CN106366176A - Pth模拟肽及其应用 - Google Patents
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Abstract
本发明公开了一种新的PTH模拟肽,该PTH模拟肽能够特异性地激活PLC非依赖、PKA非依赖的PKC信号通路,还能够有效促进成骨细胞分化,促进骨折愈合,部分效果优于PTH(1‑34)。该PTH模拟肽具有很好的科研应用以及治疗骨质疏松症的临床药用价值。
Description
技术领域
本发明属于生物技术领域,具体是涉及一种PTH模拟肽及其应用。
背景技术
骨质疏松症可以被定义为全身性骨骼疾病,具有低骨量、骨组织微观结构退化以及增加的骨脆性和易于骨折的特征。骨质疏松症是严重影响老年人群身体健康和生命存在的常见疾病。目前,治疗骨质疏松的常见药物包括抗骨吸收药物和促骨合成药物,前者不能有效提高骨质量,需要长期用药,后者能较快提高骨质量,预防骨折的发生,尤其对重度骨质疏松效果明显。
甲状旁腺素(PTH)是由甲状旁腺分泌的一种多肽激素,是生物体内调节钙、磷代谢平衡的一种重要因子。它含有84个氨基酸,此外尚存在着一些短链降解产物,这些产物都具有一定的活性,鉴于生物的复杂性,还未受到的广泛研究和应用。特立帕肽(PTH(1-34))是目前唯一的促骨合成药物,在临床应用证明了其独特的有效性。PTH(1-34)通过直接激活cAMP/PKA,PLC/PKC等信号转导途径发挥其作用。有研究证明PLC非依赖性PKC可能促进骨合成,但缺乏强有力的证据。
由于PTH(1-34)能够激活多个信号通路,兼具促骨合成和促骨吸收的作用,其净效果在小剂量间断使用时表现为骨合成,大剂量持续使用时净效果为促进骨吸收。PTH(1-34)的效果远未达到临床需要的效果。
发明内容
本发明的目的在于提供一种新的PTH模拟肽,其具有很好的应用于科研研究和临床应用。
其技术方案如下:
氨基酸序列如SEQ ID NO.1所示的PTH模拟肽。
氨基酸序列如SEQ ID NO.1所示的,前段1-18位中有1-5个的氨基酸突变但活性不变的PTH模拟肽。
优选地,所述PTH模拟肽的氨基酸序列如SEQ ID NO.2所示。
本发明的另一目的是提供上述PTH模拟肽的应用。
其技术方案如下:
上述PTH模拟肽在制备防治骨质疏松症的药物中的应用。
本发明的另一目的是提供一种防治骨质疏松症的药物。
其技术方案如下:
一种防治骨质疏松症的药物,其活性成份含有上述PTH模拟肽。
本发明根据临床经验,经过大量的实验,通过对现有的针对PTH(1-34)的一重要功能基团PTH(29-34)进行重复,并裁剪PTH(1-34)的N端两个氨基酸,设计了新的具有单一信号转导功能的模拟肽MY-1。所述的MY-1肽PTH(3-34)(29-34)的分子序列:即SEIQLMHNLGKHLNSMERVEWLRKKLQDVHNYQDVHNY其中,我们独有的创新是将第34位氨基酸F突变为Y后再将QDVHNY系列重复一次,使之具有独特的分子信号刺激特征,并具有优越的促进骨合成的效果。
我们在上述的基础上进行了进一步的突变,即MMY-1肽序列为:AibEIQLMHQHarAKWLNSMRRVEWLRKKLQDVHNYQDVHNY。发现它具有非常好的促骨合成效果。
本发明的有益效果在于:
1.本发明独特设计的PTH模拟肽能够特异性地激活PLC非依赖、PKA非依赖的PKC信号通路。可见,该PTH模拟肽可为科研研究提供了有用的工具。
2.细胞和动物实验证明,本发明所述的MY-1肽能够有效促进成骨细胞分化,促进骨折愈合,部分效果优于PTH(1-34)。可见,该PTH模拟肽具有很好的治疗骨质疏松症的临床药用价值。
附图说明
图1是实施例1中PTH模拟肽的信号转导特征的示意图;
图2是实施例3中PTH模拟肽的促进成骨细胞表达成骨基因碱性磷酸酶的示意图;
图3是实施例4中PTH模拟肽促进去势雄性小数胫骨松质骨形成的作用的示意图;
图4是实施例5中PTH模拟肽促进去势雄性小数骨折愈合的作用示意图。
具体实施方式
下面对本发明的实施例进行详细说明。
本实施例提供了一种氨基酸序列如SEQ ID NO.1所示的PTH模拟肽(MY-1肽),在该MY-1肽的基础上,其前端(从N端开始)1-17位上,可以发生1-5个氨基酸的突变,但MY-1肽所具有的活性(特异性地激活PLC非依赖、PKA非依赖的PKC信号通路,抑制成骨细胞凋亡,促进成骨细胞分化,促进骨折愈合),突变后的相应的PTH模拟肽的不会改变,例如,MY-1肽的第17位的E可以突变为R。这些位点的突变主要是增加肽与其受体的结合力从而促进生物学效果,本领域的技术人员,可以根据现有的技术报道对MY-1肽作出相应的改变。此外,SEQ IDNO.1中的(29-F34Y)部分中的Y,也可以为与天然的PTH(1-34)第34位一样,氨基酸为F,如SEQ ID NO.7。
本实施例所述的PTH模拟肽可用于制备防治骨质疏松症的药物。
本实施例还涉及一种防治骨质疏松症的药物,其活性成份含有上述PTH模拟肽。
以下具体实施例所涉及到的各种PTH肽,其具有以下氨基酸组成。
实施例1
将PTH受体(PTHR1)基因转染HEK293细胞株(不表达PTHR1),挑选稳定表达PTHR1的细胞克隆(PTHR1受体基因已经插入HEK293细胞的基因组,受体基因的表达稳定;以下称为HEK293-PTHR1细胞)。实验结果参见图1。
从图1A可以看出,(10-5M)PTH(3-34),MY-1肽(10-5M,10-6M)刺激4小时不能激活HEK293-PTHR1细胞内PLC信号从而增加IP的生成量,但是PTH(1-34)具有激活PLC的功能。图1B显示PTH(3-34)(10-5M),MY-1肽(10-5M,10-6M)4小时刺激不能促进HEK293-PTHR1细胞内的cAMP生成量。
为了检测细胞内PKC激活情况,我们将PKC激活荧光检测分子CKAR转染HEK193-PTHR1细胞(HEK193-PTHR1-CKAR细胞)(注:如果PKC激活,将引起其作用底物磷酸化,CKAR分子产生构型改变,导致CKAR分子两端的CFP,YFP荧光能量的转移发生改变,显示为C/Y比值的改变。通过检测荧光能量转移变化,显示PKC的激活情况)。用10-5M的MY-1肽刺激HEK193-PTHR1-CKAR细胞100ms后,出现荧光能量转移改变,显示PKC激活,而PKC抑制剂Go6983的加入使MY-1肽的作用发生反转,证实了MY-1肽具有激活PKC的作用。(我们另外的研究已经证明PTH(1-34)也具有类似作用。
如果将CKAR分子转染进不含PTHR1受体的细胞(HEK293-CKAR细胞),MY-1肽不能激活PKC,但激活剂TPA(无需进过特殊受体的PKC激活剂)可以激活PKC信号。
以上实验结果说明,与PTH(1-34)比,MY-1肽具有PLC非依赖(nonPLC),PKA非依赖(nonPKA)的PKC激活的独特的信号转导特征(表1)。据我们所知,目前所有的PTH模拟肽均不具有如此单纯的信号转导特性,我们创造性的重复某一特征性蛋白功能基团达到了意想不到的效果。
表1 MY-1肽具有的信号转导特点
cAMP/PKA | PLC/PKC | nonPLC/PKC | |
PTH(1-34) | Yes | Yes | Yes |
MY-1肽 | No | No | Yes |
实施例2:MY-1肽和MMY-1的抑制成骨细胞凋亡
将成骨细胞株MC3T3-E1以4x105/孔的密度接种如24孔板,等孔内细胞密度达80%(导致显微镜观察和测量)时,将10%血清+α-MEM培养基换成1%血清+α-MEM培养基继续培养24小时,10-6M的MY-1肽,10-6M的MMY-1肽和10-8M PTH(1-34)分别加入1%血清+α-MEM培养基继续培养4小时后,0.05%胰酶消化制备悬浮细胞,PI(着染受损的细胞核)和FITC(着染受损的细胞膜)染色液4℃孵育20分钟,流失细胞仪针对PI和FITC着色情况将细胞分类统计各自所占百分数,其中PI+FITC+细胞群为晚期凋亡细胞或死亡细胞,PI-FITC+为早期凋亡细胞。
从表2可以看出,成骨细胞株MC3T3-E1细胞,低血清(1%FBS)培养条件下,细胞总凋亡率为9.5%,MY-1肽降低细胞凋亡率至3.1%,MMY-1肽降低细胞凋亡率2.5%,尤其是晚期凋亡细胞降低至0.6%,均优于PTH(1-34)的4.70%。
表2 MY-1对成骨细胞凋亡的影响
实施例3:MY-1肽和MMY-1的促进成骨细胞表达成骨基因碱性磷酸酶
将成骨细胞株MC3T3-E1以1x106/孔的密度接种如6孔板,等孔内细胞密度达80%(导致显微镜观察和测量)时,将10%血清+α-MEM培养基换成1%血清+α-MEM培养基继续培养24小时,10-6M的MY-1肽,10-6M的MMY-1肽和10-8M PTH(1-34)分别加入α-MEM培养基继续培养4小时后,提取细胞总RNA,定量PCR检测碱性磷酸酶(ALP)的表达。
如图2所示,PTH(1-34)、MY-1肽和MMY-1肽均可显著促进成骨细胞成骨基因ALP的表达。
实施例4:MY-1具有促进骨合成作用
我们将7周龄C57BL雄性小鼠摘除睾丸,制作骨质疏松模型,将MY-1肽(400μg/kg/日),PTH(1-34)(40μg/kg/日),PTH(7-34)(400μg/kg/日),MY-2肽(400μg/kg/日)分别皮下注射,分别于2周和4周使用显微CT测量胫骨骨松质骨量(BV/TV),并对骨松质行三维重建(图3A)。可以看出,MY-1肽具有与PTH(1-34)等效的促进骨松质成骨的作用,结果请参见图3中的A、B、C图。
结果预示MY-1可能在未来成为有效的抗骨质疏松药物。PTH(1-34)是目前唯一的可以促进骨形成的抗骨质疏松药物,但存在连续使用促进骨吸收、不能局部应用、长期使用失敏感、动物试验证明有致癌风险等短板,上述原因可能与其具有激活多种信号转导途径的特性有关,MY-1仅激活单一信号途径,可能克服上述短板。同时,比PTH(1-34)高10倍的剂量远为达到其最佳效果(发现MY-1的体外有效剂量低于PTH(1-34)2个数量级。
实施例5:MY-1具有促进骨这愈合作用
我们将7周龄雄性小鼠摘除睾丸,制作骨质疏松模型后,在左侧股骨中段放置髓内针,剪断股骨后缝合,制作骨折模型,MY-1肽(400μg/kg/日)、PTH(1-34)(400μg/kg/日),PTH(7-34)(40μg/kg/日),MY-2肽(400μg/kg/日)分别皮下注射,分别于2周和4周使用显微CT测量骨折处骨量(BV/TV),并对骨质行三维重建(A图)。结果请参见图4中的A、B、C图。可以看出,只有MY-1肽具有与PTH(1-34)等效的促进骨折愈合的作用(A、B、C图)。
以上仅为本发明的具体实施例,并不以此限定本发明的保护范围;在不违反本发明构思的基础上所作的任何替换与改进,均属本发明的保护范围。
Claims (7)
1.氨基酸序列如SEQ ID NO.1所示的PTH模拟肽。
2.氨基酸序列如SEQ ID NO.7所示的PTH模拟肽。
3.氨基酸序列如SEQ ID NO.1所示的,前段1-18位中有1-5个的氨基酸突变但活性不变的PTH模拟肽。
4.根据权利要求3所述的PTH模拟肽,其特征在于,所述PTH模拟肽的氨基酸序列如SEQID NO.2所示。
5.根据权利要求3所述的PTH模拟肽,其特征在于,所述PTH模拟肽的氨基酸序列如SEQID NO.3所示。
6.权利要求1-5任一项所述PTH模拟肽在制备防治骨质疏松症的药物中的应用。
7.一种防治骨质疏松症的药物,其特征在于,其活性成份含有权利要求1-5任一项所述的PTH模拟肽。
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