CN114437180B - 一种蛋白酪氨酸磷酯酶1b抑制肽及其应用 - Google Patents
一种蛋白酪氨酸磷酯酶1b抑制肽及其应用 Download PDFInfo
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Abstract
本发明公开了一种海藻来源的蛋白酪氨酸磷酯酶1B抑制肽及其制备方法,包括:将螺旋藻粉加水混匀,搅拌溶胀,加入木瓜蛋白酶,酶解,离心去除沉淀,上清液分别使用Sephadex G‑15凝胶柱和EclipseXDB‑C18柱分离,组分冻干得多肽,其氨基酸序列为:Gln‑Val‑His‑Gly‑Ile‑Ser‑Pro‑Pro‑Asp‑Ser‑Thr‑Lys。实验结果表明,本发明的多肽QVHGISPPDSTK在体外显示较高的PTP1B抑制作用,在2型糖尿病小鼠模型中具有良好的降血糖效果。此外,本发明还提供一种蛋白酪氨酸磷酯酶1B抑制肽在制备降血糖药品和降血糖保健品中的应用。
Description
技术领域
本发明涉及生物活性肽技术领域,尤其涉及一种蛋白酪氨酸磷酯酶1B抑制肽及其在降血糖制品中的应用。
背景技术
糖尿病是一种慢性内分泌代谢疾病,其中2型糖尿病占糖尿病患者90%以上。2型糖尿病(旧称非胰岛素依赖型糖尿病,是一种慢性代谢疾病,多在35~40岁之后发病,特征为高血糖、相对缺乏胰岛素、胰岛素抵抗等。目前用于治疗2型糖尿病的药物主要有双胍类、磺脲类、α-糖苷酶抑制和噻唑烷二酮类等,由于它们多是针对病症而不是针对病因分子靶点药物的设计,因而存在各种弊端。因此,市场急需安全有效、价格合理且能长期安全服用的降糖药物。
胰岛素抵抗是2型糖尿病发病的关键因素。蛋白质酪氨酸磷酸酶(PTPs)是一类信号传导酶,它们通过调节细胞内酪氨酸的磷酸化水平来控制细胞的成长、分化、代谢;细胞迁移、基因转录、离子通道开闭、免疫反应、细胞凋亡以及成骨发育也受到PTPs的调控。PTPs紊乱可导致多种疾病,如癌症、糖尿病、肥胖症和骨质疏松症。PTP酶家族中,蛋白质酪氨酸磷酸酶1B(PTP1B)可通过对胰岛素受体底物-1(IRS-1)和胰岛素受体底物-2(IRS-2)的脱磷酸化作用下调胰岛素信号,故而PTP1B是开发新抗糖尿病药物的作用靶点。
PTP1B在胰岛素信号转导通路中起着重要的负调控作用。研究证实,在胰岛素敏感细胞中应用PTP1B抑制剂可使胰岛素受体及其底物磷酸化水平升高,促进葡萄糖转运子易位及增加葡萄糖的摄取等,PTP1B抑制剂起到了胰岛素类似物和胰岛素增敏剂的作用。敲除PTP1B基因或用反义核苷酸(ASO)抑制体内PTP1B蛋白及mRNA的表达,不仅可以显著提高受试小鼠对胰岛素的敏感性,而且能够明显降低肥胖症的患者几率。大量研究证实PTP1B在胰岛素信号转导中的负调控作用,它的活性增高,可能是发生胰岛素抵抗和胰岛素受体信号受损的一个致病因素。因此,寻找小分子PTP1B抑制剂已成为治疗T2DM的新靶点。
目前已经有多种从海洋藻类中筛选出具有抗氧化、抗肿瘤、ACE抑制作用的多肽,但是目前还很少有关于海藻来源的PTP1B抑制肽的报道。
发明内容
本发明解决的技术问题在于提供一种蛋白酪氨酸磷酯酶1B抑制肽及其在降血糖制品中的应用,具有显著的PTP1B抑制活性。
有鉴于此,本发明提供了一种蛋白酪氨酸磷酯酶1B抑制肽,具有如下氨基酸序列:Gln-Val-His-Gly-Ile-Ser-Pro-Pro-Asp-Ser-Thr-Lys(QVHGISPPDSTK)。
本发明还提供了,编码所述蛋白酪氨酸磷酯酶1B抑制肽的多核苷酸。
优选的,为海藻来源。
本发明还提供一种蛋白酪氨酸磷酯酶1B抑制肽的制备方法,包括以下步骤:将极大螺旋藻粉和水混合,搅拌溶胀2-4h,料水比为1:10~1:20,以极大螺旋藻粉加入量0.5-2%的酶底比加入木瓜蛋白酶,酶解条件为:pH值为7-8,温度45-55℃,酶解3-8h后,80-100℃加热灭酶;离心去除沉淀,上清液分别使用Sephadex G-15凝胶柱和Eclipse XDB-C18柱分离,组分冻干得蛋白酪氨酸磷酯酶1B抑制肽,其氨基酸序列为:Gln-Val-His-Gly-Ile-Ser-Pro-Pro-Asp-Ser-Thr-Lys(QVHGISPPDSTK)。
优选的,所述极大螺旋藻粉和水混合的时间为2-4h。
优选的,酶解时间为5h。
优选的,灭酶时间为10min。
优选的,使用Sephadex G-15凝胶柱分离的步骤为:以Sephadex G15对酶解物进行分离纯化,以去离子水作为流动相,流速控制在1mL/min,在280nm波长下检测洗脱液吸光度,依据洗脱曲线收集富含多肽组分浓缩并冻干。
优选的,使用Eclipse XDB-C18柱分离的步骤为:以Zorbax SB-Aq C18柱对G-15分离得到的组分进行分离,洗脱程序为:1-5min:5%乙腈;5-55min:5%-95%乙腈;55-60min:95%乙腈;流速为0.8mL/min。
本发明还提供一种上述蛋白酪氨酸磷酯酶1B抑制肽在制备降血糖药品中的应用。
本发明还提供一种上述蛋白酪氨酸磷酯酶1B抑制肽在制备降血糖保健品中的应用。
本发明提供了一种海藻来源的蛋白酪氨酸磷酯酶1B抑制肽及其制备方法,以极大螺旋藻粉为原料,加水混匀,搅拌溶胀,以螺旋藻加入量0.5-2%的酶底比加入木瓜蛋白酶,酶解条件为:pH7-8,温度45-55℃,酶解5h后,于80-100℃加热灭酶。离心去除沉淀,上清液分别使用Sephadex G-15凝胶柱和Eclipse XDB-C18柱分离,组分冻干得到多肽,其氨基酸序列为:Gln-Val-His-Gly-Ile-Ser-Pro-Pro-Asp-Ser-Thr-Lys(QVHGISPPDSTK)。实验结果表明,本发明的多肽QVHGISPPDSTK在体外显示较高的PTP1B抑制作用,在2型糖尿病小鼠模型中具有良好的降血糖效果。此外,本发明还提供一种蛋白酪氨酸磷酯酶1B抑制肽在制备降血糖药品和降血糖保健品中的应用。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据提供的附图获得其他的附图。
图1为本发明实施例1制备的蛋白酪氨酸磷酯酶1B抑制肽的色谱图。
具体实施方式
为了进一步理解本发明,下面结合实施例对本发明优选实施方案进行描述,但是应当理解,这些描述只是为进一步说明本发明的特征和优点,而不是对本发明权利要求的限制。
本发明实施例公开了一种蛋白酪氨酸磷酯酶1B抑制肽,具有如下氨基酸序列:Gln-Val-His-Gly-Ile-Ser-Pro-Pro-Asp-Ser-Thr-Lys(QVHGISPPDSTK)。优选的,其为海藻来源。
本发明还提供一种蛋白酪氨酸磷酯酶1B抑制肽的制备方法,包括以下步骤:将极大螺旋藻粉和水混合,搅拌溶胀2-4h,料水比为1:10~1:20,以极大螺旋藻粉加入量0.5-2%的酶底比加入木瓜蛋白酶,酶解条件为:pH值为7-8,温度45-55℃,酶解3-8h后,于80-100℃加热灭酶;离心去除沉淀,上清液分别使用Sephadex G-15凝胶柱和Eclipse XDB-C18柱分离,组分冻干得蛋白酪氨酸磷酯酶1B抑制肽,其氨基酸序列为:Gln-Val-His-Gly-Ile-Ser-Pro-Pro-Asp-Ser-Thr-Lys(QVHGISPPDSTK)。
作为优选方案,所述极大螺旋藻粉和水混合的时间为2-4h,优选采用800w的功率使用超声细胞破碎仪处理。木瓜蛋白酶酶解得到酶解时间优选为5h,酶解温度优选为45℃,灭酶时间优选为10min。
作为优选方案,本发明使用Sephadex G-15凝胶柱分离的步骤为:以Sephadex G15对酶解物进行分离纯化,以去离子水作为流动相,流速控制在1mL/min,在280nm波长下检测洗脱液吸光度,依据洗脱曲线收集富含多肽组分浓缩并冻干。使用Eclipse XDB-C18柱分离的步骤优选为:以Zorbax SB-Aq C18柱对G-15分离得到的组分进行分离,洗脱程序为:1-5min:5%乙腈;5-55min:5%-95%乙腈;55-60min:95%乙腈;流速为0.8mL/min。
相应的,本发明还提供一种上述蛋白酪氨酸磷酯酶1B抑制肽在制备降血糖药品中的应用。以及一种上述蛋白酪氨酸磷酯酶1B抑制肽在制备降血糖保健品中的应用。
从以上方案可以看出,本发明提供一种蛋白酪氨酸磷酯酶1B抑制肽及其制备方法,以极大螺旋藻粉为原料,将极大螺旋藻经木瓜蛋白酶解,并经进一步分离纯化得到一多肽,该多肽的氨基酸序列为QVHPDTGISSK。该多肽具有显著的PTP1B抑制活性,可用于制备糖尿病治疗相关的药品和功能食品。
为了进一步理解本发明,下面结合实施例对本发明提供的技术方案进行详细说明,本发明的保护范围不受以下实施例的限制。
本发明实施例采用的原料均为市购。
本发明实施例采用的
实施例1
多肽QVHGISPPDSTK的制备方法,包括以下步骤:
(1)将极大螺旋藻粉500g,加入10L蒸馏水搅拌溶胀2h,混悬液以800w的功率使用超声细胞破碎仪处理。
(2)加入5g木瓜蛋白酶酶解,酶解温度45℃,酶解pH值控制在8.0,酶解时间为5h,酶解完成之后100℃灭酶10min,过滤除杂。
(3)上清液使用70%的乙醇醇沉,除去沉淀,上清液超滤收集<3kDa的组分,浓缩至20ml冻干,制得酶解肽提取物。
(4)以Sephadex G15对酶解物进行分离纯化,以去离子水作为流动相,流速控制在1mL/min,在280nm波长下检测洗脱液吸光度,依据洗脱曲线收集富含多肽组分浓缩并冻干,然后以Zorbax SB-Aq C18柱对G-15分离得到的组分进行分离,洗脱程序为:1-5min:5%乙腈;5-55min:5%-95%乙腈;55-60min:95%乙腈;流速为0.8mL/min。依据洗脱曲线进行收集并经过适当合并得到15组分。
依据实施例2方法对15个组分进行PTP1B抑制活性筛选,其中组分6具有显著PTP1B抑制活性,在10μg/mL浓度下抑制率为89%,对该组分进行质谱分析,测定其多肽序列为QVHGISPPDSTK。
多肽纯度采用HPLC法进行分析,称取0.5mg多肽QVHGISPPDSTK样品以0.5mL超纯水溶解后以配有NanoChrom Chromcore TM120 C18(4.6*250MM*5μM)色谱柱的高效液相色谱系统对样品进行分析。上样量为40μL,流动相分别为含有0.1%三氟乙酸的乙腈和超纯水。流速为1.0mL/min,在214nm下检测出峰情况,色谱图如图1所示。以归一化方法对多肽色谱峰进行分析,多肽的纯度≥96%。该多肽在体外表现为温度、pH、模拟胃肠消化降解稳定性。
实施例2蛋白酪氨酸磷脂酶1B抑制活性测定
采用分子生物学方法,构建基因重组的hGST-PTP1B-BL21 E.Coli人类PTP1B工程菌,以GST亲和层析柱纯化hGST-PTP1B蛋白质,利用含有磷酸的多肽para-NitrophenylPhosphate(pNPP)被PTP1B酶解掉一个磷酸后的产物pNP在波长405nm处有吸收峰的原理,以PTP1B作用后生成pNP的量表示PTP1B酶活性变化以及化合物对酶活性的抑制情况,计算化合物PTP1B酶活力抑制率。结果表明,如表1所示,多肽QVHGISPPDSTK对PTP1B具有显著抑制作用,随着浓度增加抑制率逐渐升高。
表1多肽QVHGISPPDSTK对蛋白质酪氨酸磷脂酶1B抑制率(%)
实施例3多肽QVHGISPPDSTK对db/db小鼠的降糖作用
采用4周龄的雄性db/db 2型糖尿病小鼠研究多肽QVHGISPPDSTK的降血糖作用。db/db小鼠分为4组,每组10只,第1组为模型对照组,每天给予生理盐水灌胃,第2组和第3组分别为多肽QVHGISPPDSTK低剂量组(20mg/kg灌胃)和高剂量组(100mg/kg灌胃),第4组为阳性对照组,每天给以二甲双胍灌胃,第5组取10只雄性C57小鼠作为空白对照组,每天给予生理盐水灌胃,连续处理30天,于给药后7天、14天、21天和28天时禁食3小时,灌胃2小时后,尾静脉采血,测血糖。并于次日称体重1次。于29天时禁食不禁水24小时,眼眶静脉取血进行血生化分析。
与正常对照组相比,模型组在血糖持续增高,多肽QVHGISPPDSTK给药能够降低db/db小鼠升高的血糖水平,而且具有剂量依赖性,阳性对照药二甲双胍在给药后血糖与模型组相比均有明显降低。结果见表1。与正常对照组相比较,模型组在实验过程中体重增加。与模型组相比较,多肽QVHGISPPDSTK给药组在给药期间体重均未出现显著差异,说明其对小鼠体重影响不明显。
上述结果表明多肽QVHGISPPDSTK对2型糖尿病模型小鼠具有显著的降血糖作用。
ΔΔΔP<0.001与正常组比较;
*P<0.05;**P<0.01;***P<0.001与模型组比较
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
对所公开的实施例的上述说明,使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的,本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下,在其它实施例中实现。因此,本发明将不会被限制于本文所示的这些实施例,而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
<110> 申请人青岛市市立医院
<120> 一种蛋白酪氨酸磷酯酶1B抑制肽及其应用
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Claims (8)
1.一种蛋白酪氨酸磷酯酶1B抑制肽,其特征在于,其氨基酸序列为:Gln-Val-His-Gly-Ile-Ser-Pro-Pro-Asp-Ser-Thr-Lys(QVHGISPPDSTK)。
2.根据权利要求1所述的蛋白酪氨酸磷酯酶1B抑制肽,其特征在于,为海藻来源。
3.一种权利要求1所述的蛋白酪氨酸磷酯酶1B抑制肽的制备方法,其特征在于,包括以下步骤:
将极大螺旋藻粉和水混合,搅拌溶胀2-4h,料水比为1:10~1:20,以极大螺旋藻粉加入量0.5-2%的酶底比加入木瓜蛋白酶,酶解条件为:pH值为7-8,温度45-55℃,酶解3-8h后,于80-100℃加热灭酶;
离心去除沉淀,上清液分别使用Sephadex G-15凝胶柱和Eclipse XDB-C18柱分离,组分冻干得到蛋白酪氨酸磷酯酶1B抑制肽,其氨基酸序列为:Gln-Val-His-Gly-Ile-Ser-Pro-Pro-Asp-Ser-Thr-Lys (QVHGISPPDSTK)。
4.根据权利要求3所述的制备方法,其特征在于,所述极大螺旋藻粉和水混合的时间为2-4h。
5.根据权利要求3所述的制备方法,其特征在于,灭酶时间为10min。
6.根据权利要求3所述的制备方法,其特征在于,使用Sephadex G-15凝胶柱分离的步骤为:
以Sephadex G15对酶解物进行分离纯化,以去离子水作为流动相,流速控制在1mL/min,在280nm波长下检测洗脱液吸光度,依据洗脱曲线收集富含多肽组分浓缩并冻干。
7.根据权利要求3所述的制备方法,其特征在于,使用Eclipse XDB-C18柱分离的步骤为:
以Zorbax SB-Aq C18柱对G-15分离得到的组分进行分离,洗脱程序为:1-5min:5%乙腈;5-55min:5%-95%乙腈;55-60min:95%乙腈;流速为0.8mL/min。
8.一种权利要求1所述的蛋白酪氨酸磷酯酶1B抑制肽在制备降血糖药品中的应用。
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