长激素是一个分子量为22kDa的蛋白质,由含有191个氨基酸和两个二硫键和四个α-螺旋组成。信号转导开始于生长激素绑定生长激素受体的质膜。结构功能研究发现分子的一些特定区域对生长激素受体绑定非常重要。这些研究表明,生长激素与预先形成的生长激素受体二聚体的交互作用对生长激素诱导的细胞内信号转导起着关键作用。
生长激素有两个不同的结构域与两个相同的生长激素受体在细胞表面先后链接,产生的带有功能性的受体二聚体化。这一结果触发与生长激素效应有关的基因的激活或关闭。
使用生长激素治疗生长受损的儿童多年来被公认为是一种重要的治疗方法此外,生长激素替代疗法对成人的获益也已被证实。成年人的生长激素替代物能增加5-10%的肌肉质量,尽管部分效果归因于补水,而不是蛋白质的增加。此外,生长激素对身体组织的影响通常可以描述为合成代谢。这种效应与增加的游离脂肪酸通量有关。生长激素在临床应用的一个主要问题是其在循环中容易被快速清除(大约12分钟),从而导致半衰期较短。在正常生理条件下,人血浆中的生长激素是生长激素结合蛋白的复合物。生长激素结合蛋白的一个功能是将生长激素限制在血管腔室中,从而保护其免于降解并延长其生物半衰期。文献中已有不少关于稳定生长激素并延长其半衰期的研究。研究表明,生长激素与肝素的络合并未引起生长激素在三级结构中的主要分布,而是通过减少亲水环境稳定了激素。其他研究表明,被带正电荷的聚精氨酸包裹的生长激素晶体可以在若干天内释放生长激素。然而,一般的重组生长激素需要每天给患者服用,以达到最佳效果。以往研究表明,将人绒毛膜促性腺激素(hCG) β亚基的羧基末端肽(CTP)与人卵泡生成素(FSH) β亚基、人绒毛膜促性腺激素(hCG)α亚基、甲状腺激素(TSH)β亚基,或促红细胞生成素(EPO)融合,不会影响其组装、分泌、受体结合亲力以及体外生物活性。但是,含有CTP的蛋白的体内效价和循环半衰期会发生显著增加。
本申请目的是涉及一种长效人生长激素的开发。
发明内容
为了解决上述的技术问题,本发明提供一种长效人生长激素是将含有4个N-连接寡糖位点的碳水化合物肽(CL)连接到生长激素编码序列上。
本发明提供一种长效人生长激素是含有碳水化合物肽序列的生长激素嵌合基因;其中碳水化合物肽包含一个或多个N-连接寡糖识别位点;
一个或者多个碳水化合物肽的序列将被连接到生长激素cDNA编码序列的N端和/或C端。
多个碳水化合物肽连接到生长激素cDNA编码序列的N端和/或C端。
一个碳水化合物肽的序列连接到生长激素cDNA编码序列的C端,氨基酸序列如SEQID NO:1所示。
一个碳水化合物肽的序列连接到生长激素cDNA编码序列的N端,氨基酸序列如SEQID NO:2所示。
两个碳水化合物肽的序列连接到生长激素cDNA编码序列的N端和C端,氨基酸序列如SEQ ID NO:3所示。
一种长效人生长激素在制备治疗生长激素缺乏症中的应用。
本发明进一步保护将上述长效人生长激素克隆到真核表达载体中,转染到真核细胞(如CHO或HEK293细胞),筛选出稳定表达嵌合基因的克隆。从稳定的克隆中收集条件培养基,纯化生长激素变异株,使用商业试剂盒检测生长激素的浓度。生长激素变异体的生物活性将通过动物模型检测。
本发明具有如下有益效果:本发明旨在通过将人类生长激素的编码序列与含有一个或多个N-连接寡糖识别位点的碳水化合物肽连接,开发一种长效人类生长激素(记为GH-LA)。在生长激素的主干中添加N-连接寡糖将增加其循环的稳定性,从而增加其半衰期。增加生长激素的半衰期将使每周注射一次的治疗方案成为可能,而不是每天注射野生型。
附图说明
图1为本发明实施例1中一个碳水化合物肽的序列连接到生长激素cDNA编码序列的C端序列结构图。
图2为本发明中实施例2中一个碳水化合物肽的序列连接到生长激素cDNA编码序列的N端序列结构图。
图3为本发明中实施例3中两个碳水化合物肽的序列连接到生长激素cDNA编码序列的N端和C端序列结构图。
具体实施方式
下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整的描述,显然,所述的实施例只是本发明的部分具有代表性的实施例,而不是全部实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的其他所有实施例都属于本发明的保护范围。
本实施例的一种长效人生长激素含有碳水化合物肽序列的生长激素嵌合基因;碳水化合物肽包含一个或多个N-连接寡糖识别位点;
一个或者多个碳水化合物肽的序列将被连接到生长激素cDNA编码序列的N端和/或C端。
多个碳水化合物肽连接到生长激素cDNA编码序列的N端和/或C端。
实施例1:参照图1所示,一个碳水化合物肽的序列连接到生长激素cDNA编码序列的C端。
实施例2:参照图2所示,一个碳水化合物肽的序列连接到生长激素cDNA编码序列的N端。
实施例3:参照图3所示,两个碳水化合物肽的序列连接到生长激素cDNA编码序列的N端和C端。
实验例:将垂体切除的雄性大鼠饲养在有空调的房间,按计划接受12小时的光照和12小时的黑暗时间。提供标准的自由采食和饮水。在伦理委员会批准体内实验方案后,动物将接受含有生长激素变异体的条件培养基的治疗。
本实施例长效生长激素在体内的疗效将通过下丘脑切除的大鼠的体重增加和IGF-I水平来评估。(i)每5天皮下注射一次(0.6 mg/kg)本长效生长激素,先后两次(总剂量为1.2 mg/kg)后,在第11天测量垂体切除雄性大鼠的体重增加。这将与每日一次注射0.12mg/kg,连续注射10天(总剂量同样是1.2 mg/kg)的商业生长激素 (Biotropin)的相应结果进行比较。(ii)实验将在治疗前,第一次注射24小时后,以及后续的每周二次,测量所有动物的体重增加量,直到研究结束。(iii)将测量在不同剂量下,三次注射本长效生长激素后的体重增加。(iv)动物将接受不同剂量(0.6或1.8 mg/kg)的长效生长激素注射,每7天注射一次,持续治疗2周,并将其体重增加结果与每日一次注射0.12 mg/kg的商业生长激素(Biotropin)进行比较。即本实施例的长效生长激素每周一次注射与商业生长激素(Biotropin)每日一次注射,大鼠的体重增加结果相当。
本领域的技术人员在不脱离权利要求书确定的本发明的精神和范围的条件下,还可以对以上内容进行各种各样的修改。因此本发明的范围并不仅限于以上的说明,而是由权利要求书的范围来确定的。
序列表
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<120> 一种长效人生长激素
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Claims (6)
1.一种长效人生长激素,其特征在于:所述的长效人生长激素是含有碳水化合物肽序列的生长激素嵌合基因;其中碳水化合物肽包含一个或多个N-连接寡糖识别位点;
一个或者多个碳水化合物肽的序列将被连接到生长激素cDNA编码序列的N端和/或C端。
2.根据权利要求1所述的一种长效人生长激素,其特征在于:多个碳水化合物肽连接到生长激素cDNA编码序列的N端和/或C端。
3.根据权利要求1所述的一种长效人生长激素,其特征在于:一个碳水化合物肽的序列连接到生长激素cDNA编码序列的C端,其序列如SEQ ID NO:1所示。
4.根据权利要求1所述的一种长效人生长激素,其特征在于:一个碳水化合物肽的序列连接到生长激素cDNA编码序列的N端,其序列如SEQ ID NO:2所示。
5.根据权利要求1所述的一种长效人生长激素,其特征在于:两个碳水化合物肽的序列连接到生长激素cDNA编码序列的N端和C端,其序列如SEQ ID NO:3所示。
6.权利要求1所述的一种长效人生长激素在制备治疗生长激素缺乏症中的应用。
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