CN100589839C - 多肽及包含多肽的药物组合物 - Google Patents
多肽及包含多肽的药物组合物 Download PDFInfo
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- CN100589839C CN100589839C CN200480008533A CN200480008533A CN100589839C CN 100589839 C CN100589839 C CN 100589839C CN 200480008533 A CN200480008533 A CN 200480008533A CN 200480008533 A CN200480008533 A CN 200480008533A CN 100589839 C CN100589839 C CN 100589839C
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- A61K38/00—Medicinal preparations containing peptides
Abstract
本发明涉及组合物以及相关的方法,所述的组合物以及相关的方法利用激活鸟苷酸环化酶受体(GC-C)的肽以及其他的药物用于治疗IBS和其他胃肠障碍及病症,例如胃肠蠕动紊乱、功能性胃肠病、胃食管返流疾病(GERD)、节段性回肠炎、溃疡性结肠炎、肠炎、功能性胃灼热、消化不良(包括功能性消化不良或非溃疡性消化不良)、胃病、慢性假性肠梗塞(或结肠假性肠梗塞)及合并便秘的机能障碍和病症,例如使用镇痛剂相关的便秘、术后便秘、与神经失调以及其他病症以及机能障碍相关的便秘。
Description
技术领域
本发明涉及用于治疗各种病症包括胃肠病、肥胖症、充血性心力衰竭及良性前列腺肥大的方法和组合物。
现有技术
过敏性肠综合征是一种常见的肠道慢性病,仅在美国就影响了2千万-6千万人(Lehman Brother,Global Healthcare-Irritable bowel syndrome industryupdate,September 1999)。IBS是胃肠专家所诊断的病症中最常见的(占被检查患者的28%),并且占就诊于初级医师的12%(Camilleri 2001,Gastroenterology 120:652-668)。在美国,由于治疗的直接花费和旷工的间接花费,IBS对经济的影响估计每年在250亿美元(Talley 1995,Gastroenterology109:1736-1741)。IBS患者有三次以上旷工并报告降低了生活质量。患病者不能或不愿意参加社会活动、坚持工作或者甚至短途旅行(Drossman 1993,Dig Dis Sci 38:1569-1580)。由于没有几种用于治疗IBS的药方可供选择,在这一人群中有巨大的未满足的药物需求。
患有IBS的患者遭受腹痛和紊乱的肠状态。IBS患者的三个亚群以主要的肠习性为基础定义:便秘为主的(c-IBS)、腹泻为主的(d-IBS)或二者交替出现的(a-IBS)。患有c-IBS的个体的估计占IBS患者的20-50%,经常引用的数字是30%。和其他两种具有相似的性别比的亚群相反,c-IBS在女性中更为常见(比率为3∶1)(Talley等1995,Am J Epidemiol 142:76-83)。
IBS的定义和诊断标准已经在“Rome Criteria”中成为书面形式(Drossman等1999,Gut 45:suppl II:1-81),已经在临床应用中被广泛接受。然而,症状的复杂性尚未被解剖学的异常或代谢的改变所揭示。这导致了IBS作为一种功能性胃肠病的分类,其诊断以Rome准则为基础并且其评价局限于排除器官疾病(Ringel等2001,Annu Rev Med 52:319-338)。IBS被认为是一种由三个相互作用的机制联合导致的“生物社会心理性”疾病:肠蠕动改变、肠或结肠对疼痛刺激的敏感性增加(内脏敏感性)和社会心理因素(Camilleri 2001,Gastroenterology 120:652-668)。最近,关于炎症在IBS病因学中的作用的证据越来越多。研究表明IBS患者的群体存在结肠炎和肥大细胞很小的但是很明显的增加、可诱导的一氧化氮(NO)和一氧化氮合酶(iNOS)的增加及炎症因子表达的改变(见Talley 2000,Medscape Coverage ofDDW week)。
发明概述
本发明的特征在于组合物和相关方法,所述的组合物和相关方法用于治疗IBS和其他胃肠障碍和病症,例如胃肠蠕动紊乱、功能性胃肠病、胃食管返流疾病(GERD)、节段性回肠炎、溃疡性结肠炎、肠炎、功能性胃灼热、消化不良(包括功能性消化不良或非溃疡性消化不良)、胃病、慢性假性肠梗塞(或结肠假性肠梗塞)及合并便秘的机能障碍和病症,例如使用镇痛剂相关的便秘、术后便秘、与神经失调以及其他病症和机能障碍相关的便秘。所述的组合物特征在于激活鸟苷酸环化酶C(GC-C)受体的肽。
本发明也涉及用于治疗肥胖、充血性心力衰竭及良性前列腺肥大(BPH)的组合物和相关方法。
不受限于任何特定的理论,在IBS和其他胃肠病的情况下,肽很有用,因为其能增加胃肠的蠕动。
不受限于任何特定的理论,在IBS和其他胃肠失调的情况下,肽很有用,部分因为其能减少炎症。
不受限于任何特定的理论,在IBS和其他胃肠失调的情况下,肽很有用,因为能减少胃肠的疼痛或内脏的疼痛。
本发明特征在于药物组合物,所述的组合物包含一些能激活鸟苷酸环化酶C(GC-C)受体的肽。在本发明的范围内包括含本发明的肽的药物组合物,以及包括本发明的肽和第二种治疗药物的联合使用的组合物,所述的第二种治疗药物例如治疗便秘的药物(例如,SPI-0211;SucampoPharmaceuticals,Inc.;Bethesda,MD)或者治疗一些其他胃肠病的药物。第二种治疗药物的例子包括:抑酸剂如质子泵抑制剂及H2受体阻断剂、促蠕动剂如5HT受体激动剂(例如)、抗炎剂、抗痉挛剂、抗抑郁剂、中枢镇痛剂如阿片受体激动剂、阿片受体拮抗剂、肠炎疾病治疗药、用于治疗胃肠或内脏疼痛的节段性回肠炎和溃疡性肠炎药物(例如Traficet-ENTM(ChemoCentryx,Inc.;San Carlos,CA)和cGMP磷酸化抑制剂(莫他匹酮、扎普司特及suldinac sulfone)。例如,药物组合物可包含选自下述的镇痛剂:钙通道阻滞剂(例如齐考诺肽)、5HT受体拮抗剂(例如5HT3、5HT4及5HT1受体拮抗剂)、阿片受体激动剂(例如,洛哌丁胺、非多托秦、芬太尼、纳洛酮、纳屈酮、methyl nalozone、纳美芬、cypridime、beta funaltrexamine、纳洛肼、naltrindole、norbinaltorphimine、吗啡、diphenyloxylate、脑啡肽和曲美布汀)、NK1受体拮抗剂(例如依洛匹坦和SR-14033)、CCK受体激动剂(如氯谷胺)、NK1受体拮抗剂、NK3受体拮抗剂(如他奈坦、奥沙奈坦(SR-142801))、去甲肾上腺素-5-羟色胺重摄取抑制剂(NSRI;如米那普仑)、香草酸及cannabanoid受体激动剂(例如arvanil)、sialorphin、包含氨基酸序列QHNPR(SEQ ID NO:)的sialorphin相关肽,例如VQHNPR(SEQ ID NO:);VRQHNPR(SEQ ID NO:);VRGQHNPR(SEQ ID NO:);VRGPQHNPR(SEQID NO:);VRGPRQHNPR(SEQ ID NO:);VRGPRRQHNPR(SEQ ID NO:);和RQHNPR(SEQ ID NO:)、为中性溶酶抑制剂的化合物或肽类、氟雷法胺H-Tyr-D-Ala-Phe(F)-Phe-NH2;WO 01/019849A1)、洛哌丁胺、Tyr-Arg京都啡肽、CCK受体激动剂(蛙皮素)、芋螺毒素肽、胸腺素肽、氯谷胺、右氯谷胺(氯谷胺的R-异构体)(WO 88/05774)以及能和本发明肽联合使用或连接到本发明肽的其他镇痛作用的肽和化合物。
本发明包括通过给予能起部分或完全的GC-C受体激动剂作用的肽治疗各种胃肠病的方法。所述的肽包括至少6个能形成二硫键的半胱氨酸。在一些实施方案中,二硫键被其他的共价交叉连接所代替,而且在一些情况下,半胱氨酸被以提供可替换的共价交叉连接的其他残基代替。所述肽包括至少一个胰蛋白酶或胰凝乳蛋白酶切割位点及/或羧基端镇痛作用的肽或小分子,例如,AspPhe或几种其他镇痛作用的肽。当存在于肽中时,胰蛋白酶或胰凝乳蛋白酶切割位点位于镇痛作用的肽或小分子之前以使镇痛作用的肽或小分子释放。本发明的肽及方法也可用于治疗与多种疾病包括胃肠病的有关的疼痛和炎症。一些肽包括功能性的胰岛素或胰凝乳蛋白酶切割位点,以便切割使肽失活。一些含有功能性切割位点肽的发生切割并在消化道中逐渐失活,在一些情况下这是所需要的。在一些肽中,功能性的胰蛋白酶位点被改变,以增加肽在体内的稳定性。
本发明包括治疗其他病症如充血性心力衰竭及良性前列腺肥大的方法,例如通过给予能起GC-C受体激动剂作用的肽或小分子(非肠道或口服)。这些药物可与钠尿肽(例如,心房肽、脑钠尿肽或C-型钠尿肽)、利尿剂或血管紧张素抑制剂联用。
本发明涉及增加肠蠕动的方法和组合物。肠蠕动涉及自发协调的胃、肠、结肠和直肠不一致(dissention)以及收缩以便在消化过程中通过消化道运送食物。
在一些实施方案中,所述的肽在羧基端含有一个或二个或更多个相邻的带负电的氨基酸(例如,Asp或Glu);或者一个或二个或更多个相邻的带正电的氨基酸(例如,Lys或Arg);或者一个或二个或更多个相邻的带正电或负电的氨基酸。在这些实施方案中,所有在羧基端一侧的氨基酸都带有正电或负电。在另外的实施方案中,在羧基端带电的氨基酸之前为Leu。例如,以下的氨基酸序列可以被加到肽的羧基端:Asp;Asp Lys;Lys Lys LysLys Lys Lys;Asp Lys Lys Lys Lys Lys Lys;Leu Lys Lys;和Leu Asp。也可能简单地在羧基端加入Leu。
第一方面,本发明特征在于一种肽,包含下述氨基酸序列(I)、由下列氨基酸序列(I)组成或基本上由下述氨基酸序列(I)组成:Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5为Asn Ser Ser Asn Tyr或缺失或Xaa1Xaa2Xaa3Xaa4缺失。在一些实施方案中,Xaa8、Xaa9、Xaa12、Xaa13、Xaa14、Xaa17和Xaa19可为任意氨基酸。在一些实施方案中,Xaa5为Asn、Trp、Tyr、Asp或Phe。在其他实施方案中,Xaa5也可以是Thr或Ile。在其他的实施方案中,Xaa5为Tyr、Asp或Trp。在一些实施方案中,Xaa8为Glu、Asp、Gln、Gly或Pro。在其他实施方案中,Xaa8为Glu;在一些实施方案中,Xaa9为Leu、Ile、Val、Ala、Lys、Arg、Trp、Tyr或Phe。在一些实施方案中,Xaa9为Leu、Ile、Val、Lys、Arg、Trp、Tyr或Phe。
在一些实施方案中,氨基酸能被非天然存在的氨基酸或天然的或非天然存在的氨基酸类似物所代替。例如,氨基酸能被3,4-二羟基-L-苯丙氨酸、3-碘-L-酪氨酸、三碘甲腺原氨酸、L-甲状腺素、苯基甘氨酸(Phg)或正-酪氨酸(正Tyr)替代。Phg及正Tyr和其他氨基酸包括Phe和Tyr能被例如卤素、-CH3、-OH、-CH2NH3、-C(O)H、-CH2CH3、-CN、-CH2CH2CH3、-SH或其他基团取代。
在一些实施方案中,Xaa12为Asn、Tyr、Asp或Ala。在其他实施方案中,Xaa12为Asn。在一些实施方案中,Xaa13为Ala、Pro或Gly,而在其他实施方案中,其为Pro。在一些实施方案中,Xaa14为Ala、Leu、Ser、Gly、Val、Glu、Gln、Ile、Leu、Lys、Arg或Asp,且在其他实施方案中,其为Ala或Gly,在另外一些实施方案中,其为Ala。在一些实施方案中,Xaa16为Thr、Ala、Asn、Lys、Arg、Trp;Xaa17为Gly、Pro或Ala;Xaa19选自Trp、Tyr、Phe、Asn和Leu或Xaa19选自Trp、Tyr和Phe或Xaa19选自Leu、Ile和Val;或Xaa19为His或Xaa19选自Trp、Tyr、Phe、Asn、Ile、Val、His和Leu;且Xaa20Xaa21为AspPhe或缺失,或者Xaa20为Asn或Glu且Xaa21缺失或Xaa19Xaa20Xaa21缺失。本发明也涉及通过给予包含前面提到的肽的组合物治疗胃肠疾病(例如,胃肠蠕动紊乱、过敏性肠综合征、慢性便秘、功能性胃肠病、胃食管返流疾病、功能性胃灼热、消化不良、功能性消化不良、无溃疡性消化不良、胃轻瘫、慢性假性肠梗塞、假性结肠梗塞)、肥胖症、充血性心力衰竭或良性前列腺增生的方法。
当Xaa9为Trp、Tyr或Phe或者当Xaa16为Trp的时候,所述的肽含有潜在的功能性胰凝乳蛋白酶切割位点,在此位点切割将使和肽结合的GC-C受体失活。当Xaa9为Lys或Arg或者当Xaa16为Lys或Arg的时候,所述肽含有潜在的功能性胰蛋白酶切割位点,在此位点切割能使和肽结合的GC-C受体失活。
当Xaa19为Trp、Tyr或Phe的时候,肽含有胰凝乳蛋白酶切割位点,在此位点切割将释放肽的羧基端到Xaa19的部分。当Xaa19为Leu、Ile或Val的时候,肽含有胰凝乳蛋白酶切割位点,在此位点切割将释放肽的氨基端到Xaa19的部分。在pH相对较高的情况下,当Xaa19为His时可见相同的结果。当Xaa19为Lys或Arg的时候,该肽含有胰蛋白酶切割位点,在此位点切割将释放肽的羧基端到Xaa19的部分。因此,如果该肽包含羧基端至Xaa19的镇痛作用的肽,该肽接触到适当的蛋白酶时候将释放到消化道中。在这些镇痛作用的肽中可包括的有:AspPhe(如Xaa20Xaa21)、内吗啡肽-1、内吗啡肽-2、nocistatin、达拉根、醋酸亮丙瑞林及P物质和其他在此所述的镇痛作用的肽。这些肽,例如能用于替换Xaa20Xaa21。
当Xaa1或者本发明的肽的氨基端氨基酸(例如Xaa2或Xaa3)为Trp、Tyr或Phe,该肽含有胰凝乳蛋白酶切割位点,在此位点切割将连同Xaa1、Xaa2或Xaa3释放肽的氨基端释放至Xaa1(或Xaa2或Xaa3)的部分。当Xaa1或者本发明的肽的氨基端氨基酸(例如Xaa2或Xaa3)为Lys或Arg的时候,该肽含有胰蛋白酶切割位点,在此位点切割能将连同Xaa1(或Xaa2或Xaa3)释放肽的氨基端至Xaa1(或Xaa2或Xaa3)的部分。当Xaa1或者本发明的肽的氨基端氨基酸为Leu、Ile或Val的时候,该肽含有胰凝乳蛋白酶切割位点,在此位点切割将释放肽的氨基端至Xaa1的部分。在pH相对较高的情况下,当Xaa1为His时可见相同的结果。因此,例如,如果该肽包含氨基端至Xaa1的镇痛作用的肽,该肽接触到适当的蛋白酶将被释放到消化道中,这些镇痛作用的肽中可包括有:内吗啡肽-1、内吗啡肽-2、nocistatin、达拉根、醋酸亮丙瑞林及P物质和其他在此所述的镇痛作用的肽。
当充分折叠的时候,二硫键出现在Cys6和Cys11;Cys7和Cys15;以及Cys10和Cys18之间。本发明肽带有一些和ST肽相似的序列。然而,其中包括改善功能的氨基酸的改变和/或增加。这些改变能够,例如,增加或降低活性(例如,增加或降低肽刺激肠蠕动的能力),改变肽正确折叠的能力、肽的稳定性、肽与GC-C受体结合的和/或降低毒性的能力。在一些情况下,该肽比野生型ST肽作用更理想。例如,其能减少副作用,如腹泻和脱水。
在一些实施方案中,一个或更多对通常能形成二硫键的Cys残基中的一个或两个基团能被高半胱氨酸、3-巯基脯氨酸(Kolodziej等1996Int J PeptProtein Res 48:274);β-二甲基半胱氨酸(Hunt等1993Int J Pept Protein Res 42:249)或二氨基丙酸(Smith等1978J Med Chem 21:117)替代,以便在通常二硫键的位点形成代替的内部交联。
另外,一个或多个二硫键能够被替代性的共价交叉连接所代替,如酰胺键、酯连接、烷基连接、硫酯连接、内酰胺桥、氨基甲酰基连接、脲连接、硫脲连接、磷酸酯连接、烷基连接、烯键连接、醚、硫醚连接或氨基连接。例如,Ledu等(Proceedings Nat′1Acad.Sci.100:11263-78,2003)描述了用以制备内酰胺和酰胺连接的方法。Schafmeister等(J.Am.Chem.Soc.122:5891,2000)描述了所有的稳定的碳交叉连接。在一些情况下,这些替代性连接的产生需要用其他的残基如Lys或Glu或非天然存在的氨基酸代替Cys残基。
在包含序列(I)的肽的情况下,序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5缺失和/或序列Xaa19Xaa20Xaa21缺失,该肽仍能包含附加羧基端或氨基端的氨基酸或两者都含有。例如,该肽能包括一种促进该肽重组的产生并能在患者给药前断开的氨基端序列。该肽也能包含其他的氨基端或羧基端的氨基酸。在一些情况下,附加的氨基酸保护肽、稳定肽或改变肽的活性。在一些情况下,一些或所有这些附加的氨基酸对患者给予肽之前除去。肽在其氨基端或羧基端或两端能包含1、2、3、4、5、10、15、20、25、30、40、50、60、70、80、90、100或更多的氨基酸。两侧氨基酸数不需要一样。例如,在氨基端有10个附加的氨基酸,而在羧基端没有。
在一个实施方案中,该肽包括氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5缺失;Xaa8为Glu;Xaa9为Leu、Ile、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn;Xaa13为Pro;Xaa14为Ala;Xaa16为Thr、Ala、Lys、Arg、Trp;Xaa17为Gly;Xaa19为Tyr或Leu;以及Xaa20Xaa21为AspPhe或缺失。在一些实施方案中,在Xaa20Xaa21和/或Xaa1Xaa2Xaa3Xaa4Xaa5缺失时,可能有附加的侧翼(flanking)氨基酸。
第二方面,本发明也以一种治疗或预防的方法为特征,包括给予包含氨基酸序列(I)的肽:Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5为Asn Ser Ser Asn Tyr或缺失,或Xaa1Xaa2Xaa3Xaa4缺失以及Xaa5为Asn、Trp、Tyr、Asp、Ile、Thr或Phe;Xaa8为Glu、Asp、Gln、Gly或Pro;Xaa9为Leu、Ile、Val、Ala、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn、Tyr、Asp或Ala;Xaa13为Pro或Gly;Xaa14为Ala、Leu、Ser、Gly、Val、Glu、Gln、Ile、Leu、Lys、Arg和Asp;Xaa16为Thr、Ala、Asn、Lys、Arg、Trp;Xaa17为Gly、Pro或Ala;Xaa19为Trp、Tyr、Phe或Leu;以及Xaa20Xaa21为AspPhe或缺失,或Xaa20为Asn或Glu以及Xaa21缺失或Xaa19Xaa20Xaa21缺失。
在一些治疗或预防方法的实施方案中,该肽包括氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5缺失;Xaa8为Glu;Xaa9为Leu、Ile、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn;Xaa13为Pro;Xaa14为Ala;Xaa16为Thr、Ala、Lys、Arg、Trp或Xaa16为任意氨基酸或Xaa16为Thr、Ala、Lys、Arg、Trp或Xaa16是任意的非芳香性的氨基酸;Xaa17为Gly;Xaa19为Tyr或Leu;以及Xaa20Xaa21为AspPhe或缺失。
在一些实施方案中,本发明以一种纯化的多肽为特征,包含氨基酸序列(II):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Asn12Pro13Ala14Cys15Xaa16Gly17Cys18Xaa19Xaa20Xaa21,其中
XXaa1Xaa2Xaa3Xaa4Xaa5为Asn Ser Ser Asn Tyr或缺失,或Xaa1Xaa2Xaa3Xaa4缺失以及Xaa5为Asn;
Xaa8为Glu或Asp;
Xaa9为Leu、Ile、Val、Trp、Tyr或Phe;
Xaa16为Thr、Ala、Trp;
Xaa19为Trp、Tyr、Phe或Leu或缺失;
Xaa20Xaa21为AspPhe。
在多种优选的实施方案中,本发明以一种纯化多肽为特征,包括氨基酸序列(II):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Asn12Pro13Ala14Cys15Xaa16Gly17Cys18Xaa19Xaa20Xaa21,其中Xaa9为Leu、Ile或Val,且Xaa16为Trp、Tyr或Phe;Xaa9为Trp、Tyr或Phe和Xaa16为Thr或Ala;Xaa19为Trp、Tyr、Phe而且Xaa20Xaa21为AspPhe;以及Xaa1Xaa2Xaa3Xaa4缺失和Xaa5为Asn;该肽包括少于50、40、30或25个氨基酸;在Cys6之前少于5个氨基酸。
所述肽能与包括镇痛作用的肽或镇痛剂的其他肽中的任意一种联合给药或进行连接,例如,共价连接。例如,本发明的治疗肽能连接到选自以下的镇痛剂:Ca通道阻滞剂(例如齐考诺肽)、完全的或部分的5HT受体拮抗剂(例如,5HT3、5HT4和5HT1受体拮抗剂)、完全的或部分的5HT受体激动剂包括5HT3、5HT4(例如,替加色罗、莫沙必利和伦扎必利)和5HT1受体激动剂、CRF受体激动(NBI-34041)、β-3肾上腺素受体受体激动剂、阿片样受体激动剂(例如,氯苯哌酰胺、非多托嗪、芬太尼、纳洛酮、纳曲酮、methyl nalozone、纳美芬、cypridime、beta funaltrexamine、纳洛肼、naltrindole、norbinaltorphimine、吗啡、diphenyloxylate、脑腓肽、五肽、阿西马多林和曲美布汀)、NK1受体激动剂(例如依洛匹坦和SR-14033),CCK受体激动剂(例如氯谷胺)、NK1受体拮抗剂、NK3受体激动剂(例如,他奈坦、奥沙奈坦(SR-142801))、去甲肾上腺素-5-羟色胺重摄取抑制剂(NSRI;例如米那普仑)、香草酸受体和cannabanoid受体激动剂(例如arvanil)、sialorphin、包含氨基酸序列QHNPR(SEQ ID NO:)的sialorphin相关肽,例如VQHNPR(SEQID NO:);VRQHNPR(SEQ ID NO:);VRGQHNPR(SEQ ID NO:);VRGPQHNPR(SEQ ID NO:);VRGPRQHNPR(SEQ ID NO:);VRGPRRQHNPR(SEQ ID NO:);和RQHNPR(SEQ ID NO:)、为中性溶酶抑制剂的化合物或肽类、氟雷法胺(H-Tyr-D-Ala-Phe(F)-Phe-NH2;WO01/019849A1)、洛哌丁胺、Tyr-Arg(京都啡肽)、CCK受体激动剂(蛙皮素)、芋螺毒素肽、胸腺素的肽类似物、氯谷胺、右氯谷胺(氯谷胺的R-异构体)(WO88/05774)以及能和本发明肽联合使用或连接到本发明肽的其他镇痛作用的肽和化合物。
氨基酸、非氨基酸、肽和非肽间隔区能插入到作为GC-C受体激动剂的肽和具有其他生物学功能的肽之间,例如镇痛作用的肽或用于治疗肥胖症的肽。连接基团可以是在体内从侧翼肽切断的,或是体内保留与侧翼肽连接。例如,甘氨酸、β-丙氨酸、甘氨酰甘氨酸、甘氨酰β-丙氨酸、γ-氨基丁酸、6-氨基己酸、L-苯丙氨酸、L-色氨酸、甘氨酸-L-缬氨酰-L-苯丙氨酸可作为间隔区(Chaltin等2003Helvetica Chimica Acta 86:533-547;Caliceti等1993FARMCO 48:919-32),象聚乙二醇(Butterworth等1987J.Med.Chem30:1295-302)和马来酰亚胺衍生物一样(King等2002 Tetrahedron Lett.43:1987-1990)。各种其他的连接基团如文献所述(Nestler 1996 MolecularDiversity 2:35-42;Finn等1984Biochemistry 23:2554-8;Cook等1994Tetrahedron Lett.35:6777-80;Brokx等2002 Journal of Controlled Release 78:115-123;Griffin等2003 J.Am.Chem.Soc.125:6517-6531;Robinson等1998Proc.Natl.Acad.Sci.USA 95:5929-5934)。
所述肽包含通常存在于脊椎动物(例如哺乳动物)物种或细菌物种中的肽的氨基酸序列。另外,所述肽可以是部分或完全的非天然存在的肽。本发明还包含与本发明肽相应的模拟肽(peptidomimetics)。在多种实施方案中,患者患有胃肠病;患者患有选自如下的疾病:胃肠蠕动紊乱、过敏性肠综合征、慢性便秘、功能性胃肠病、胃食管返流疾病、功能性胃灼热、消化不良、功能性消化不良、无溃疡性消化不良、胃轻瘫、慢性假性肠梗塞、节段性回肠炎、溃疡性结肠炎、过敏性肠综合征、假性结肠梗塞、肥胖症、充血性心力衰竭或良性前列腺增生;组合物口服给药;该肽包括30个或更少的氨基酸,该肽包括20个或更少的氨基酸,在Cys6之前不多于5个氨基酸;该肽包括150、140、130、120、110、100、90、80、70、60、50、40或30或更少的氨基酸。在其他实施方案中,该肽包括20或更少的氨基酸。在其他实施方案中,在Cys18之后该肽包括不超过20、15、10或5个肽结构。在一些实施方案中,Xaa19为胰凝乳蛋白酶或胰蛋白酶切割位点,镇痛作用的肽紧跟着Xaa19出现。
第三方面,本发明涉及治疗患有便秘的患者的方法。临床公认的定义便秘的标准是以肠运动的频率、排泄物的粘度和肠运动的轻松度进行定义。便秘的一个共同定义为每周少于三次肠运动。其他的定义包括不规则的坚硬的大便或者过度用力排便(Schiller 2001,Aliment Pharmacol Ther 15:749-763)。便秘可以是原发性的(功能性便秘或慢通过性便秘)或继发于包括神经系统、代谢或内分泌失调的其他因素。这些病症包括糖尿病、甲状腺功能减退、甲状腺功能亢进、低钙血症、多发性硬化症、帕金森病、脊索损害、多发性神经纤维瘤、自主神经病、查加斯病、先天性巨结肠病和囊性纤维病。便秘也可能是由于手术的原因(手术后的肠梗阻)或由于使用如镇痛药(如鸦片)、抗高血压药、抗惊厥剂、抗抑郁药、解痉药、抗精神病药导致的。
所述的方法包括给予包含纯化多肽的组合物,包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5为Asn SerSer Asn Tyr或缺失或Xaa1Xaa2Xaa3Xaa4缺失以及Xaa5为Asn、Trp、TYr、Asp、Ile、Thr或Phe;Xaa8为Glu、Asp、Gln、Gly或Pro;Xaa9为Leu、Ile、Val、Ala、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn、Tyr、Asp或Ala;Xaa13为Pro或Gly;Xaa14为Ala、Leu、Ser、Gly、Val、Glu、Gln、Ile、Leu、Lys、Arg和Asp;Xaa16为Thr、Ala、Asn、Lys、Arg、Trp;Xaa17为Gly、Pro或Ala;Xaa19为Trp、Tyr、Phe或Leu;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe或缺失,或Xaa20为Asn或Glu并且Xaa21缺失,或Xaa19Xaa20Xaa21缺失。
在所述方法的一个实施方案中,该肽包括氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5缺失;Xaa8为Glu;Xaa9为Leu、Ile、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn;Xaa13为Pro;Xaa14为Ala;Xaa16为Thr、Ala、Lys、Arg、Trp;Xaa17为Gly;Xaa19为Tyr或Leu;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe或缺失。
在多种优选的实施方案中,便秘和治疗药物的使用有关;便秘和神经失调有关;便秘是术后便秘(手术后肠梗阻);并且便秘和胃肠病有关;便秘是原发性的(功能性便秘或慢通过性便秘);便秘与神经系统、代谢或内分泌失调有关(例如,糖尿病、甲状腺功能减退、甲状腺功能亢进、低钙血症、多发性硬化症、帕金森病、脊索损害、多发性神经纤维瘤、自主神经病、查加斯病、先天性巨结肠病和囊性纤维病)。便秘也可能是由于手术的原因(手术后的肠梗阻)或由于使用如镇痛药(如鸦片)、抗高血压药、抗惊厥剂、抗抑郁药、解痉药、抗精神病药导致的。
第四方面,本发明是以一种治疗患有胃肠病的患者的方法为特征的,所述的方法包括给予患者一种包含纯化多肽的组合物,所述的纯化多肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5为Asn Ser Ser Asn Tyr或缺失或Xaa1Xaa2Xaa3Xaa4缺失以及Xaa5为Asn、Trp、Tyr、Asp、Ile、Thr或Phe;Xaa8为Glu、Asp、Gln、Gly或Pro;Xaa9为Leu、Ile、Val、Ala、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn、Tyr、Asp或Ala;Xaa13为Pro或Gly;Xaa14为Ala、Leu、Ser、Gly、Val、Glu、Gln、Ile、Leu、Lys、Arg和Asp;Xaa16为Thr、Ala、Asn、Lys、Arg、Trp;Xaa17为Gly、Pro或Ala;Xaa19为Trp、Tyr、Phe或Leu;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe或缺失或Xaa20为Asn或Glu和Xaa21缺失或Xaa19Xaa20Xaa21缺失。
在所述方法的一个实施方案中,所述的肽包括氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5缺失;Xaa8为Glu;Xaa9为Leu、Ile、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn;Xaa13为Pro;Xaa14为Ala;Xaa16为Thr、Ala、Lys、Arg、Trp;Xaa17为Gly;Xaa19为Tyr或Leu;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe或缺失。
在多种实施方案中,患者患有胃肠病症;患者患有选自如下疾病的病症:胃肠蠕动紊乱、过敏性肠综合征、慢性便秘、功能性胃肠病、胃食管返流疾病、功能性胃灼热、消化不良、功能性消化不良、无溃疡性消化不良、胃轻瘫、慢性假性肠梗塞、节段性回肠炎、溃疡性结肠炎、肠应激综合症、假性结肠梗塞、肥胖症、充血性心力衰竭或良性前列腺增生。
在多种实施方案中,Xaa9为Leu、Ile或Val以及Xaa16为Trp、Tyr或Phe;Xaa9为Trp、Tyr或Phe以及Xaa16为Thr或Ala;Xaa19为Trp、Tyr、Phe;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe;Xaa1Xaa2Xaa3Xaa4缺失和Xaa5为Asn。
第五方面,本发明以增加患者的胃肠蠕动的方法为特征,该方法包括给予患者包含一种纯化多肽的组合物,所述的纯化多肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5为Asn Ser Ser Asn Tyr或缺失,或Xaa1Xaa2Xaa3Xaa4缺失及Xaa5为Asn、Trp、Tyr、Asp、Ile、Thr或Phe;Xaa8为Glu、Asp、Gln、Gly或Pro;Xaa9为Leu、Ile、Val、Ala、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn、Tyr、Asp或Ala;Xaa13为Pro或Gly;Xaa14为Ala、Leu、Ser、Gly、Val、Glu、Gln、Ile、Leu、Lys、Arg和Asp;Xaa16为Thr、Ala、Asn、Lys、Arg、Trp;Xaa17为Gly、Pro或Ala;Xaa18为Trp、Tyr、Phe或Leu;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe或缺失或Xaa20为Asn或Glu和Xaa21缺失或Xaa19Xaa20Xaa21缺失。
在一个实施方案中,该肽包括氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5缺失;Xaa8为Glu;Xaa9为Leu、Ile、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn;Xaa13为Pro;Xaa14为Ala;Xaa16为Thr、Ala、Lys、Arg、Trp;Xaa17为Gly;Xaa19为Tyr或Leu;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe或缺失.
第六方面,本发明以增加患者的肠的鸟苷酸环化酶(GC-C)受体的活性为特征,该方法包括:给予患者包含一种纯化多肽的组合物,所述的纯化多肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5为Asn Ser Ser Asn Tyr或缺失,或Xaa1Xaa2Xaa3Xaa4缺失,且Xaa5为Asn、Trp、Tyr、Asp、Ile、Thr或Phe;Xaa8为Glu、Asp、Gln、Gly或Pro;Xaa9为Leu、Il e、Val、Ala、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn、Tyr、Asp或Ala;Xaa13为Pro或Gly;Xaa14为Ala、Leu、Ser、Gly、Val、Glu、Gln、Ile、Leu、Lys、Arg和Asp;Xaa16为Thr、Ala、Asn、Lys、Arg、Trp;Xaa17为Gly、Pro或Ala;Xaa19为Trp、Tyr、Phe或Leu;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe或缺失或Xaa20为Asn或Glu和Xaa21缺失或Xaa19Xaa20Xaa21缺失。
在一个实施方案中,该肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5缺失;Xaa8为Glu;Xaa9为Leu、Ile、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn;Xaa13为Pro;Xaa14为Ala;Xaa16为Thr、Ala、Lys、Arg、Trp;Xaa17为Gly;Xaa19为Tyr或Leu;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe或缺失。
第七方面,本发明以包含编码一种多肽的分离的核酸分子为特征,所述的多肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5为Asn Ser Ser Asn Tyr或缺失,或Xaa1Xaa2Xaa3Xaa4缺失和Xaa5为Asn、Trp、Tyr、Asp、Ile、Thr或Phe;Xaa8为Glu、Asp、Gln、Gly或Pro;Xaa9为Leu、Ile、Val、Ala、Lys、Arg、Trp、tyr或Phe;Xaa12为Asn、tyr、Asp或Ala;Xaa13为Pro或Gly;Xaa14为Ala、Leu、Ser、Gly、Val、Glu、Gln、Ile、Leu、Lys、Arg和Asp;Xaa16为Thr、Ala、Asn、Lys、Arg、Trp;Xaal为Gly、Pro或Ala;Xaa19为Trp、Tyr、Phe或Leu;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe或缺或Xaa20为Asn或Glu和Xaa21缺失或Xaa19Xaa20Xaa21缺失。
在一个实施方案中,该肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5缺失;Xaa8为Glu;Xaa9为Leu、Ile、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn;Xaa13为Pro;Xaa14为Ala;Xaa16为Thr、Ala、Lys、Arg、Trp;Xaa17为Gly;Xaa19为Tyr或Leu;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe或缺失。
第八方面,本发明以治疗便秘的方法为特征,所述的方法包括:给予肠鸟苷酸环化酶(GC-C)受体激动剂。在多种实施方案中,激动剂是一种肽,该肽包含形成二个二硫键的四个Cys,该肽包含形成三个二硫键的六个Cys。
第九方面,本发明以一种治疗胃肠病、胃肠蠕动紊乱、过敏性肠综合征、慢性便秘、功能性胃肠病、胃食管返流疾病、功能性胃灼热、消化不良、功能性消化不良、无溃疡性消化不良、胃轻瘫、慢性假性肠梗塞、节段性回肠炎、溃疡性结肠炎、肠炎、肥胖症,充血性心力衰竭或良性前列腺增生的方法为特征,所述的方法包括:口服、使用直肠栓剂或非经肠地给予鸟苷酸环化酶(GC-C)受体激动剂。在多种实施方案中,该激动剂为一种肽,该肽包含四个形成二个二硫键的Cys,和该肽包含六个形成三个二硫键的Cys。
第十方面,本发明以治疗胃肠病症的方法为特征,所述的胃肠病症选自胃肠蠕动紊乱、过敏性肠综合征、慢性便秘、功能性胃肠病、胃食管返流疾病、功能性胃灼热、消化不良、功能性消化不良、无溃疡性消化不良、胃轻瘫、慢性假性肠梗塞、节段性回肠炎、溃疡性结肠炎、肠炎,所述的方法包括给予鸟苷酸环化酶受体激动剂。在多种实施方案中,口服给予组合物,该肽包含30个或更少的氨基酸,该肽包含20个或更少的氨基酸,该肽Cys5之前包含不超过5个氨基酸。
在多种实施方案中,所述的激动剂为一种肽,该肽包含四个形成二个二硫键的Cys,和该肽包含六个形成三个二硫键的Cys。
第十一方面,本发明以治疗肥胖症的方法为特征,所述的方法包括给予肠鸟苷酸环化酶受体激动剂。在多种实施方案中,所述的激动剂为一种肽,该肽包含四个形成二个二硫键的Cys,和该肽包含六个形成三个二硫键的Cys。
第十二方面,本发明以治疗肥胖症的方法为特征,所述的方法包括给予多肽,所述的多肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5为Ash Ser Ser Asn Tyr或缺失,或Xaa1Xaa2Xaa3Xaa4缺失以及Xaa5为Asn、Trp、Tyr、Asp、Ile、Thr或Phe;Xaa8为Glu、Asp、Gln、Gly或Pro;Xaa9为Leu、Ile、Val、Ala、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn、Tyr、Asp或Ala;Xaa13为Pro或Gly;Xaa14为Ala、Leu、Ser、Gly、Val、Glu、Gln、Ile、Leu、Lys、Arg和Asp;Xaa16为Thr、Ala、Asn、Lys、Arg、Trp;Xaa17为Gly、Pro或Ala;Xaa19为Trp、Tyr、Phe或Leu;以及Xaa20Xaa21为AspPhe或缺失,或Xaa20为Asn或Glu和Xaa21缺失,或者Xaa19Xaa20Xaa21缺失。该肽可以单独给药或者和另外的治疗肥胖的药物联用,例如,西布曲明或另外的药物,如在此所述的药物。
在一个实施方案中,该肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5缺失;Xaa8为Glu;Xaa9为Leu、Ile、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn;Xaa13为Pro;Xaa14为Ala;Xaa16为Thr、Ala、Lys、Arg、Trp;Xaa17为Gly;Xaa19为Tyr或Leu;以及Xaa20Xaa21为AspPhe或缺失。
第十三方面,本发明特征在于包含在此所述的多肽的药物组合物。
第十四方面,本发明以治疗充血性心力衰竭的方法为特征,所述的方法包括给予患者包含纯化多肽的组合物,所述的纯化多肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5为Asn Ser Ser Asn Tyr或缺失,或Xaa1Xaa2Xaa3Xaa4缺失,且Xaa5为Asn、Trp、Tyr、Asp、Ile、Thr或Phe;Xaa8为Glu、Asp、Gln、Gly或Pro;Xaa9为Leu、Ile、Val、Ala、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn、Tyr、Asp或Ala;Xaa13为Pro或Gly;Xaa14为Ala、Leu、Ser、Gly、Val、Glu、Gln、Ile、Leu、Lys、Arg和Asp;Xaa16为Thr、Ala、Asn、Lys、Arg、Trp;Xaa17为Gly、Pro或Ala;Xaa19为Trp、Tyr、Phe或Leu;Xaa20Xaa21为AspPhe或缺失或Xaa20为Asn或Glu且Xaa21缺失或Xaa19Xaa20Xaa21缺失。该肽可以和另外的治疗充血性心力衰竭的药物联合给药,例如钠尿肽,如心房肽、脑钠尿肽或C-型钠尿肽、利尿剂或血管紧张素转换酶抑制剂。
在一个实施方案中,该肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5缺失;Xaa8为Glu;Xaa9为Leu、Ile、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn;Xaa13为Pro;Xaa14为Ala;Xaa16为Thr、Ala、Lys、Arg、Trp;Xaa17为Gly;Xaa19为Tyr或Leu;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe或缺失。
第十五方面,本发明以一种治疗良性前列腺增生的方法为特征,所述的方法包括给予患者包含纯化多肽的组合物,所述的纯化多肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5为Asn Ser Ser Asn Tyr或缺失或Xaa1Xaa2Xaa3Xaa4缺失和Xaa5为Asn、Trp、Tyr、Asp、Ile、Thr或Phe;Xaa8为Glu、Asp、Gln、Gly或Pro;Xaa9为Leu、Ile、Val、Ala、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn、Tyr、Asp或Ala;Xaa13为Pro或Gly;Xaa14为Ala、Leu、Ser、Gly、Val、Glu、Gln、Ile、Leu、Lys、Arg和Asp;Xaa16为Thr、Ala、Asn、Lys、Arg、Trp;Xaa17为Gly、Pro或Ala;Xaa19为Trp、Tyr、Phe或Leu;Xaa19为Lys或Arg;Xaa20Xaa21为AspPhe或缺失或Xaa20为Asn或Glu和Xaa21缺失或Xaa19Xaa20Xaa21缺失。
该肽可以和另外的治疗BPH的药物联合给药,例如5-α还原酶抑制剂(例如非那司提)或α肾上腺素能拮抗剂(例如doxazosine)。
在一个实施方案中,该肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5缺失;Xaa8为Glu;Xaa9为Leu、Ile、Lys、Arg、Trp、Tyr或Phe;Xaa12为Asn;Xaa13为Pro;Xaa14为Ala;Xaa16为Thr、Ala、Lys、Arg、Trp;Xaa17为Gly;Xaa19为Tyr或Leu;Xaa20Xaa21为AspPhe或缺失。
第十六方面,本发明以治疗或减少疼痛的方法为特征,所述的疼痛包括内脏痛和胃肠病症有关的疼痛或与其他一些病症有关的疼痛,该方法包括给予患者含有纯化多肽的组合物,所述的纯化多肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,例如,含有在此所述的氨基酸序列的纯化多肽。
第十七方面,本发明以治疗炎症的方法为特征,所述的炎症包括胃肠道炎症,例如与胃肠病症或感染或一些其他病症有关的炎症,所述的方法包括给予患者含有纯化多肽的组合物,所述的纯化多肽包含氨基酸序列(I):Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,例如,含有在此所述的氨基酸序列的纯化多肽。
在一些实施方案中,该肽包括或由下列氨基酸序列组成,Xaa1Xaa2Xaa3Xaa4Xaa5Cys Cys Glu Xaa9 Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Xaa20Xaa21(II)(SEQ ID N O:_),其中,Xaa9为任意氨基酸,其中Xaa9为除Leu之外的任意氨基酸,其中Xaa9选自Phe、Trp和Tyr;其中Xaa9选自其他任意的天然或非天然芳香族氨基酸,其中Xaa9为Tyr;其中Xaa1Xaa2Xaa3Xaa4Xaa5为Asn Ser Ser Asn Tyr;其中Xaa1Xaa2Xaa3Xaa4和Xaa5缺失;其中Xaa1Xaa2Xaa3和Xaa4缺失;其中Xaa1、Xaa2和Xaa3缺失;其中Xaa1和Xaa2缺失;其中Xaa1缺失;其中Xaa20Xaa21为AspPhe或缺失,或Xaa20为Asn或Glu并且Xaa21缺失或Xaa19Xaa20Xaa21缺失。关于包含以下序列(I)的肽:Xaa1Xaa2Xaa3Xaa4Xaa5Cys6Cys7Xaa8Xaa9Cys10Cys11Xaa12Xaa13Xaa14Cys15Xaa16Xaa17Cys18Xaa19Xaa20Xaa21,其中:Xaa1Xaa2Xaa3Xaa4Xaa5缺失和/或序列Xaa19Xaa20Xaa21缺失,该肽仍能包含带有羧基端或氨基端的氨基酸或二者均有。
其中含有或由下列氨基酸序列组成,或基本上由下列氨基酸序列组成:Xaa1Xaa2Xaa3Xaa4Xaa5Cys Cys Glu Xaa9Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr Xaa20Xaa21(II)(SEQ ID NO:---)有用的肽为下列肽:
Gln Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:---)
Asn Thr Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:---)
Asn Leu Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:---)
Asn Ile Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly CysTyr(SEQ ID NO:---)
Asn Ser Ser Gln Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:---)
Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:---)
Gln Ser Ser Gln Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:---)
Ser Ser Gln Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:---)。
Asn Ser Ser Asn Tyr Cys Cys Glu Ala Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Arg Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Asn Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Asp Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Cys Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Gln Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Glu Cys Cys Asn Pro Ala Cys Thr GlyCysTyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Gly Cys Cys Asn Pro Ala Cys Thr GlyCys Yyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu His Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Ile Cys Cys Asn Pro Ala Cys Thr Gly CysTyr(SEQ ID NO)
Asn Ser Ser Asn Tyr Cys Cys Glu Lys Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Met Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID 10NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Pro Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Ser Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Asn Ser Ser Asn Tyr Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:)
Cys Cys Glu Ala Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Arg Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Asn Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Asp Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Cys Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Gln Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Glu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Gly Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu His Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Ile Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Gys Glu Lys Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Met Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Pro Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Ser Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:)
第十八方面,本发明以一种治疗充血性心力衰竭的方法为特征,所述的方法包括给予肠鸟苷酸环化酶(GC-C)受体完全或部分激动剂。该激动剂可以和另外的治疗充血性心力衰竭的药物联合给药,例如钠尿肽,如心房肽、脑钠尿肽或C-型钠尿肽、利尿剂或血管紧张素转换酶抑制剂。
第十九方面,本发明以治疗BPH的方法为特征,所述的方法包括给予肠鸟苷酸环化酶(GC-C)受体完全或部分激动剂。该激动剂可以和另外的治疗BPH的药物联合给药,例如5-α还原酶抑制剂(例如非那司提)或α肾上腺素能拮抗剂(例如doxazosine)。
第二十方面,本发明以治疗肥胖的方法为特征,所述的方法包括给予鸟苷酸环化酶(GC-C)受体完全或部分激动剂。激动剂可以和另外的治疗肥胖的药物联合给药,例如,胃肠激素片段肽YY3-36(PYY3-36)(N.Engl.J.Med.349:941,2003;ikpeapge daspeelnry yaslrhylnl vtrqry)、glp-1(胰高血糖素样肽-1)、毒蜥外泌肽-4(glp-1抑制剂)、西布曲明、苯丁胺、苯甲曲秦、盐酸苄非他明(Didrex)、奥利斯特(Xenical)、盐酸安非泼拉酮(Tenuate)、氟西汀(Prozac)、丁氨苯丙酮、麻黄、铬、柬埔寨藤黄(garcinia cambogia)、苯佐卡因、墨角藻(用于囊切开术)、壳聚糖、nomame herba、山羊豆(Goat′s Rue,French Lilac)、共轭亚油酸、L-肉碱、纤维(欧车前、车前属、guar fiber)、咖啡因、脱氢表雄酮、石蚕属植物(teucrium chamaedrys)、β-羟基-甲基丁酸酯或丙酮酸酯。用于治疗肥胖症的肽能作为一个独立的分子或作为本发明肽融合的蛋白的一部分和本发明肽联合治疗。例如,PYY3-36能融合到本发明的肽的羧基端或氨基端。这样的融合蛋白包括胰凝乳蛋白酶或胰蛋白酶切割位点,在此能切割分离为两段肽。
该肽和肠鸟苷酸环化酶(GC-C)受体激动剂能用于治疗便秘或肠运动降低、消化减慢或胃排空减慢。该肽能用于缓解一种或多种下述症状:IBS(胃气胀、疼痛、便秘)、GERD(酸反流到食管中)、机能性消化不良或胃轻瘫(恶心、呕吐、胃气胀、胃排空延迟)和在此所述的其他病症的症状。
本发明的一个或更多的实施方案的详细资料在所附说明书中阐述。所有的公开、专利和专利申请列入此处作为参考。
附图简述
图1a描述了重组MM-416776肽和MD-915肽的LCMS分析结果。
图1b和c描述合成的MD-1100肽和空白对照的LCMS分析结果。
图2描述合成的MM-416776肽、MD-915肽和两种不同的MD-1100肽的肠GC-C受体活性分析结果。
图4a和4b描述肽MD-915、MD-1100和MM-416776在急性鼠科胃肠道转运模型中的作用。
图4c描述MD-1100肽在慢性鼠科胃肠道转运模型中的作用。
图6a和6b描述MM 416776、MD-1100和MD-915肽在小鼠胃肠道分泌模型中的作用。
图7显示了试验结果,其中分析了MD-1100在TNBS结肠扩张模型中的活性。
图8a和8b显示了不同剂量的MD-915和MD-1100在PBQ扭体测定试验(writhing assay)中的结果。
图9显示了使用MD-1100的Kd检测分析的结果,采用竞争性放射性配体结合分析法。
图10a和10b显示了IV和口服给药MD-1100的生物利用度结果,采用ELISA分析和LCMS方法。
发明详述
本发明肽与肠鸟苷酸环化酶(GC-C)受体结合,后者是肠中液体和电解质平衡的重要调节剂。当受到刺激,位于肠上皮表面顶膜的该受体导致肠内膜环磷鸟苷(cGMP)的增加。cGMP的增加被认为引起了水和钠吸收的减少、氯和钾离子分泌增加,这样导致肠液和电解质转运的改变和肠能动性增强。肠内GC-C受体具有细胞外的配体结合部位、跨膜部位、细胞内蛋白激酶样部位和环化酶催化区。GC-C受体提议的功能为液体和电解质平衡作用、调节上皮细胞增殖和诱导凋亡(Shalubhai 2002Curr Opin Drug Dis Devel5:261-268)。
除在肠中被胃肠上皮细胞表达外,GC-C在肠外的组织包括肾、肺、胰腺、脑垂体、肾上腺、发育的肝(参考Vaandrager 2002,Mol Cell Biochem 230:73-83)及雄性和雌性的生殖系统组织中表达(参考Vaandrager 2002Mol CellBiochem 230:73-83)。这提示GC-C受体激动剂能用于治疗胃肠道以外的病症,例如充血性心力衰竭和良性前列腺增生。
由胃分泌的激素肽Ghrelin,是一种重要的人的食欲调节剂。禁食和胃排空调节Ghrelin的表达水平(Kim等,2003,Neuroreprt 14:1317-20;Gualillo等,2003,FEBS Letts 552:105-9)。因此,GC-C受体激动剂通过增加胃肠蠕动也许也能用于调节肥胖。
人的GC-C受体被鸟苷蛋白(Gn)(U.S.Patent 5,96,097)、uroguanylin(Ugn)(U.S.5,140,102)和lymphoguanylin(Forte等,1999,Endocrinology 140:1800-1806)激活。有趣的,这些药物的效价比一种称为ST的细菌的衍生的肽低10-100倍(见Gianella 1995J Lab Clin Med 125:173-181的评论)。ST肽被认为是高级GC-C受体激动剂,并很好地抵抗蛋白水解的降解。
ST肽能刺激肠的神经系统(Rolfe等,1994,J Physiolo 475:531-537;Rolfe等,1999,Gut 44:615-619;Nzegwu等,1996,Exp Physiol 81:313-315)。在多种疼痛动物模型中,cGMP已被报道有抗感受伤害的作用(Lazaro Ibanez等,2001,Eur JPharmacol 426:39-44;Soares等,2001,British JPharmacol 134:127-131;Jain等,2001,Brain Res 909:170-178;Amarante等,2002,Eur JPharmacol 454:19-23)。因此,GC-C激动剂可具有抗炎作用以及镇痛作用。
细菌的ST肽来源于一种通常至少含有70个氨基酸的前原蛋白。前(序列)区和原(序列)区作为分泌过程的部分被切割,得到的通常含有少于20个氨基酸的成熟蛋白具有生物活性。
已知的细菌ST肽有:E.coliST Ib(Moseley等(1983)Infect.Immun.39:1167),其具有成熟的氨基酸序列Asn Ser Ser Asn Tyr Cys Cys Glu Leu CysCys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:_);E.coli ST Ia(So和McCarthy(1980)Proc.Natl.Acad.Sci.USA 77:4011),其具有成熟的氨基酸序列Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly CysTyr(SEQ ID NO NO:_);E.coli ST I*(Chan和Gialnnella(1981)J.Biol.Chem.256:7744),其具有成熟的氨基酸序列Asn Thr Phe Tyr Cys Cys Glu Leu CysCys Tyr Pro Ala Cys Ala Gly Cys Asn(SEQ ID NO NO:_);C.freundii ST肽(Guarino等(1989)Infect.Immun.57:649),其具有成熟的氨基酸序列Asn ThrPhe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr(SEQ IDNO NO:_);结肠耶氏菌ST肽、Y-ST(Y-STa)、Y-STb和y-STc(参考Huang等(1997)Microb.Pathog 22:89的评论),其具有以下原型氨基酸序列:GlnAla Cys Asp Pro Pro Ser Pro Pro Ala Glu Val Ser Ser Asp Trp Asp Cys Cys AspVal Cys Cys Asn Pro Ala Cys Ala Gly Cys(SEQ ID NO NO:_)(以及Y-STa的Ser-7至Leu-7的变体(SEQ ID NO:NO:_),(Takao等(1985)Eur.J.Biochem.152:199));Lys Ala Cys Asp Thr Gln Thr Pro Ser Pro Ser Glu Glu Asn Asp AspTrp Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Ala Gly Cys(SEQ ID NO:_);Gln Glu Thr Ala Ser Gly Gln Val Gly Asp Val Ser Ser Ser Thr Ile Ala Thr Glu ValSer Glu Ala Glu Cys Gly Thr Gln Ser Ala Thr Thr Gln Gly Glu Asn Asp Trp AspTrp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Phe Gly Cys(SEQ ID NO:_),分别地;Y.kristensenii ST肽,具有成熟的氨基酸序列Ser Asp Trp Cys Cys GluVal Cys Cys Asn Pro Ala Cys Ala Gly Cys(SEQ ID NO:_);V.cholerae non-01ST肽(Takao等(1985)FEBS lett.193:250),具有成熟的氨基酸序列Ile AspCys Cys Glu Ile Cys Cys Asn Pro Ala Cys Phe Gly Cys Leu Asn(SEQ ID NO:_);V.mimicus ST肽(Arita(1991)等FEMS Microbiol.Lett 79:105),具有成熟的氨基酸序列Ile Asp Cys Cys Glu Ile Cys Cys Asn Pro Ala Cys Phe Gly CysLeu Asn(SEQ ID NO:_)。下表提供了许多成熟ST肽的所有或一部分序列。
E.coli ST-1A(ST-P)蛋白的未成熟型(包括前(序列)区和原(序列)区)含有的序列:mkklmlaifisvlsfpsfsqstesldsskekitletkkcdvvknnsekksenmnntf yccelccnpaca gcy(SEQ ID NO:_);见Accession No.P01559(gi:123711)。前序列从aa 1-19延伸。前序列从aa 20-54延伸。成熟蛋白从55-72延伸。E.coli ST-1B(ST-H)蛋白的未成熟型(包括前(序列)区和原(序列))含有序列:mkksilfiflsvlsfspfaqdakpvesskelcitleskkcniakksnksgpesmnssnyccelccnpactgcy(SEQ ID NO:_);见Accession No.P07965(gi:3915589)。Y.enterocolitica ST蛋白未成熟型(包括前(序列)区和原(序列))含有的序列:mkkivfvlvlmlssfgafgqetvsgqfsdalstpitaevykqacdpplppaevssdwdccdvccnpacagc(SEQ ID NO:_);见Accession No.S25659(gi:282047)。
本发明的肽,象细菌ST肽一样含有六个Cys残基。这六个Cys残基在成熟型和激活型肽上形成三个二硫键。如果六个Cys残基从所述肽的氨基端到羧基端,定义为A、B、C、D、E、F,那么二硫键形成如下:A-D、B-E和C-F。这些键的形成对于GC-C受体结合很重要。本发明的一些肽,包含潜在的功能性的胰凝乳蛋白酶切割位点,例如,位于Cys B和Cys D之间或Cys E和Cys F之间的Trp、Tyr或Phe。在任一胰凝乳蛋白酶切割位点切割,减弱少或消除该肽与GC-C受体结合的能力。
在人体内,胰凝乳蛋白酶的非活性形式胰凝乳蛋白酶原是在胰腺中产生的。当这种非活性酶到达小肠,通过切除两个二肽转化为活性胰凝乳蛋白酶。活性胰凝乳蛋白酶能将Trp、Tyr或Phe羧基端侧的肽键切断肽。消化道中活性胰蛋白酶的存在,能导致具有合适的功能性胰蛋白酶的切割位点的本发明的肽的切割。当具有合适的胰蛋白酶切割位点的本发明的肽经过消化道时,预期胰凝乳蛋白酶的切割将缓和其作用。
胰蛋白酶原,与胰凝乳蛋白酶一样,是一种在胰腺产生并存在于消化道中的丝氨酸蛋白酶。其活性形式,胰蛋白酶将切割含有Lys或Arg的肽。消化道中活性胰蛋白酶的存在,能导致一种具有合适的功能性胰蛋白酶的切割位点的本发明的肽的切割。当具有合适的胰蛋白酶切割位点的本发明的肽经过消化道时,预期胰凝乳蛋白酶的切割将缓和其作用。
包括IBS的很多胃肠病症伴随腹痛或内脏痛。本发明的一些肽含有止痛或抗感觉伤害标记,例如羧基端序列紧接着能产生功能性胰凝乳蛋白酶切割位点的Trp、Tyr或Phe,或能产生功能性胰蛋白酶切割位点的Lys或Arg。消化道中的胰凝乳蛋白酶可能能切割羧基端紧连Trp、Phe或Tyr残基的肽,释放出AspPhe二肽。这二肽在动物模型上已经显示出镇痛活性(Abdikkahi等2001,Fundam Clin Pharmacol 15:117-23;Nikfar等1997,29:583-6;Edmundson等1998,Clin Pharmacol Ther 63:580-93)。在这种方法中,该肽能治疗疼痛和炎症。其他的镇痛作用的肽存在于该肽(功能性切割位点之后)的羧基端,包括:内吗啡肽-1、内吗啡肽-2、nocistatin、达拉根、醋酸亮丙瑞林和P物质。大量的有用的肽以核心序列为基础:Cys Cys GluLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr。为了产生具有能够使肽失活的、潜在的功能性的胰凝乳蛋白酶切割位点的变异体,下划线的Leu或Thr能被Trp、Phe或Tyr替代,或Leu和Thr两者都能单独地被Trp、Phe或Tyr替代。为了产生含有止痛的二肽的变异体,核心序列之后接着为Asp Phe。核心序列的羧基端Tyr能允许Asp Phe二肽在消化道通过胰凝乳蛋白酶被释放。核心序列之前任选为Asn Ser Ser Asn Tyr或Asn。
因此,以核心序列为基础的有用的变异体序列包括:
Asn Ser Ser Asn Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:--;MM-416776)
Asn Ser Ser Asn Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Trp GlyCys Tyr(SEQ ID NO:---)
Asn Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr(SEQ ID NO:---;MD-915)
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ IDNO:--;MM416774)
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Trp Gly Cys Tyr(SEQ IDNO:---)
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ IDNO:--;MD-1100)
Asn Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ IDNO:---)
Asn Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Trp Gly Cys Tyr(SEQ IDNO:---)
Asn Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ IDNO:---)
Asn Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ IDNO:---)
Asn Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ IDNO:---)
Asn Cys Cys Glu Arg Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ IDNO:---)
Asn Cys Cys Glu Lys Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ IDNO:---)
Asn Ser Ser Asn Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr Asp Phe(SEQ ID NO:---)
Asn Ser Ser Asn Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Trp GlyCys Tyr Asp Phe(SEQ ID NO:---)
Asn Ser Ser Asn Tyr Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr Asp Phe(SEQ ID NO:---)
Asn Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr Asp Phe(SEQ ID NO:---)
Asn Ser Ser Asn Tyr Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr GlyCys tyr Asp Phe(SEQ ID NO:---)
Asn Ser Ser Asn Tyr Cys Cys Glu Arg Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr Asp Phe(SEQ ID NO:---)
Asn Ser Ser Asn Tyr Cys Cys Glu Lys Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr Asp Phe(SEQ ID NO:---)
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe(SEQID NO:---)
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Trp Gly Cys Tyr Asp Phe(SEQID NO:---)
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe(SEQID NO:---)
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe(SEQID NO:---)
Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe(SEQID NO:---)
Cys Cys Glu Arg Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe(SEQID NO:---)
Cys Cys Glu Lys Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe(SEQID NO:---)
Asn Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe(SEQ ID NO:---)
Asn Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Trp Gly Cys Tyr Asp Phe(SEQ ID NO:---)
Asn Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe(SEQ ID NO:---)
Asn Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe(SEQ ID NO:---)
Asn Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe(SEQ ID NO:---)
Asn Cys Cys Glu Arg Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe(SEQ ID NO:---)
Asn Cys Cys Glu Lys Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe(SEQ ID NO:---)
在一些情况下,本发明肽以前原蛋白产生的,含有氨基端引导序列:mkksilfiflsvlsfspfaqdakpvesskekitleskkcniakksnksgpesmn。其中肽由一种细菌细胞如E.coli产生,切割前述的引导序列,细菌细胞将有效地分泌成熟肽。美国专利5,395,490描述了载体、表达体系、从细菌细胞有效产生ST肽的方法以及有效获得成熟ST肽分泌的方法。美国专利5,395,490所述载体、表达体系和方法可用于生产本发明的ST肽和ST肽变异体。
变异肽
本发明包括变异肽,其可包含一、二、三、四、五、六、七、八、九或十(在一些实施方案中,少于5或少于3或2或者更少的)个氨基酸取代,与SEQ ID NOs:_到_相比。该取代可以为保守的或非保守的。天然存在的氨基酸能被任意氨基酸、非天然的氨基酸和其他基团的D-异构体所取代。保守的氨基酸置换导致了氨基酸转换为具有相似作用的氨基酸,或具有类似电荷、极性、疏水性的氨基酸。在一些位置,即便保守氨基酸的置换也能降低肽的活性。在天然存在的氨基酸置换中通常认为是保守的有:
在一些情况下,希望用与肠GC-C受体结合并激活受体但活性低于非变异体形式的变异肽治疗患者。这种降低的活性可由对受体的亲和力降低或一旦结合激活受体的能力下降或肽的稳定性下降引起。
在一些肽的通常形成二硫键的Cys残基对中,一个或配对的二者能被高半胱氨酸、3-巯基脯氨酸(Kolodziej等1996Int J Pept Protein Res48:274)、β,β-二甲基半胱氨酸(Hunt等1993Int J Pept Protein Res 42:249)或二氨基丙酸(Smith等1978J Med Chem 21:117)所替代,在通常二硫键的位置形成可替代的内部的交联。
肽的制备
有用的肽可以用细菌,包括但不限于E.coli或其他肽或蛋白产物的产生体系生产(例如,枯草杆菌,使用Drosophila Sf9细胞的杆状病毒表达体系、酵母或丝状的真菌表达体系,哺乳动物细胞表达体系),或可以化学合成。
如果肽或变异肽是用细菌生产的,例如E.coli,编码肽的核苷酸分子将优选地也编码一个允许成熟肽从细胞分泌的引导序列。因此,编码该肽的序列能包括例如天然存在的细菌ST肽前序列和序列。分泌的成熟肽能通过培养基纯化。
本发明的编码肽的序列优选地被插入能在细菌细胞中转运和保留核苷酸分子的载体中。DNA分子可被插入到自主地复制的载体中(适当的载体包括例如pGEM3Z、pcDNA3及其衍生物)。载体核苷酸可以是细菌或噬菌体DNA,例如λ噬菌体或M13及其衍生物。构建一种包含所述核酸的载体然后转化宿主细胞如细菌。合适的细菌宿主包括但不限于E.coli、B.subtilis、Pseudomonas、Salmonella。遗传构建也包括除编码核苷酸分子以外允许表达的元件,例如启动因子和调控序列。表达载体可能包含控制转录启动的转录控制序列,例如启动子、增强子、操纵子和阻抑物序列。许多转录控制序列是本领域熟知的。表达载体也包括翻译调控序列(例如,非翻译的5′序列,非翻译的3′序列或内核糖体进入位点)。载体能自主复制或整合到宿主DNA以便在肽产生过程中确保稳定性。
为了便于纯化,包括本发明肽的蛋白编码序列也能和编码多肽亲和标记物的核苷酸融合,例如谷胱甘肽S-转移酶(GST)、麦芽糖E结合蛋白、蛋白A、FLAG标记物、六-组氨酸、myc标记物或流行性感冒HA标记物。亲和标记物或报告融合物将相关肽的读码框连接到编码亲和标志基因的读码框以产生翻译融合。融合基因的表达导致了单个多肽的翻译,包括兴趣肽和亲和标记物二者。在一些使用亲和标记物的情况下,编码了蛋白酶识别位点的DNA序列将融合于亲和标记物的读码框和兴趣肽之间。
适合于制备非成熟型和成熟型本发明肽和变异体的遗传构建和方法,除细菌以外的蛋白表达体系,并且是本领域熟知的技术,也能在生物体系中用于制备肽。
成熟的肽和其变异体能通过固相的方法使用自动肽合成仪合成。例如,使用双偶合程序在Cyc(4-CH2Bxl)-OCH2-4-(甲氧基)-苯乙酰胺基甲基树脂上合成该肽。必须使用合适的保护基来产生正确的二硫键结构。例如,可利用下列保护基:叔丁氧羰基(α-氨基);乙酰氨基甲基(Cys残基B和E的巯基);4-甲基苄基(Cys残基C和F的巯基);苄基(谷氨酸的y-羧基和苏氨酸的羟基,如果存在);和溴代苄基(酪氨酸的酚基,如果存在)。利用叔丁氧基羰基氨基酸的对称酐或羟基苯并三唑酯进行偶联(天(门)冬酰胺或谷氨酰胺残基),该肽被去保护和从载体上裂解,在氟化氢、二甲基硫化物、茴香醚和p-硫甲酚比例为8/1/1/0.5(v/v/v/w)在0℃处理60分钟。通过减压除去氟化氢和二甲基硫化物,通过乙醚和乙酸乙酯连续萃取的方法除去茴香醚和p-硫甲酚,粗肽用0.5M的磷酸钠缓冲液(pH8.0)和N,N-二甲基甲酰胺采用1/1的比例(v/v)萃取。Cys残基B和E的二硫键是用二甲基亚砜形成的(Tam等(1991)J.Am.Chem.Soc.113:6657-62)。所得到的肽经反向色谱纯化。Cys残基C和F之间的二硫键首先通过用50%的乙酸水溶液溶解该肽形成。加入饱和的碘的冰醋酸溶液(1ml碘溶液/100ml溶液)。室温下在密封的玻璃容器中孵育2天,溶液用去离子水稀释5倍并用乙醚萃取4次以除去未反应的碘。通过旋转蒸发仪除去残余的乙醚后,用粗品溶液冻干并连续经反相色谱纯化。
肠GC-C受体结合测定
肽和其他药物与肠GC-C受体结合的能力可如下测定。T84人结肠癌细胞系细胞(American Type Culture Collection(Bethesda,Md.),在24孔培养板上生长至融合,培养基为Ham’s F12培养基与Dulbecco’s modified Eagle’smedium(DMEM)培养基以1∶1混合,添加5%胎牛血清。测定中所用的细胞典型地位于54-60传代之间。简要地,用1ml结合缓冲液(含有0.05%牛血清白蛋白和25mM HEPES的DMEM,pH7.2)冲洗24孔板上的T84单层细胞2次,然后与成熟的放射性标记E.coli ST肽和不同浓度的试验物质在37℃孵育30分钟。然后用1ml的DMEM冲洗细胞4次并用0.5ml/孔1NNaOH溶解。溶解物的放射性强度水平用标准方法测定。
实施例1:变异型ST肽和野生型ST肽的制备
1a:重组变异型ST肽和野生型ST肽的制备
变异型ST肽,指的是MD-915,被重组产生并在动物模型上进行试验。MD-915含有序列:Asn Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro AlaCys Thr Gly Cys Tyr(SEQ ID NO:---)。也制备了含有野生型ST肽序列的肽(MM-416776)。
MD-915和MM-416776肽使用如下生产的载体,作为前原蛋白被产生。编码热稳定的肠毒素前-原序列的序列从pGK51/pGSK51(ATCC 67728)扩增出来,利用寡核苷酸MO3514(5′CACACCATATGAAGAAATCAATATTATTTATTTTTCTTTCTG 3′(SEG ID NO:))和寡核苷酸酶M03515(5′CACACCTCGAGTTAGGTCTCCATGCTTTCAGGACCACTTTTATTAC 3′(SEQ ID NO:_))。扩增产物片段用NdeI/XhoI消化并连接到用NdeI/XhoI消化的T7表达载体,pET26b(+)(Novagen)从而构造质粒MB3976。测序编码前原蛋白的区域并找到,并发现编码氨基酸序列:mkksilfiflsvlsfspfaqdakpagsskekitleskkcnivkkn spesm(SEQ ID NO:_),其与热急定的肠毒素前体a2(sta2;mkksilfiflsvlsfspfaqdakpagsske kitleskkcn ivkknnesspesm(SEQ ID NO:_);Accession No.Q47185,GI:3913876)的氨基酸序列在羧基端附近的三个位置(下画线和粗体表示)不同。为了用pre-pro序列产生表达载体,为每个ST肽变异型或野生型ST肽编码的互补寡核苷酸被退火并克隆到MB3976表达载体中。为产生MB3984(编码MM-416776肽的全长和野生型ST肽作为前原蛋白),其包含融合前-原序列下游的氨基酸序列:NSSNYCCELCCNPACTGCY(SEQ ID NO:_),MB3976用Bsal/XhoI消化并连接到退火的寡核苷酸MO3621(5′GCATGAATAGTAGCAATTACTGCTGTGAATTGTGTTGTAATCCTGCTTGTACCGGGTGCTATTAATAAC 3′(SEQ ID NO:_)和MO3622(5′TCGAGTTATTAATAG CACCCGGTACAAGCAGGATTACAACACAATTCACAG CAGTA ATTGCT ACTATTC 3′(SEQ ID NO:_)。为产生MB3985(编码MD-915作为前原蛋白),其包含融合前-原序列下游的下列氨基酸序列:NSSNYCCEYCCNPACTGCY,MB 3976用BsaI/XhoI消化并连接到退火的寡核苷酸MO3529(5′GCATGAATAGTAGCAATTACT GCTGTGAATATTGTTGTAATCCTGCTTGTACC GGGTGCTATTAATAAC 3′(SEQ IDNO:_))和MO3530(5′TCGAGTTATTAATAGCACC CGGTACA AGCAGGATTACAACAATATTCACAGC AGTAATTGCTACTATTC3′(SEQ ID NO:_)。
MD-915肽和MM-416776肽制备如下。表达载体转化到E.coli细菌宿主BL21λDE3(Invitrogen)上。单克隆接种并在30℃在L肉汤+25mg/l卡那霉素中震摇过夜培养。将过夜的培养物加到3.2L的批培养基中(葡萄糖25g/l,Caseamino Acids 5g/l,酵母提取物5g/l,KH2PO413.3g/l,(NH4)2HPO44g/l,MgSO4-7H2O 1.2g/l,柠檬酸1.7g/l,EDTA 8.4mg/l,CoCl2-6H2O 2.5mg/l,MnCl2-4H2O 15mg/l,CuCl2-4H2O 1.5mg/l,H3BO33mg/l,Na2MoO4-2H2O2.5mg/l,醋酸锌-2H2O 13mg/l,柠檬酸铁100mg/l,卡那霉素25mg/l,消泡剂DF2O41ml/l),并使用下列方法参数发酵:只用碱控制(28%NH4OH),pH6.7,30C,通气:5L/分钟。在葡萄糖开始被消耗后(以监测溶解氧(DO)的水平),加入1.5L营养培养基(葡萄糖700g/l,Caseamino Acids 10g/l,酵母提取液10g/l,MgSO4-7H2O 4g/l,EDTA 13mg/l,CoCl2-6H2O 4mg/l,MnCl2-4H2O 23.5mg/l,CuCl2-4H2O 2.5mg/l,H3BO35mg/l,Na2MoO4-2H2O 4mg/l,醋酸锌-2H2O 16mg/l,柠檬酸铁40mg/l,消泡剂DF2O41ml/l),给料速率控制在维持20%DO。在开始给料2小时后加入IPTG至0.2mM。整个进行时间大约为40-45小时(直到养料耗尽)。
在5,000g离心10分钟收集细胞。弃去细胞沉淀,上清液通过50Kd超滤单元。50Kd滤液(0.6升)负载到110ml的Q-琼脂糖快速流动柱(Amersham Pharmacia,用20mM Tris-HCl调节平衡,pH7.5)中,流速为400ml/小时。用6体积的20mM Tris-HCl(pH7.5)冲洗柱子,蛋白用50mM的乙酸洗脱下来,收集50ml流份。含有ST肽变异型或野生型ST肽的流份被混合,溶剂通过旋转蒸发除去。干燥的蛋白用10ml的8%乙酸和0.1%三氟醋酸重悬并负载到Varian Polaris C18-A柱(250×21.2mm 10μm,利用相同的缓冲液平衡)上,流速为20ml/分钟。柱子用100ml的8%甲醇和0.1%TFA冲洗,并用300ml的24-28%甲醇和0.1%TFA梯度冲洗,收集5ml流份。含有肽的流份被混合,溶剂通过旋转蒸发除去。该肽溶解在0.1%TFA并冻干。
使用标准LCMS和HPLC分析MD-915肽和MM-416776肽流份。LCMS分析显示MD-915比MM-416776更同质。(见图1a;指出肽MD-915显示比MM-416776(Panel A)较少的峰(Panel B))。
1b:合成的变异型ST肽和野生型ST肽的制备
肽通过商品化肽合成公司化学合成。获得肽的收率依赖于化学合成的效率。因此,四种肽,按照收率的降序排列为:Cys Cys Glu Tyr Cys Cys AsnPro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:--;MD-1100),产率为10-20%;CysCys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:--;MM416774);Asn Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala CysThr Gly Cys Tyr(SEQ ID NO:--;MD-915);Asn Ser Ser Asn Tyr Cys Cys GluLeu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(SEQ ID NO:--MM-416776),产率<5%。因此引入肽中的特定的氨基酸变化能提高产率。
图1b显示了合成的IM-1100全部离子色谱图。图1c显示了空白对照的全部离子色谱图。在样品MD-1100有一个主峰出现,在对照样品中没有出现。定量分析表明MD-1100的纯度大于>98%。
实施例2:变异型ST肽和ST肽对肠GC-C受体的激活作用
MD-915、MM-416776和MD-1100激活肠GC-C受体的能力采用T84人结肠癌细胞系(American Type Culture Collection(Bethesda,Md.)测定来评价。为了测定,细胞在24孔板上生长至融合,培养基为Ham’s F12培养基与DMEM培养基的1∶1混合物,添加5%胎牛血清,在54-60传代之间使用。
简要地,将24孔板上的T84细胞单层用1ml/孔DMEM冲洗2次,然后与含有1mM异丁基甲基黄嘌呤(IBMX)的0.45ml DMEM在37℃孵育10分钟,IBMX为一种环核苷酸磷酸二酯酶抑制剂。然后加入被检肽(50μl)并在37℃孵育30分钟。吹打培养基,加入冰冷的0.5ml的0.1N HCl中止反应。样品在冰上放置20分钟,然后使用加热枪或真空离心蒸发干燥。干燥的样品使用Cayman Chemical Cyclic GMP EIA试剂盒(Cayman Chemical,Ann Arbor,MI)中提供的0.5ml磷酸缓冲液重悬。按照Cayman ChemicalCyclic GMP EIA试剂盒描述的方法,用EIA法测定环磷鸟苷。
图2表示的是化学合成肽变异体在GC-C受体活性分析中的活性。在此分析中,MM-416776和两种不同的D-1100肽(MD-1100(a)和MD-1100(b),通过两种不同的方法合成的)有与MM-416776相当的活性。肽MD-915和MM-416776都是用与合成MD-1100(b)相同的方法合成。
实施例3:MD-915和MM-416776增加小鼠的肠转运
为了测定肽是否增加了胃肠运输率,使用鼠科肠转运(GIT)测定法检测该肽和对照物(Moon等Infection and Immunity 25:127,1979)。在这个试验中,在给予小鼠被检化合物以后,给予小鼠可以在胃肠道中明显地显现的炭。测量炭移动的距离并表示为结肠总长度的百分比。
在用肽或对照缓冲液治疗前,小鼠被禁食12到16小时,自由饮水。在给予口服剂量5%活性碳(Aldrich 242276-250G)7分钟以前,口服给予1μg/kg-1mg/kg肽的缓冲液(20mM Tris,pH7.5)。在给予活性碳剂量以前,对照小鼠只给予缓冲液。15分钟以后处死小鼠,解剖从胃到盲肠那段肠。测量每只动物的肠的总长以及从胃到炭前端的移动距离,结果表示为炭经过肠占总长度百分比。所有的结果以10只小鼠的平均值±标准差表示。使用Student’st检验,比较给予肽的小鼠和只给予溶媒的小鼠的炭移动距离,P<0.05认为统计学上差异显著。P值利用假定不等方差的双边t-检验计算。
如图3a所示,野生型ST肽(MM-416776,(Sigma-Aldrich,St Louis,MO;0.1mg/kg)、合成MD-1100及(0.1mg/kg),一种被批准用于IBS的5-羟色胺受体5HT4激动剂,在这个模型中能增加胃肠的转运率。图4a显示研究结果表明,随着重组合成的MM-416776或MD-915剂量的增加肠的转运率增加。图4b显示的研究结果表明,化学合成的MM-416776或MD-1100肽两者都比单独的Tris缓冲液或相当剂量的Zelnorn更能增加肠转运率。
进行同样的实验以确定MD-1100长期定量给药治疗法是否有效。简要地,8周CD1雌性小鼠口服给药MD 1100(0.06mg/kg或0.25mg/kg,溶于20mM Tris,pH7.5)或只给予缓冲液(20mM Tris pH7.5),一天一次,给药5天。在第5天,除了给予200μl 10%炭溶液外,和上面同样的进行GIT试验。图4c显示的结果表明,在小鼠胃肠蠕动性试验中,长期给药(每天给药,共5天),化学合成的MD-1100或两者均有效。其结果和快速给药(1天)相似。
实施例4:MD-915肽和MM-416776肽增加乳鼠的肠分泌(SuMi试验)
使用肠分泌乳鼠模型检测MD-915肽和MM-416776肽增加肠分泌的能力。在这个模型中,将被检测混合物给予7-9天的乳鼠。在小鼠被处死后,解剖从胃到盲肠的胃肠道(“肠子”)。称重剩余部分(“屠体”)和肠子,计算肠子占体重的比例。如果比率超过0.09,可以推断此混合物增加肠分泌。图5a显示了在这个模型中的野生型ST肽(MM-416776)的剂量反应曲线。图5b显示了在这个模型中的肽MD-1100的剂量反应曲线。这些数据表明野生型ST肽(购于TDT公司,West Chester,PA)和MD-1100肽增加肠分泌。的作用也进行了研究。从图5可以看到,在这个模型中,0.2mg/kg的不能增加肠分泌。图6a显示如上所述的重组MM-416776肽和重组MD-915肽的剂量反应曲线。图6a中从可以看出,两种肽均增加这个模型中的肠分泌。相似地,图6b显示了化学合成的MD 915、MD-1100、MM 416776以及野生型ST肽(购自Sigma-Aldrich,St Louis,MO)的剂量反应曲线。
结肠痛觉过敏动物模型
对结肠直肠的扩张的超敏性在患有IBS的患者中很常见,而且可能是造成大部分疼痛症状的主要原因。对扩张-内脏痛觉过敏的炎性的和非炎性动物模型已经用于研究化合物对IBS中内脏疼痛的影响。
I.三硝基苯磺酸(TNBS)诱导的直肠的异常性疼痛模型
雄性Wistar大鼠(220-250g)经腹腔注射(IP)预先给药乙酰丙嗪0.5mg/kg,并肌注100mg/kg的氯胺酮进行麻醉。将一对镍铬丝电极(60cm长,直径为80μm)埋入腹部横纹肌,腹白线旁开2cm处。电极的自由端在颈后部从腹中外置,并由塑料管包裹附着于皮肤上。在手术5天后开始记录肌电图(EMG)。腹部的横纹肌电活动用脑电图仪(Mini VIII Alvar,Paris,France)记录,用很短的恒定的时间(0.03秒)消除低频信号(<3Hz)。
手术后10天,给予三硝基苯磺酸(TNBS)来诱发直肠炎。在轻度的乙醚麻醉下,在距肛门3cm处,通过硅橡胶导管的导入进行经直肠给药TNBS(80mgkg-1,溶于0.3ml 50%乙醇中),如(Morteau等1994Dig Dis Sci 39:1239)中所述。在给药TNBS后,将大鼠放置于塑料管中,在结肠直肠的扩张以前严格限制其活动。CRD之前,给予实验化合物,在肛门1cm,用乳胶避孕套制成的4厘米长的气球插入直肠造成CRD(Gue等,1997NeurogastroenterolMotil.9:271)。气球固定在从栓子切除术的探针上(Fogarty)取下的硬导管上。连接气球的导管固定在尾巴根部。气球连接到气压计上,以每次15mmHg渐进地从0到60mmHg加压,每次持续5分钟。直肠滴注给药TNBS之前(1-2天)或之后(3天),用肌电图测定评价直肠的敏感性。
每隔5分钟测定相应于腹部收缩的峰电位爆发数。腹部收缩数的统计学分析和剂量效应关系的评价是通过方差分析方法(ANOVA)继之后设验证(Student或Dunnett检验)进行的,如果合适可进行ED50的回归分析。
图7显示了在TNBS结肠直肠模型中MD-1100活性的实验结果。0.3μg/kg和3μg/kg的MD-1100的腹反应明显减少。这些结果表明MD-1100减少了这个动物模型中的结肠扩张有关的疼痛。
II.应激诱导的痛觉过敏模型
如TNBS一样,模型雄性wistar大鼠(200-250g)通过手术植入镍铬丝电极。外科植入手术10天后,进行如Williams等所述的局部的约束应力(PRS)2小时(Williams等1988Gastroenterology 64:611)。简要地,在轻微乙醚麻醉下,肩膀前、前肢和胸部躯干上面用纸带的约束带包上,但不妨碍身体移动。假应激对照组动物被麻醉但不包裹。在PRS期结束前30分钟给与测试混合物或溶媒。在完成PRS 30分钟到1小时后,如TNBS模型所述,用气压计在15、30、45和60mm Hg压力下进行CRD扩张。爆发次数的统计学分析测定和分析如同上面的TNBS模型。
苯基苯醌诱导的扭体模型
PBQ诱导的扭体模型可用于评定本发明的肽和GC-C受体激动剂的止痛活性。这个模型由Siegmund等所描述(1957Proc.Soc.Exp.Bio.Med.95:729-731)。简要地,口服给药实验混合物后1小时,例如肽、吗啡或溶媒,给小鼠腹腔注射0.02%的苯基苯醌(PBQ)溶液(12.5mL/kg)kg。在给药PBQ后第5到第10分钟记录伸展和扭体的次数,并且还可以计算第35到第40分钟和第60到第65分钟的次数以进行动态分析。结果表示为伸展和扭体的次数(平均数±SEM)以及由溶媒治疗组的平均值计算的感受伤害阈的变化的百分比。治疗组和对照组的统计学的显著性差异的统计使用SigmaStat软件进行方差分析后(P<0.05),使用剩余方差的Dunnett′s test进行检测。
图8a和8b显示不同剂量的MD-915和MD-1100在PBQ扭体实验的结果。消炎痛,一种已知的有抑制疼痛活性NSAID(非甾体抗炎药),在试验中被用做阳性对照。与溶媒对照组比较,可见MD-915(剂量:1mg/kg)和MD-1100(剂量:2.5mg/kg)的扭体明显减少。实验的高剂量没有作用,这在其他的化合物(如5HT-3拮抗剂)的类似的试验中也可观察到。研究结果表明MD-915和MD-1100在这个内脏疼痛模型上都具有和消炎痛中剂量相当的镇痛作用。
实施例5:MD-1100Kd的测定
为了测定MD-1100对大鼠肠粘膜上的GC-C受体的亲合力,使用大鼠的肠上皮细胞进行了竞争性结合实验。来源于大鼠小肠的上皮细胞如Kessler等所述方法(J.Biol.Che7n.245:5281-5288(1970))制备。简要地,处死动物暴露它们的腹腔。用300ml冰冷的生理盐水或PBS漂洗小肠。距离幽门10厘米处的10厘米的小肠被切除并切成1英寸的节段。在一块薄膜和P-1000移液管顶端之间用温和的压力从肠中挤压出肠粘膜。将肠上皮细胞置于2ml PBS中,用5毫升移液管上下地吹打制成细胞悬液。使用Bradford的方法测定悬液的蛋白浓度((Anal.Biochem.72:248-254(1976))。
以Giannella等的方法为基础在[125I]标记的MM-416776和MD-1100之间进行竞争性结合试验(Am.J Physiol.245:G492-G498)。实验混合物包含:0.5ml的DME,含有20mM HEPES-KOH(pH7.0),0.9mg的上述细胞悬液,21.4fmol [125I]-MM-416776(42.8pM)和不同浓度的竞争剂MD-1100(0.01到1000nM)。混合物在室温下孵育1小时,并通过将混合物加到GF/B玻璃纤维过滤器(Whatman)中终止反应。用5ml冰冷的PBS冲洗过滤器并测定放射性。图9显示在这个试验中MD-1100的Kd是4.5nm。%B/Bo是各样品(B)与没有加冷的竞争剂的对照样品(Bo)相比捕获的放射性比值的百分比。Giannella等(Am J.Physiol.245:G492-G498)观察到在前述的试验中野生型ST肽的Kd大约为13nm。
实施例6:MD-1100的药代动力学特征
为研究MD 1100的药代动力学特征,通过给8周大的CD1小鼠尾静脉注射或口服灌胃MD 1100来研究其吸收。收集各个时间点的动物的血清,采用竞争性的酶联免疫吸收法(Oxoid ST EIA kit,Cat#TD0700)检测MD-1100的量。实验使用抗ST肽的单克隆抗体(抗体由Oxoid kit提供)和合成制备的MD-1100。图10a显示的是用酶联免疫吸附试验测定的静脉或口服给药MD 1100的吸收值。MD-1100呈现最低限度地全身吸收并且生物利用度<2.2%。进行了相对生物利用度研究,其中使用LCMS而不是ELISA检测MD-1100。首先,从治疗组和对照组小鼠全血中提取血清样品,然后不用进一步处理,直接地注入(10mL)到串联的固相萃取(SPE)柱(Waters OasisHLB 25mm柱,2.0×15mm直接连接)。SPE柱上的样品用5%甲醇、95%dH2O溶液(2.1mL/分钟,1.0分钟)冲洗,然后装入使用开关阀的分析柱,开关操纵SPE柱于反向流程至分析柱(Waters Xterra MS C85mm IS柱,2.1×20mm)。样品从分析柱用反相梯度洗脱(流动相A:10mM氢氧化铵的dH2O溶液,流动相B:10mM氢氧化铵的80%乙腈溶液和20%甲醇;第一个3分钟用20%B,然后用4分钟跳到95%B,保留2分钟,所有的流速为0.4mL/分钟)。在9.1分钟,梯度回到20%B的初始的条件下1分钟。在1.45分钟MD-1100从分析柱上洗脱,三-四极杆质谱(MRM,764+2电荷状态)>182(+1电荷状态)Da;锥体电压(cone voltage)=30V;碰撞(collision)=20eV;基峰的母分辨率(parent resolution)=2Da;基峰的子分辨率=2Da)。通过与采用同样步骤制备和注入小鼠血清的、已知量的化学合成MD-1100的标准曲线相比,设备的感应转变为浓度单位。
图10b显示由LCMS检测的静脉注射和口服给药MD-1100的吸收值。在这个试验中,MD-1100呈现类似的最低限度的全身吸收而且生物利用度<0.11%。
肽和GC-C受体激动剂的给药
为了治疗胃肠病,本发明的肽和激动剂优选地口服给药,例如以片剂、凝胶、糊剂、膏剂、液体剂、粉剂或以其他剂型。口服给药的组合物包括,粘合剂、调味剂和润湿剂。肽和激动剂可以和其他治疗胃肠病症的药物联用,包括但不限于抑酸剂,如组胺-2受体激动剂(H2As)和质子泵抑制剂(PPIs)。肽和激动剂也可以直肠栓剂给药。对于治疗胃肠道以外的病症如充血性心力衰竭和良性前列腺肥大,肽和激动剂优选地非经肠地或口服给药。
这里描述的肽可以单独使用或和其他药物联用。例如,该肽可以和镇痛作用的肽或化合物一起给药。镇痛作用的肽或化合物可以共价结合到所述肽上,或可作为单独的药物和所述肽一起或先后地给药进行联合治疗。
联合治疗可以通过给予两种或更多种的药来实现,例如,这里描述的肽和镇痛作用的肽或化合物,每一种都分别配方和给药或将两种或多种药制成一个制剂。其他组合也包含在联合治疗中。例如,两种药物可以一起制成一个制剂并和包含第三种药物的单独制剂联合给药。尽管联合治疗的两种或更多种药能同时给药,但不是必须如此。例如,第一种药物(或组合药物)可以在第二种药物(或组合药物)之前几分钟、几小时、几天或几周给药。因此,两种或更多种药物能在相互几分钟内或相互1、2、3、6、9、12、15、18或24小时内或相互1、2、3、4、5、6、7、8、9、10、12、14天内或相互2、3、4、5、6、7、8、9或10周内给药。一些情况下甚至可能是更长的时间间隔。尽管在许多条件下,联合治疗使用的两种或更多种药物可同时存在于患者的身体中,但不是必须这样。
联合治疗也包括一种或更多种联合使用的药物两次或更多次的给药。例如药物X和药物Y联合使用,在任何组合中,一种药物可以一次或更多次的给药,例如按照X-Y-X、X-X-Y、Y-X-Y、Y-Y-X、X-X-Y-Y等顺序。
单独使用或联合使用的药物能和任何可药用的载体或介质结合。因此,当对患者给药时,这些药物可以和不产生副作用、过敏或其他不良反应的物质结合。这些载体和介质包括溶剂、分散剂、涂覆剂、促吸收剂和控释剂等。
药物无论是游离形式或是盐都能和聚合物结合来制备缓释剂型,例如聚乳酸-羟基乙酸(PLGA)、聚-(I)-乳酸-羟基乙酸-酒石酸(P(I)LGT)(WO01/12233)、聚乙醇酸(U.S.3,773,919)、聚乳酸(U.S.4,767,628);聚(ε-己内酯)。这样的制剂可用于埋植剂,取决于聚合物、聚合物粒子的大小和植入物的大小能释放肽或其他药物超过几天、几周或几个月(例见U.S.6,620,422)。其他缓释制剂如EP 0 467 389 A2、WO 93/241150、U.S.5,612,052;WO 97/40085、WO 94/155587、U.S.5,672,659、U.S.5,893,985、U.S.5,134,122、U.S.5,192,741、U.S.5,192,741和U.S.5,445,832中所述。在这种缓释制剂中,肽的微粒和聚合物的微粒结合。一个或更多的缓释植入剂可放置在大肠、小肠或两者都放。
药物可通过例如静脉注射、肌内注射、皮下注射或其他途径给药。药物可通过口服例如以片剂、凝胶、糊剂、膏剂、液体剂、粉剂或以其他剂型给药。口服给药的组合物包括,粘合剂、调味剂和润湿剂。药物可含在牙膏或漱口剂中。因此,口腔剂可包含磨粉和发泡剂。药物也可以经皮给药或栓剂给药。
药物可以是游离酸、碱或其可药用的盐。在给药之前或更早,固体要被溶解或分散。在一些情况下,制剂含有抑制微生物的生长的防腐剂。可药用的注射剂包括无菌水、有机溶液或分散剂,包括例如水、乙醇、有机溶剂、油或其他溶剂和分散剂(例如,甘油、丙二醇、聚乙二醇和植物油)。药物可通过滤过除菌或其他合适的方法灭菌。
本发明的合适的药物组合物通常包含带有可药用的稀释剂和赋形剂如无菌水的一定量的活性化合物,例如根据预定的用途以调节终浓度范围。制备技术通常是在这个领域熟知的,例示Remington′s PharmaceuticalSciences(18th Edition,Mack Publishing Company,1995)。
所述药物和联合治疗药物可以包装成一个试剂盒,其中包括两种或更多种药物的单剂量或多剂量,分别包装或制剂,或者两种或更多种药物的单剂量或多剂量包装成制剂或者联用。因此,一种或更多种药物存在于第一个容器中,并且试剂盒可在第二个容器中任选地含有一或多种药物。容器或多个容器放置在包装中,包装中任选地含有药物服用方法和剂量说明书。试剂盒可含有附加部件如注射器,或其他给药工具和稀释剂,及其他制剂工具。
镇痛剂
这里描述的肽可用于与镇痛剂的联合治疗,例如镇痛化合物或镇痛作用的肽。镇痛剂可任选地共价结合到所述肽上。其中有用的镇痛作用的肽有:Ca通道阻滞剂、5HT受体拮抗剂(例如5HT3、5HT4和5HT1受体拮抗剂)、阿片样受体激动剂(洛哌丁胺、非多托秦和芬太尼)、NE1受体拮抗剂、CCK受体激动剂(例如氯谷胺)、NK1受体拮抗剂、NK3受体拮抗剂、去甲肾上腺素-5-羟色胺重摄取抑制剂(NSRI)、香草酸和cannabanoid受体激动剂和sialorphin。各种类型镇痛剂如文献所述。
Sialorophin相关肽是有用的镇痛作用的肽之一,包括那些含有氨基酸序列QHNPR(SEQ ID NO:)的肽,包括:VQHNPR(SEQ ID NO:);VRQHNPR(SEQ ID NO:);VRGQHNPR(SEQ ID NO:);VRGPQHNPR(SEQ ID NO:);VRGPRQHNPR(SEQ ID NO:);VRGPRRQHNPR(SEQ ID NO:);和RQHNPR(SEQ ID NO:)。Sialorphin相关肽和中性溶酶结合并抑制由中性溶酶介导的P物质和甲硫啡肽的降解。因此,为中性溶酶抑制剂的化合物或肽是有用的镇痛剂,可以和本发明肽联合治疗或连接到本发明肽上,例如通过共价键。Sialophin和相关肽如US6,589,750;US20030078200A1;和WO 02/051435A2所述。
阿片类受体拮抗剂和激动剂能和本发明肽联合治疗给药或结合到本发明肽上,例如通过共价键。例如阿片类受体拮抗剂,如纳洛酮、纳曲酮、甲基纳洛酮、纳美芬、cypridime、β-funaltrexamine、纳洛肼、naltrindole及nor-binaltorphimine被认为可用于治疗IBS。制成能够延迟和持续释放剂型的阿片类受体拮抗剂是有用的,这样在小肠和/或升结肠的中部和末端开始释放拮抗剂。这些拮抗剂如WO01/32180A2所述。脑啡肽五肽(HOE825;Tyr-D-Lys-Gly-Phe-L-同型丝氨酸)是一种mu和delta阿片受体激动剂,被认为有益于增加肠蠕动性(Eur.J.Pharm.219:445,1992),而且这种肽可和本发明肽联合使用。曲美布汀也有同样的作用,曲美布汀被认为可以和mu/delta/kappa阿片受体结合并促进促胃动素的释放和调节胃泌激素、血管紧张素肽、胃泌激素和胰高血糖素的释放。Kappa阿片类受体激动剂例如非多托嗪、酮基环唑新和WO 03/097051A2中所述的化合物可以和本发明肽联合使用或连接至本发明的肽上。另外,可以使用mu阿片类受体激动剂例如吗啡、diphenyloxylate、氟雷法胺(H-Tyr-D-Ala-Phe(F)-Phe-NH2;WO01/019849A1)和洛哌丁胺。
Tyr-Arg(京都啡肽)是一种二肽,通过刺激甲硫啡肽的释放诱导止痛效应而起作用(J.Biol.Chem 262:8165,1987)。京都啡肽可与本发明肽一起联合使用或连接至本发明的肽上。
CCK受体激动剂,例如来源于两栖类和其他物种的蛙皮素,是可与本发明肽联合使用或连接至本发明的肽上的有用的镇痛剂。
芋螺毒素肽代表一类作用于电压门控式钙通道、NMDA受体或烟碱受体的镇痛作用的肽。这些肽可与本发明肽联合使用或连接至本发明的肽上。
胸腺素的肽类似物(FR申请2830451)具有镇痛活性,可与本发明肽联合使用或连接至本发明的肽上。
CCK(CCKa或CCKb)受体拮抗剂,包括氯谷胺和右氯谷胺(氯谷胺的R-异构体)(WO 88/05774)具有镇痛活性,可与本发明肽联合使用或连接至本发明的肽上。
其他有用的镇痛剂包括5-HT4激动剂如替加色罗/和利沙必利。这些激动剂如EP1321142A1,WO03/053432A1,EP 505322A1,EP505322BI,US 5,510,353,EP 507672A1,EP 507672B1和US 5,273,983中所述。
钙通道阻滞剂如齐考诺肽和相关化合物,例如在EP625162B1,US 5,364,842,US 5,587,454,US 5,824,645,US 5,859,186,US 5,994,305,US 6,087,091,US 6,136,786,WO 93/13128A1,EP 1336409A1,EP 835126A1,EP 835126B1,US 5,795,864,US 5,891,849,US 6,054,429,WO 97/01351A1中,可与本发明肽联合使用或连接至本发明的肽上。
NK-1、NK-2和NK-3受体的多种拮抗剂(见Giardina等2003Drugs 6:758)可与本发明肽联合使用或连接至本发明的肽上。
NK1拮抗剂如:阿瑞吡坦(Merck & Co Inc)、沃氟匹坦、依洛匹坦(Pfizer,Inc.)、R-673(HofEnann-La Roche Ltd)、SR-14033和例如在EP 873753A1、US 20010006972A1、US 20030109417A1和WO01/52844A1中所述相关化合物,可与本发明肽联合使用或连接至本发明的肽上。
NK-2受体拮抗剂如奈帕坦特(Menarini Ricerche SpA)、沙瑞度坦(Sanofi-Synthelabo)、SR-144190(Sanofi-Synthelabo)和UK-290795(Pfizer Inc)可与本发明肽联合使用或连接至本发明的肽上。
NK3受体拮抗剂如奥沙奈坦(Sanofi-Synthelabo)、他奈坦和例如在WO02/094187A2,EP 876347A1,WO 97/21680A1,US 6,277,862,WO 98/11090,WO 95/28418,WO 97/19927和Boden等(J Med Chem.39:1664-75,1996)中所述的相关化合物,可与本发明肽联合使用或连接至本发明的肽上。
去甲肾上腺素-5-羟色胺重摄取抑制剂如米那普仑和在WO 03/077897A1中所述化合物可与本发明肽联合使用或连接至本发明的肽上。
香草酸受体拮抗剂如arvanil和在WO 01/64212A1中所述的化合物与本发明肽一起使用或连接至本发明的肽上。
当镇痛剂是一种肽并和所述肽共价连接的时候,所得到的肽也可包含至少一个胰蛋白酶或胰凝乳蛋白酶切割位点。当存在于肽内,镇痛作用的肽可能位于能释放镇痛作用的肽的胰凝乳蛋白酶或胰蛋白酶切割位点之前(如果在羧基端)或之后(如果是在氨基端)。
除sialorphin相关肽以外,镇痛作用的肽包括:AspPhe、内吗啡肽-1、内吗啡肽-2、nocistatin、达拉根、醋酸亮丙瑞林、齐考诺肽和P物质。
治疗方法
本发明肽可用于治疗或预防癌症、前期癌变或转移癌。例如,可用于预防或治疗:结肠直肠/局部转移结肠直肠癌、胃肠道癌、肺癌、上皮细胞癌或前期癌变或转移、息肉、乳腺、结肠直肠、肺、卵巢、胰脏、前列腺、肾脏、胃、膀胱、肝、食管和睾丸的转移癌,癌(例如,基底细胞癌、basosquamous、Brown-Pearce、导管癌、Ehrlich肿瘤、Krebs癌、Merkel细胞癌、小或非小细胞肺癌、燕麦形细胞癌、乳头状癌、细支气管癌、鳞状上皮细胞癌、移行细胞癌、Walker癌)、非白血性白血病(例如,B细胞、T-细胞、HTLV、急性或慢性淋巴细胞、肥大细胞、脊髓)、组织细胞增多症(histiocytonia)、组织细胞增多病、何杰金(氏)病、非何杰金(氏)淋巴瘤、浆细胞瘤、网状内皮组织增殖、腺瘤、腺癌、腺纤维瘤、腺淋巴瘤、造釉细胞瘤、血管角质瘤、嗜曙红细胞增多性血管淋巴样增生、硬化性血管瘤、多发性血管瘤、胺前体摄取脱羧(化)细胞瘤、branchionia、恶性类癌综合征、类癌瘤心脏病、癌肉瘤、牙骨质瘤、胆管细胞癌、胆脂瘤、软骨肉瘤、成软骨细包瘤、软骨肉瘤、脊索瘤、迷芽瘤、颅咽管瘤、chrondrorna、圆柱瘤、囊腺癌、囊腺瘤、cystosarconia phyllodes、无性细胞瘤、室管膜瘤、尤因肉瘤、纤维瘤、纤维肉瘤、巨细胞瘤、神经节瘤、恶性胶质瘤、血管球瘤、粒层细胞瘤、两性胚细胞瘤、错构瘤血管内皮瘤、血管瘤、血管外皮细胞瘤、血管肉瘤、肝癌、岛细胞癌、卡波西肉瘤、平滑肌瘤、平滑肌肉瘤、白血病性肉瘤、间质细胞瘤、脂(肪)瘤、脂肉瘤、lymphaugioma、淋巴管肌瘤、淋巴管肉瘤、成神经管细胞瘤、脑(脊)膜瘤、间叶瘤、中肾瘤、间皮瘤、成肌细胞瘤、肌瘤、肌肉瘤、粘液瘤、粘液肉瘤、神经鞘瘤、神经瘤、成神经细胞瘤、神经上皮瘤、神经纤维瘤、多发性神经纤维瘤、牙瘤、骨瘤、骨肉瘤、绒毛状瘤、神经节细胞瘤、副神经节非嗜铬的、松果体瘤、横纹肌瘤、横纹肌肉瘤、塞托利细胞瘤、畸胎瘤、膜细胞瘤和其他细胞发育异常、细胞永生或细胞转化的疾病。
本发明肽可用于治疗或预防:先发于结肠癌、遗传非息肉结肠直肠癌(HNPCC)和遗传常染色体显性综合征的家族性腺瘤性息肉病(FAP)(常染色体显性综合征)。
为治疗或预防癌症、前期癌变或转移癌,本发明的肽能和放疗或cGMP依赖磷酸二酯酶抑制剂或选择性的环氧化酶-2抑制剂的化疗药物联合治疗(许多的环氧化酶-2抑制剂如W002062369中所述,作为参考列入此处)。
所述肽能用于治疗或预防炎症。因此可以单独使用或与cGMP依赖磷酸二酯酶抑制剂或选择性的环氧化酶-2抑制剂联用治疗用于治疗:器官炎症、IBD(例如节段性回肠炎、溃疡性结肠炎)、哮喘、肾炎、肝炎、胰腺炎、支气管炎、囊性纤维化、缺血性肠疾病、肠炎/变态反应、腹部疾病、直肠炎、eosnophilic胃肠炎、肥大细胞增生病和其他炎症。
所述肽也能用于治疗或预防胰岛素相关疾病,例如:II型糖尿病、高血糖症、肥胖症和葡萄糖紊乱或电解质转运和细胞胰岛素分泌内分泌病症或内分泌病症相关的疾病。该药也可以用于胰岛素耐受性治疗和术后和非术后胰岛素应答下降。
所述肽能用于预防或治疗呼吸系统病症,包括吸入、通气和粘液分泌疾病、肺动脉高压、气管和气道慢性梗阻和气管和支气管不可逆的阻塞。
所述肽能用于和磷酸二酯酶抑制剂的联合治疗(这种抑制剂的例子可见US6,333,354,作为参考列入此处)。
所述肽也能用于预防或治疗:视网膜病、肾病、糖尿病性血管病和水肿形成。
所述肽也能用于预防或治疗神经障碍,例如头痛、焦虑、运动障碍、攻击、精神病、癫痫发作、恐慌发作、癔病、睡眠障碍、抑郁、情感分裂性精神障碍、睡眠性呼吸暂停、注意力缺陷综合症、记忆丧失和嗜睡。所述肽也能用于镇静。
所述和可检测的标记肽能用作标记来鉴别、检查、进展或诊断小肠疾病和状态,包括:节段性回肠炎、大肠炎、肠炎、肿瘤、良性肿瘤、例如良性间质瘤、腺瘤、血管瘤、腺瘤的(具柄的和无柄的)息肉、恶性的、类癌瘤、内分泌细胞瘤、淋巴瘤、腺癌、前肠、中肠和后肠癌、胃肠基质癌(GIST)、例如平滑肌瘤、细胞平滑肌瘤、成平滑肌瘤和平滑肌肉瘤、胃肠植物性神经瘤、malabsorption syndromes、乳糜泻、憩室病、Meckel′s憩室病、结肠憩室、巨结肠、先天性巨结肠疾病、过敏性肠综合征肠系膜缺血、缺血性结肠炎、结肠直肠癌、结肠息肉、息肉综合征、肠腺癌、利德尔综合征、Brody肌病(Brody myopathy)、婴儿惊厥和舞蹈徐动症。
所述肽能和另外的分子(例如诊断和治疗分子)偶联,以靶向带有GCC受体的细胞,例如囊性纤维化损害和内衬于肠道的特定细胞。因此,所述肽能将放射性的部分和治疗部分靶向肠,有助于成像和诊断或治疗结肠直肠/转移或局部结肠直肠癌并能将抑癌基因p53正常拷贝输送到肠道中。
所述肽能用于单独治疗或联合治疗以治疗勃起机能障碍。
所述肽能用于单独治疗或联合治疗内耳疾病,例如治疗Meniere′s疾病,包括疾病的症状如眩晕、听觉缺失、耳鸣、耳充满感和保持内耳体液内环境稳定。
所述肽能用于单独或联合治疗与体液及钠滞留有关的疾病,例如肾脏、消化道和泌尿生殖系统、充血性心力衰竭、高血压、低血压、肝硬变和肾病综合征的电解质-水/电解质转运体系疾病。另外,所述肽能利尿和控制肠液。
所述肽能用于单独或联合治疗与碳酸氢盐分泌有关的疾病,例如囊性纤维化。
所述肽能用于单独或联合治疗与肝细胞再生相关的疾病。
序列表
<110>Currie,Mark G.
Mahajan-Miklos,Shalina
<120>治疗胃肠病的方法和组合物
<130>14184-039001
<140>US 10/766,735
<141>2004-01-28
<150>US 60/443,098
<151>2003-01-28
<150>US 60/471,288
<151>2003-05-15
<150>US 60/519,460
<151>2003-11-12
<160>128
<170>FastSEQ for Windows Version 4.0
<210>1
<211>19
<212>PRT
<213>大肠肝菌(Escherichia coli)
<400>1
Asn Ser Ser Asn Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>2
<211>18
<212>PRT
<213>大肠肝菌(Escherichia coli)
<400>2
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly
1 5 10 15
Cys Tyr
<210>3
<211>18
<212>PRT
<213>大肠肝菌(Escherichia coli)
<400>3
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Tyr Pro Ala Cys Ala Gly
1 5 10 15
Cys Asn
<210>4
<211>18
<212>PRT
<213>Citrobacter freundii
<400>4
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly
1 5 10 15
Cys Tyr
<210>5
<211>30
<212>PRT
<213>Yersinia enterocolitica
<400>5
Gln Ala Cys Asp Pro Pro Ser Pro Pro Ala Glu Val Ser Ser Asp Trp
1 5 10 15
Asp Cys Cys Asp Val Cys Cys Asn Pro Ala Cys Ala Gly Cys
20 25 30
<210>6
<211>30
<212>PRT
<213>Yersinia enterocolitica
<400>6
Lys Ala Cys Asp Thr Gln Thr Pro Ser Pro Ser Glu Glu Asn Asp Asp
1 5 10 15
Trp Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Ala Gly Cys
20 25 30
<210>7
<211>53
<212>PRT
<213>Yersinia enterocolitica
<400>7
Gln Glu Thr Ala Ser Gly Gln Val Gly Asp Val Ser Ser Ser Thr Ile
1 5 10 15
Ala Thr Glu Val Ser Glu Ala Glu Cys Gly Thr Gln Ser Ala Thr Thr
20 25 30
Gln Gly Glu Asn Asp Trp Asp Trp Cys Cys Glu Leu Cys Cys Asn Pro
35 40 45
Ala Cys Phe Gly Cys
50
<210>8
<211>16
<212>PRT
<213>Yersinia kristensenii
<400>8
Ser Asp Trp Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Ala Gly Cys
1 5 10 15
<210>9
<211>17
<212>PRT
<213>Vibrio cholerae
<400>9
Ile Asp Cys Cys Glu Ile Cys Cys Asn Pro Ala Cys Phe Gly Cys Leu
1 5 10 15
Asn
<210>10
<211>17
<212>PRT
<213>Vibrio mimicus
<400>10
Ile Asp Cys Cys Glu Ile Cys Cys Asn Pro Ala Cys Phe Gly Cys Leu
1 5 10 15
Asn
<210>11
<211>18
<212>PRT
<213>大肠肝菌(Escherichia coli)
<400>11
Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Pro
1 5 10 15
Cys Tyr
<210>12
<211>13
<212>PRT
<213>Vibrio cholerae
<400>12
Ile Asp Cys Cys Glu Ile Cys Cys Asn Pro Ala Cys Phe
1 5 10
<210>13
<211>14
<212>PRT
<213>Vibrio cholerae
<400>13
Ile Asp Cys Cys Glu Ilc Cys Cys Asn Pro Ala Cys Phe Gly
1 5 10
<210>14
<211>17
<212>PRT
<213>Vibrio mimicus
<400>14
Ile Asp Cys Cys Glu Ile Cys Cys Asn Pro Ala Cys Phe Gly Cys Leu
1 5 10 15
Asn
<210>15
<211>17
<212>PRT
<213>Vibrio mimicus
<400>15
Ile Asp Arg Cys Glu Ile Cys Cys Asn Pro Ala Cys Phe Gly Cys Leu
1 5 10 15
Asn
<210>16
<211>16
<212>PRT
<213>Yersinia enterocolitica
<400>16
Asp Trp Asp Cys Cys Asp Val Cys Cys Asn Pro Ala Cys Ala Gly Cys
1 5 10 15
<210>17
<211>16
<212>PRT
<213>Yersinia enterocolitica
<400>17
Asp Trp Asp Cys Cys Asp Val Cys Cys Asn Pro Ala Cys Ala Gly Cys
1 5 10 15
<210>18
<211>17
<212>PRT
<213>Yersinia enterocolitica
<400>18
Asn Asp Asp Trp Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Ala Gly
1 5 10 15
Cys
<210>19
<211>16
<212>PRT
<213>Yersinia enterocolitica
<400>19
Trp Asp Trp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Phe Gly Cys
1 5 10 15
<210>20
<211>72
<212>PRT
<213>大肠肝菌(Escherichia coli)
<400>20
Met Lys Lys Leu Met Leu Ala Ile Phe Ile Ser Val Leu Ser Phe Pro
1 5 10 15
Ser Phe Ser Gln Ser Thr Glu Ser Leu Asp Ser Ser Lys Glu Lys Ile
20 25 30
Thr Leu Glu Thr Lys Lys Cys Asp Val Val Lys Asn Asn Ser Glu Lys
35 40 45
Lys Ser Glu Asn Met Asn Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys
50 55 60
Asn Pro Ala Cys Ala Gly Cys Tyr
65 70
<210>21
<211>72
<212>PRT
<213>大肠肝菌(Escherichia coli)
<400>21
Met Lys Lys Ser Ile Leu Phe Ile Phe Leu Ser Val Leu Ser Phe Ser
1 5 10 15
Pro Phe Ala Gln Asp Ala Lys Pro Val Glu Ser Ser Lys Glu Lys Ile
20 25 30
Thr Leu Glu Ser Lys Lys Cys Asn Ile Ala Lys Lys Ser Asn Lys Ser
35 40 45
Gly Pro Glu Ser Met Asn Ser Ser Asn Tyr Cys Cys Glu Leu Cys Cys
50 55 60
Asn Pro Ala Cys Thr Gly Cys Tyr
65 70
<210>22
<211>71
<212>PRT
<213>Yersinia enterocolitica
<400>22
Met Lys Lys Ile Val Phe Val Leu Val Leu Met Leu Ser Ser Phe Gly
1 5 10 15
Ala Phe Gly Gln Glu Thr Val Ser Gly Gln Phe Ser Asp Ala Leu Ser
20 25 30
Thr Pro Ile Thr Ala Glu Val Tyr Lys Gln Ala Cys Asp Pro Pro Leu
35 40 45
Pro Pro Ala Glu Val Ser Ser Asp Trp Asp Cys Cys Asp Val Cys Cys
50 55 60
Asn Pro Ala Cys Ala Gly Cys
65 70
<210>23
<211>54
<212>PRT
<213>人工序列
<220>
<223>合成产生的氨基端前导序列
<400>23
Met Lys Lys Ser Ile Leu Phe Ile Phe Leu Ser Val Leu Ser Phe Ser
1 5 10 15
Pro Phe Ala Gln Asp Ala Lys Pro Val Glu Ser Ser Lys Glu Lys Ile
20 25 30
Thr Leu Glu SerLys Lys Cys Asn Ile Ala Lys Lys Ser Asn Lys Ser
35 40 45
Gly Pro Glu Ser Met Asn
50
<210>24
<211>53
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>24
Met Lys Lys Ser Ile Leu Phe Ile Phe Leu Ser Val Leu Ser Phe Ser
1 5 10 15
Pro Phe Ala Gln Asp Ala Lys Pro Ala Gly Ser Ser Lys Glu Lys Ile
20 25 30
Thr Leu Glu Ser Lys Lys Cys Asn Ile Val Lys Lys Ser Asn Lys Ser
35 40 45
Gly Pro Glu Ser Met
50
<210>25
<211>53
<212>PRT
<213>大肠肝菌(Escherichia coli)
<400>25
Met Lys Lys Ser Ile Leu Phe Ile Phe Leu Ser Val Leu Ser Phe Ser
1 5 10 15
Pro Phe Ala Gln Asp Ala Lys Pro Ala Gly Ser Ser Lys Glu Lys Ile
20 25 30
Thr Leu Glu Ser Lys Lys Cys Asn Ile Val Lys Lys Asn Asn Glu Ser
35 40 45
Ser Pro Glu Ser Met
50
<210>26
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>26
Asn Ser Ser Asn Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>27
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>27
Asn Ser Ser Asn Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Trp
1 5 10 15
Gly Cys Tyr
<210>28
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>28
Asn Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>29
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>29
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>30
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>30
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Trp Gly Cys Tyr
1 5 10
<210>31
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>31
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>32
<211>15
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>32
Asn Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10 15
<210>33
<211>15
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>33
Asn Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Trp Gly Cys Tyr
1 5 10 15
<210>34
<211>15
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>34
Asn Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10 15
<210>35
<211>15
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>35
Asn Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10 15
<210>36
<211>15
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>36
Asn Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10 15
<210>37
<211>15
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>37
Asn Cys Cys Glu Arg Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10 15
<210>38
<211>15
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>38
Asn Cys Cys Glu Lys Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10 15
<210>39
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>39
Asn Ser Ser Asn Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr Asp Phe
20
<210>40
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>40
Asn Ser Ser Asn Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Trp
1 5 10 15
Gly Cys Tyr Asp Phe
20
<210>41
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>41
Asn Ser Ser Asn Tyr Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr Asp Phe
20
<210>42
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>42
Asn Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr Asp Phe
20
<210>43
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>43
Asn Ser Ser Asn Tyr Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr Asp Phe
20
<210>44
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>44
Asn Ser Ser Asn Tyr Cys Cys Glu Arg Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr Asp Phe
20
<210>45
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>45
Asn Ser Ser Asn Tyr Cys Cys Glu Lys Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr Asp Phe
20
<210>46
<211>16
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>46
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe
1 5 10 15
<210>47
<211>16
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>47
Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Trp Gly Cys Tyr Asp Phe
1 5 10 15
<210>48
<211>16
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>48
Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe
1 5 10 15
<210>49
<211>16
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>49
Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe
1 5 10 15
<210>50
<211>16
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>50
Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe
151015
<210>51
<211>16
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>51
Cys Cys Glu Arg Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe
1 5 10 15
<210>52
<211>16
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>52
Cys Cys Glu Lys Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp Phe
1 5 10 15
<210>53
<211>17
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>53
Asn Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp
1 5 10 15
Phe
<210>54
<211>17
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>54
Asn Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Trp Gly Cys Tyr Asp
1 5 10 15
Phe
<210>55
<211>17
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>55
Asn Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp
1 5 10 15
Phe
<210>56
<211>17
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>56
Asn Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp
1 5 10 15
Phe
<210>57
<211>17
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>57
Asn Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp
1 5 10 15
Phe
<210>58
<211>17
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>58
Asn Cys Cys Glu Arg Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp
1 5 10 15
Phe
<210>59
<211>17
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>59
Asn Cys Cys Glu Lys Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Asp
1 5 10 15
Phe
<210>60
<211>42
<212>DNA
<213>人工序列
<220>
<223>合成产生的寡核苷酸
<400>60
cacaccatat gaagaaatca atattattta tttttctttc tg 42
<210>61
<211>46
<212>DNA
<213>人工序列
<220>
<223>合成产生的寡核苷酸
<400>61
cacacctcga gttaggtctc catgctttca ggaccacttt tattac 46
<210>62
<211>69
<212>DNA
<213>人工序列
<220>
<223>合成产生的寡核苷酸
<400>62
gcatgaatag tagcaattac tgctgtgaat tgtgttgtaa tcctgcttgt accgggtgct 60
attaataac 69
<210>63
<211>69
<212>DNA
<213>人工序列
<220>
<223>合成产生的寡核苷酸
<400>63
tcgagttatt aatagcaccc ggtacaagca ggattacaac acaattcaca gcagtaattg 60
ctactattc 69
<210>64
<211>69
<212>DNA
<213>人工序列
<220>
<223>合成产生的寡核苷酸
<400>64
gcatgaatag tagcaattac tgctgtgaat attgttgtaa tcctgcttgt accgggtgct 60
attaataac 69
<210>65
<211>69
<212>DNA
<213>人工序列
<220>
<223>合成产生的寡核苷酸
<400>65
tcgagttatt aatagcaccc ggtacaagca ggattacaac aatattcaca gcagtaattg 60
ctactattc 69
<210>66
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<220>
<221>VARIANT
<222>9
<223>Xaa=任意的氨基酸;或Xaa=除Leu之外的任意氨基酸;或Xaa=Phe,Trp,和Tyr;
或选自其他的天然或非天然的芳香族氨基酸;或Xaa=Tyr
<220>
<221>VARIANT
<222>1,2,3,4,5
<223>Xaa1=Asn,Xaa2=Ser,Xaa3=Ser,Xaa4=Asn,
Xaa5=Tyr;或Xaa1-Xaa5缺失;或Xaa1-Xaa4缺失
;或Xaa1-Xaa3缺失;或Xaa1和
Xaa2缺失;或Xaa1缺失
<220>
<221>VARIANT
<222>19,20,21
<223>Xaa 20=Asp,Xaa21=Phe或缺失;或Xaa20=
Asn或Glu和Xaa21缺失;或X19-Xaa21缺失
<220>
<221>VARIANT
<222>(1)...(21)
<223>Xaa=任意的氨基酸
<400>66
Xaa Xaa Xaa Xaa Xaa Cys Cys Glu Xaa Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr Xaa Xaa
20
<210>67
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>67
Gln Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>68
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>68
Asn Thr Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>69
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>69
Asn Leu Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>70
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>70
Asn Ile Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>71
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>71
Asn Ser Ser Gln Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>72
<211>18
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>72
Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly
1 5 10 15
Cys Tyr
<210>73
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>73
Gln Ser Ser Gln Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>74
<211>18
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>74
Ser Ser Gln Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly
1 5 10 15
Cys Tyr
<210>75
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>75
Asn Ser Ser Asn Tyr Cys Cys Glu Ala Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>76
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>76
Asn Ser Ser Asn Tyr Cys Cys Glu Arg Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>77
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>77
Asn Ser Ser Asn Tyr Cys Cys Glu Asn Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>78
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>78
Asn Ser Ser Asn Tyr Cys Cys Glu Asp Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>79
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>79
Asn Ser Ser Asn Tyr Cys Cys Glu Cys Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>80
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>80
Asn Ser Ser Asn Tyr Cys Cys Glu Gln Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>81
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>81
Asn Ser Ser Asn Tyr Cys Cys Glu Glu Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>82
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>82
Asn Ser Ser Asn Tyr Cys Cys Glu Gly Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>83
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>83
Asn Ser Ser Asn Tyr Cys Cys Glu His Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>84
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>84
Asn Ser Ser Asn Tyr Cys Cys Gl u Ile Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>85
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>85
Asn Ser Ser Asn Tyr Cys Cys Glu Lys Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>86
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>86
Asn Ser Ser Asn Tyr Cys Cys Glu Met Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>87
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>87
Asn Ser Ser Asn Tyr Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>88
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>88
Asn Ser Ser Asn Tyr Cys Cys Glu Pro Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>89
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>89
Asn Ser Ser Asn Tyr Cys Cys Glu Ser Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>90
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>90
Asn Ser Ser Asn Tyr Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>91
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>91
Asn Ser Ser Asn Tyr Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>92
<211>19
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>92
Asn Ser Ser Asn Tyr Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Thr
1 5 10 15
Gly Cys Tyr
<210>93
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>93
Cys Cys Glu Ala Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>94
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>94
Cys Cys Glu Arg Cys CysAsn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>95
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>95
Cys Cys Glu Asn Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>96
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>96
Cys Cys Glu Asp Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>97
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>97
Cys Cys Glu Cys Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>98
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>98
Cys Cys Glu Gln Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>99
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>99
Cys Cys Glu Glu Cys Cys Asn Pro Ala Cys Thr Gly CysTyr
1 5 10
<210>100
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>100
Cys Cys Glu Gly Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>101
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>101
Cys Cys Glu His Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>102
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>102
Cys Cys Glu Ile Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>103
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>103
Cys Cys Glu Lys Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>104
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>104
Cys Cys Glu Met Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>105
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>105
Cys CysGlu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>106
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>106
Cys Cys Glu Pro Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>107
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>107
Cys Cys Glu Ser Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>108
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>108
Cys Cys Glu Thr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>109
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>109
Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>110
<211>14
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>110
Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
1 5 10
<210>111
<211>5
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>111
Gln His Asn Pro Arg
1 5
<210>112
<211>6
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>112
Val Gln His Asn Pro Arg
1 5
<210>113
<211>7
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>113
Val Arg Gln His Asn Pro Arg
1 5
<210>114
<211>8
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>114
Val Arg Gly Gln His Asn Pro Arg
1 5
<210>115
<211>9
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>115
Val Arg Gly Pro Gln His Asn Pro Arg
1 5
<210>116
<211>10
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>116
Val Arg Gly Pro Arg Gln His Asn Pro Arg
1 5 10
<210>117
<211>11
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>117
Val Arg Gly Pro Arg Arg Gln His Asn Pro Arg
1 5 10
<210>118
<211>6
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>118
Arg Gln His Asn Pro Arg
1 5
<210>119
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<220>
<221>VARIANT
<222>1,2,3,4
<223>Xaa=缺失
<220>
<221>VARIANT
<222>1,2,3,4,5
<223>Xaa=Xaa1=Asn,Xaa2=Ser,Xaa3=Ser,Xaa4=
Asn,Xaa5=Tyr;或缺失
<220>
<221>VARIANT
<222>8,9,12,13,14,17,19
<223>Xaa=任意的氨基酸
<400>119
Xaa Xaa Xaa Xaa Xaa Cys Cys Xaa Xaa Cys Cys Xaa Xaa Xaa Cys Xaa
1 5 10 15
Xaa Cys Xaa Xaa Xaa
20
<210>120
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<220>
<221>VARIANT
<222>1,2,3,4,5
<223>Xaa缺失
<220>
<221>VARIANT
<222>8
<223>Xaa=Glu
<220>
<221>VARIANT
<222>9
<223>Xaa=Leu,Ile,Lys,Arg,Trp,Tyr或Phe
<220>
<221>VARIANT
<222>12
<223>Xaa=Asn
<220>
<221>VARIANT
<222>13
<223>Xaa=Pro
<220>
<221>VARIANT
<222>14
<223>Xaa=Ala
<220>
<221>VARIANT
<222>16
<223>Xaa=Thr,Ala,Lys,Arg,Trp
<220>
<221>VARIANT
<222>17
<223>Xaa=Gly
<220>
<221>VARIANT
<222>19
<223>Xaa=Tyr或Leu
<220>
<221>VARIANT
<222>20,21
<223>Xaa20=Asp;Xaa21=Phe,或缺失
<400>120
Xaa Xaa Xaa Xaa Xaa Cys Cys Xaa Xaa Cys Cys Xaa Xaa Xaa Cys Xaa
1 5 10 15
Xaa Cys Xaa Xaa Xaa
20
<210>121
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<220>
<221>VARIANT
<222>1,2,3,4,5
<223>Xaa1=Asn,Xaa2=Ser,Xaa3=Ser,Xaa4=Asn,
Xaa5=Tyr或缺失
<220>
<221>VARIANT
<222>1,2,3,4
<223>Xaa=缺失
<220>
<221>VARIANT
<222>5
<223>Xaa=Asn,Trp,Tyr,Asp,Ile,Thr或Phe
<220>
<221>VARIANT
<222>8
<223>Xaa=Glu,Asp,Gln,Gly或Pro
<220>
<221>VARIANT
<222>9
<223>Xaa=Leu,Ile,Val,Ala,Lys,Arg,Trp,Tyr或
Phe
<220>
<221>VARIANT
<222>12
<223>Xaa=Asn,Tyr,Asp或Ala
<220>
<221>VARIANT
<222>13
<223>Xaa=Pro或Gly
<220>
<221>VARIANT
<222>14
<223>Xaa=Ala,Leu,Ser,Gly,Val,Glu,Gln,Ile,Leu,
Lys,Arg,和Asp
<220>
<221>VARIANT
<222>16
<223>Xaa=Thr,Ala,Asn,Lys,Arg
<220>
<221>VARIANT
<222>17
<223>Xaa=Gly,Pro或Ala
<220>
<221>VARIANT
<222>19
<223>Xaa=Trp,Tyr,Phe或Leu
<220>
<221>VARIANT
<222>19-21
<223>Xaa20=Asp,Xaa21=Phe或缺失;或Xaa20=
Asn,或Glu和Xaa21缺失;或Xaa19,Xaa20,
Xaa21=缺失
<400>121
Xaa Xaa Xaa Xaa Xaa Cys Cys Xaa Xaa Cys Cys Xaa Xaa Xaa Cys Xaa
1 5 10 15
Xaa Cys Xaa Xaa Xaa
20
<210>122
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<220>
<221>VARIANT
<222>1,2,3,4,5
<223>Xaa=缺失
<220>
<221>VARIANT
<222>8
<223>Xaa=Glu
<220>
<221>VARIANT
<222>9
<223>Xaa=Leu,Ile,Lys,Arg,Trp,Tyr,或Phe
<220>
<221>VARIANT
<222>12
<223>Xaa=Asn
<220>
<221>VARIANT
<222>13
<223>Xaa=Pro
<220>
<221>VARIANT
<222>14
<223>Xaa=Ala
<220>
<221>VARIANT
<222>16
<223>Xaa=Thr,Ala,Lys,Arg,Trp;或X16=任意的氨基酸;或X16=Thr,Ala,Lys,
Arg,Trp;或任意的非芳香性的氨基酸
<220>
<221>VARIANT
<222>17
<223>Xaa=Gly
<220>
<221>VARIANT
<222>19
<223>Xaa=Tyr或Leu
<220>
<221>VARIANT
<222>20,21
<223>Xaa20=Asp,Xaa21=Phe或缺失
<400>122
Xaa Xaa Xaa Xaa Xaa Cys Cys Xaa Xaa Cys Cys Xaa Xaa Xaa Cys Xaa
1 5 10 15
Xaa Cys Xaa Xaa Xaa
20
<210>123
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<220>
<221>VARIANT
<222>1,2,3,4,5
<223>Xaa1=Asn,Xaa2=Ser,Xaa3=Ser,Xaa4=Asn,
Xaa5=Tyr或缺失;或Xaa1-Xaa4缺失
和Xaa5=Asn
<220>
<221>VARIANT
<222>8
<223>Xaa=Glu或Asp
<220>
<221>VARIANT
<222>9
<223>Xaa=Leu,Ile,Val,Trp,Tyr或Phe
<220>
<221>VARIANT
<222>16
<223>Xaa=Thr,Ala,或Trp
<220>
<221>VARIANT
<222>19
<223>Xaa=Trp,Tyr,或Leu或缺失
<220>
<221>VARIANT
<222>20,21
<223>Xaa20=Asp,Xaa21=Phe
<400>123
Xaa Xaa Xaa Xaa Xaa Cys Cys Xaa Xaa Cys Cys Asn Pro Ala Cys Xaa
1 5 10 15
Gly Cys Xaa Xaa Xaa
20
<210>124
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<220>
<221>VARIANT
<222>1,2,3,4
<223>Xaa=缺失
<220>
<221>VARIANT
<222>5
<223>Xaa=Asn
<220>
<221>VARIANT
<222>9
<223>Xaa=Trp,Tyr或Phe;
<220>
<221>VARIANT
<222>16
<223>Xaa=Thr或Ala
<220>
<221>VARIANT
<222>19
<223>Xaa=Trp,Tyr,Phe
<220>
<221>VARIANT
<222>20,21
<223>Xaa20=Asp,Xaa21=Phe,
<400>124
Xaa Xaa Xaa Xaa Xaa Cys Cys Xaa Xaa Cys Cys Asn Pro Ala Cys Xaa
1 5 10 15
Gly Cys Xaa Xaa Xaa
20
<210>125
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<220>
<221>VARIANT
<222>1,2,3,4,5
<223>Xaa=Xaa1=Asn,Xaa2=Ser,Xaa3=Ser,Xaa4=
Asn,Xaa5=Tyr,或缺失;或Xaa1-Xaa4缺失和
Xaa5=Asn,Trp,Tyr,Asp,Ile,Thr
<220>
<221>VARIANT
<222>8
<223>Xaa=Glu,Asp,Gln,Gly或Pro
<220>
<221>VARIANT
<222>9
<223>Xaa=Leu,Ile,Val,Ala,Lys,Arg,Trp,Tyr或
Phe
<220>
<221>VARIANT
<222>12
<223>Xaa=Asn,Tyr,Asp或Ala
<220>
<221>VARIANT
<222>13
<223>Xaa=Pro或Gly
<220>
<221>VARIANT
<222>14
<223>Xaa=Ala,Leu,Ser,Gly,Val,Glu,Gln,Ile,Leu,
Lys,Arg或Asp
<220>
<221>VARIANT
<222>16
<223>Xaa=Thr,Ala,Asn,Lys,Arg,Trp
<220>
<221>VARIANT
<222>17
<223>Xaa=Gly,Pro或Ala
<220>
<221>VARIANT
<222>19
<223>Xaa=Trp,Tyr,Phe或Leu;或Xaa=Lys或Arg
<220>
<221>VARIANT
<222>20
<223>Xaa=Xaa20=Asp,Xaa21=Phe或缺失;或
Xaa20=Asn或Glu and Xaa21缺失
<220>
<221>VARIANT
<222>19,21
<223>Xaa缺失
<400>125
Xaa Xaa Xaa Xaa Xaa Cys Cys Xaa Xaa Cys Cys Xaa Xaa Xaa Cys Xaa
1 5 10 15
Xaa Cys Xaa Xaa Xaa
20
<210>126
<211>21
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<220>
<221>VARIANT
<222>1,2,3,4,5
<223>Xaa缺失
<220>
<221>VARIANT
<222>8
<223>Xaa=Glu
<220>
<221>VARIANT
<222>9
<223>Xaa=Leu,Ile,Lys,Arg,Trp,Tyr或Phe
<220>
<221>VARIANT
<222>12
<223>Xaa=Asn
<220>
<221>VARIANT
<222>13
<223>Xaa=Pro
<220>
<221>VARIANT
<222>14
<223>Xaa=Ala
<220>
<221>VARIANT
<222>16
<223>Xaa=Thr,Ala,Lys,Arg,Trp
<220>
<221>VARIANT
<222>17
<223>Xaa=Gly
<220>
<221>VARIANT
<222>19
<223>Xaa=Tyr或Leu;或Xaa=Lys或Arg
<220>
<221>VARIANT
<222>20,21
<223>Xaa20=Asp,Xaa21=Phe或缺失
<400>126
Xaa Xaa Xaa Xaa Xaa Cys Cys Xaa Xaa Cys Cys Xaa Xaa Xaa Cys Xaa
1 5 10 15
Xaa Cys Xaa Xaa Xaa
20
<210>127
<211>5
<212>PRT
<213>人工序列
<220>
<223>合成产生的肽
<400>127
Asn Ser Ser Asn Tyr
1 5
<210>128
<211>30
<212>PRT
<213>Yersinia enterocolitica
<400>128
Gln Ala Cys Asp Pro Pro Leu Pro Pro Ala Glu Val Ser Ser Asp Trp
1 5 10 15
Asp Cys Cys Asp Val Cys Cys Asn Pro Ala Cys Ala Gly Cys
20 25 30
Claims (2)
1.一种多肽或其可药用盐,其中所述多肽由氨基酸序列:Cys Cys GluTyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr组成。
2.一种药用组合物,包括权利要求1的多肽或其可药用盐和可药用载体或赋形剂。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102875655A (zh) * | 2012-09-29 | 2013-01-16 | 深圳翰宇药业股份有限公司 | 一种合成利那洛肽的方法 |
CN102875655B (zh) * | 2012-09-29 | 2014-12-17 | 深圳翰宇药业股份有限公司 | 一种合成利那洛肽的方法 |
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