CN1321687C - 具有增强的细胞保护效应的阿黑皮素原荷尔蒙的两个生物活性片段 - Google Patents
具有增强的细胞保护效应的阿黑皮素原荷尔蒙的两个生物活性片段 Download PDFInfo
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Abstract
应用计算分析定义了阿黑皮素原的重复的且具有生物活性的片段SYSMEHFRWGKPV与YGGFM。采用乙醇诱导的胃损伤细胞保护模型证实与这两个序列分别应用相比较,SYSMEHFRWGKPV与YGGFM序列的结合物具有增强的细胞保护效果。SYSMEHFRWGKPV与YGGFM这两个序列的结合物用KOMET表示并申请专利。引入KOMET的目的是为了在全身性和局部炎症和伤口愈合的协调上获得更好和更强的药物学效果。显示这两个序列的不同结合物的补充的结构分子式也进行了如下的定义:KOMET-1的序列为YGGFMSYSMEHFRWGKPVYGGFM,KOMET-2的序列为YGGFMSYSMEHFRWGKPV,KOMET-3的序列为SYSMEHFRWGKPVYGGFM。
Description
技术领域
本发明涉及从阿黑皮素原荷尔蒙中提取的两个具有生物活性的肽链的结合物,其具有增加的细胞保护效应,以及炎症反应与组织/伤口愈合之间的调节作用。这两种阿黑皮素原的肽链的结合物具有更佳的药理作用和组织损伤愈合的效果。
背景技术
蛋白质与基因序列中具有生物活性的部分,其长度通常是5至15个氨基酸和重复的肽,其间被更长的未知功能肽链片断(1-5)分割开来。将计算分析应用于该基序的提取以及随后对它们的蛋白质区域的生物活性的控制(1-5)。本发明提出了该具有增强的细胞保护和药理功能的阿黑皮素原荷尔蒙中两个重复且具有生物活性的片断的结合物。
发明内容
在一个单一蛋白质或蛋白质族中重复的肽链片段,以及与其相匹配的互补的序列显示与更大分子结构的生物活性相关联的区域(1-5)。
现代的编程技术、软件以及蛋白质和基因结构数据库的发展使人们利用计算机对不同蛋白质中更大数量的重复的、具有生物活性的和互补的结构进行模拟成为可能(1-5)。因此,人们可以在个人计算机上快速而非常方便地提取相对短小的、重复性的基序(1-5)。为了获得具有增加的药理作用和细胞保护效果的可能的要素的结合物,我们通过软件SCAN(3-5)对阿黑皮素原分子中的重复性的并具有生物活性的肽进行了分析。
附图说明
图1显示了阿黑皮素原分子的两个具有生物活性的肽片段SYSMEHFRWGKPV与YGGFM,及其结合物KOMET在乙醇诱导大鼠胃损伤标准模型中的细胞保护作用。
具体实施方式
本发明的目的在于通过对阿黑皮素原荷尔蒙分子中的两个重复性的和具有生物活性的肽进行结合获得增强的细胞保护药理效果。
实际上,本发明是利用软件SCAN来从阿黑皮素原蛋白质的基序中提取两个重复性的并具有生物活性的序列(SYSMEHFRWGKPV与YGGFM),而不是对该蛋白质的基序进行随机性的筛选。上述两个提取的序列可以在以下分子中找到:阿黑皮素原前体、阿黑皮素原、促肾上腺皮质激素、促黑素细胞激素、β-促脂解素、脑啡肽原、前脑啡肽原、β-内啡肽以及adrenorphin(表1)。
通过利用96%乙醇诱导的雄性Wistar大鼠胃部损伤的标准细胞保护模型(6、7),对SYSMEHFRWGKPV与YGGFM这两个具有生物活性的肽段分别及以结合物进行测试。用生理盐水处理的对照组的8个大鼠,其胃部损伤区域为255.5±78.1mm2(平均值±标准偏差,如图1)(7)。用SYSMEHFRWGKPV(1mg/kg)与YGGFM(10mg/kg)两种肽的结合物处理的8个大鼠组成的试验组,其胃部损伤区域为0.3±0.7mm2(与对照组相比,P<0.05,如图1)(7)。用SYSMEHFRWGKPV(1mg/kg)处理的8个大鼠组成的试验组,其胃部的损伤区域为5.9±8mm2(与对照组相比,P<0.05,如图1)(7)。而用YGGFM(10mg/kg)处理的8个大鼠的试验组,其胃部损伤区域为139.4±36.1mm2(与控制组相比,P<0.05,如图1)(7)。能够提供最佳细胞保护作用的SYSMEHFRWGKPV与YGGFM这两种肽的结合物将以KOMET的名字进行专利申请。上述肽及其组合物对正常的胃黏膜没有刺激作用(7)。
对本发明可能应用的描述
在表1中定义的具有生物活性的序列KOMET,及其结构分子式的组合KOMET-1、KOMET-2以及KOMET-3可以在炎症反应和创伤愈合的调节过程方面用作生物活性肽。对从阿黑皮素原荷尔蒙的活性片段中(6-9)获得的KOMET-1、KOMET-2以及KOMET-3进行定义的目的在于以一种快捷而有效的方式获得可能的药物的分子式(序列)。
本发明的KOMET、KOMET-1、KOMET-2以及KOMET-3的目的是为了能够获得一种药物,该药物可预防和消除组织和肌体在炎症和自我免疫疾病中,以及在下列部位的外伤、感染和烧伤所带来的损伤:
1、结缔组织、关节以及骨骼;
2、中枢神经以及周围神经系统、视神经、眼睛和耳朵;
3、皮肤、毛发和指甲;
4、消化系统、肝脏、胰腺、口腔、牙齿以及鼻窦;
5、免疫系统、骨髓、淋巴结以及脾脏;
6、心血管系统;
7、呼吸系统;
8、生殖系统。
本发明的工业应用
阿黑皮素原中具有生物活性的序列KOMET、KOMET-1、KOMET-2以及KOMET-3可以施用于皮下、肌肉内、腹膜内以及静脉内。局部施用包括软膏、乳膏、凝胶剂、栓剂、阴道栓、滴眼剂、滴耳剂。
参考文献
1.L.Baranyi,W.Campbell,K.Ohishima et al.,Nature Medicine 1(1995)R94-901.
2.J.E.Blalock,Nature Medicine 1(1995)876-878.
3.N.
tambuk,On the Optimization of Complementary Protein Coding,in:S.Ohno,K.Aoki,M.Usui,E.Uchio(Eds.),Uveitis Today,Elsevier,Amsterdam,1998,pp315-318.
5.N.
tambuk,N.Gotovac,M.Martinis et al.Simple Three-step Method for theAnalysis and Design of Repetitive and Bioactive protein Motifs,in:V.B.Baji
(Ed.),Advances in Systems Signals Control and Computers vol.II,IAAMSAD,and ANS,Durban,1998,pp310-311.
8.J.M.Lipton and A.Catania,Immunol.Today18(1997)140-145.
表1
定义了以KOMET命名的阿黑皮素原的两种具有生物活性的序列的结合物,以及化学结构分子式分别为KOMET-1、KOMET-2以及KOMET-3(通过组合单一的分子结构式获得)的三种结合物。
两种具有生物活性的且重复的蛋白质基序(肽YGGFM与肽SYSMEHFRWGKPV)的结合物,是利用SCAN软件(3-5)从阿黑皮素原前体以及阿黑皮素原分子中通过计算得出的。重复性肽YGGFM同样存在于脑啡肽原、前脑啡肽原、β-促脂解素、β-内啡肽以及adrenorphin分子中(a)。而肽SYSMEHFRWGKPV则存在于促黑素细胞激素及促肾上腺皮质激素分子中(b)。
阿黑皮素原中两种具有生物活性的肽YGGFM与肽SYSMEHERWGKPV的结合物是以KOMET的名字申请专利的。
这两种肽的其他结合物是以如下的名字和结构分子式申请专利的:
KOMET-1特征为其结构分子式是YGGFMSYSMEHERWGKPVYGGFM,
KOMET-2特征为其结构分子式是YGGFMSYSMEHERWGKPV以及
KOMET-3特征为其结构分子式是SYSMEHERWGKPVYGGFM。
序号 | 序列YGGFM | 残基 |
1 | adrenorphin | 1~5 |
2 | β-内啡肽 | 1~5 |
3 | 前脑啡肽原 | 54~58,61~65,90~94,140~144,164~168,215~219 |
4 | 脑啡肽原 | 100~104,107~111,136~140,186~190,210~215,261~265 |
5 | β-促脂解素 | 59~63,61~65 |
6 | 阿黑皮素原前体 | 232~236 |
7 | 阿黑皮素原 | 3~7,237~241 |
表1(a)
序号 | 序列SYSMEHFRWGKPV | 残基 |
1 | 促黑素细胞激素 | 1~13 |
2 | 促肾上腺皮质激素 | 1~13 |
3 | 阿黑皮素原前体 | 133~145 |
4 | 阿黑皮素原 | 138~150 |
表1(b)
图1
阿黑皮素原分子中该具有生物活性的肽段SYSMEHFRWGKPV与YGGFM在乙醇诱导胃损伤的大鼠模型中的细胞保护效果。与单独的肽序列相比较,序列KOMET(SYSMEHFRWGKPV+YGGFM)的结合物显示出更强的细胞保护效果。
Claims (5)
1、两个具有生物活性的且重复的阿黑皮素原序列的结合物,其特征在于其结构分子式是SYSMEHFRWGKPV与YGGFM。
2、由两个具有生物活性的且重复的阿黑皮素原序列构成的结合物,其特征在于其结构分子式是YGGFMSYSMEHFRWGKPVYGGFM。
3、由两个具有生物活性的且重复的阿黑皮素原序列构成的结合物,其特征在于由结构分子式是YGGFMSYSMEHFRWGKPV组成。
4、由两个具有生物活性的且重复的阿黑皮素原序列构成的结合物,其特征在于由结构分子式是SYSMEHFRWGKPVYGGFM组成。
5、根据权利要求1~4任意一项所述的结合物在制备预防和消除组织和肌体在炎症、过敏及自身免疫疾病中损伤的药物中的用途。
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EP (1) | EP1435999B1 (zh) |
JP (1) | JP2005508356A (zh) |
CN (1) | CN1321687C (zh) |
AU (1) | AU2002240733B2 (zh) |
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AU2011265315B2 (en) * | 2004-05-12 | 2014-08-28 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Methods related to the treatment of neurodegenerative and inflammatory conditions |
WO2010054446A1 (en) | 2008-11-11 | 2010-05-20 | Ademovic Zlatko | Combination of two or more peptides in a single stable lyophilized pharmaceutical compound |
WO2015033175A1 (en) | 2013-09-06 | 2015-03-12 | Zlatko Ademovic | Combination of pro-opiomelanocortin endogenous peptides in autoimmune disease treatment |
US10644009B2 (en) | 2017-12-21 | 2020-05-05 | Renesas Electronics Corporation | Semiconductor memory device |
CN109824772B (zh) * | 2019-02-28 | 2022-07-29 | 海南大学 | 一组提高血清糖皮质激素水平的基因重组人促皮质素前体及制备方法 |
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WO2000069900A2 (en) * | 1999-05-17 | 2000-11-23 | Conjuchem, Inc. | Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components |
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Non-Patent Citations (2)
Title |
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Anti-inflammatory actions of the neuroimmunomodulatoralppha-MSH J.M. Lipton et al,Immunology Today,Elsevier Publications Cambridge,GB,Vol.18 No.3 1997 * |
Methionine enkephalin" a new cytokine-human studies N.P. Plotnikoff et al,Clinical Immunology and Immunopathology,Vol.182 No.2 1997 * |
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WO2003033017A1 (en) | 2003-04-24 |
BR0117155A (pt) | 2004-10-26 |
RU2004114992A (ru) | 2005-04-20 |
CA2462713A1 (en) | 2003-04-24 |
US7544653B2 (en) | 2009-06-09 |
AU2002240733B2 (en) | 2009-04-09 |
CY1114016T1 (el) | 2016-07-27 |
JP2005508356A (ja) | 2005-03-31 |
ES2391551T3 (es) | 2012-11-27 |
CA2462713C (en) | 2014-03-18 |
PT1435999E (pt) | 2012-10-24 |
CN1558772A (zh) | 2004-12-29 |
RU2297238C2 (ru) | 2007-04-20 |
NO20042001L (no) | 2004-05-14 |
US20050014696A1 (en) | 2005-01-20 |
EP1435999A1 (en) | 2004-07-14 |
DK1435999T3 (da) | 2012-10-22 |
MXPA04003504A (es) | 2005-06-20 |
EP1435999B1 (en) | 2012-07-18 |
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