CN103641892A - 用于治疗组织炎症和癌变的鸟苷酸环化酶受体激动剂 - Google Patents
用于治疗组织炎症和癌变的鸟苷酸环化酶受体激动剂 Download PDFInfo
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- CN103641892A CN103641892A CN201310447292.9A CN201310447292A CN103641892A CN 103641892 A CN103641892 A CN 103641892A CN 201310447292 A CN201310447292 A CN 201310447292A CN 103641892 A CN103641892 A CN 103641892A
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Abstract
本发明涉及用于治疗组织炎症和癌变的鸟苷酸环化酶受体激动剂。本发明公开在哺乳动物中治疗组织发炎，癌变前或癌变的方法。该治疗涉及施用至少一种鸟苷酸环化酶的肽激动剂和/或其他增强细胞内cGMP产量的小分子的组合物。该鸟苷酸环化酶的肽激动剂可以单独施用或同抑制依赖cGMP的磷酸二酯酶的抑制剂联合施用。抑制剂可为小分子、肽、蛋白质或其他抑制cGMP降解的其他化合物。不需要特定作用机制，该治疗可以重建受治疗者上皮细胞群中增殖和凋亡的平衡，并抑制癌变。因此，该方法可用于治疗包括胃肠道炎症、普通器官发炎和哮喘的炎症和肺、胃肠道、膀胱、睾丸、前列腺和胰腺的癌变，或息肉。
Description
相关申请的交叉引用
本发明要求以下美国临时申请的权益：2001年3月29日提交的60/279，438；2001年3月29日提交的60/279，437；2001年6月27日提交的60/300，850；2001年7月10日提交的60/303，806；2001年7月25日提交的60/307，358；2002年1月17日提交的60/348，646.
发明领域
本发明涉及鸟苷酸环化酶受体激动剂作为提高细胞内cGMP产量的方法，在治疗上的用途。该激动剂可以单独使用或者与cGMP-特异的磷酸二酯酶的抑制剂联合使用，以预防或治疗癌变的、癌变前的以及转移性的肿瘤生长，尤其是在胃肠道及肺部。除此以外，该激动剂还可以用于治疗炎症，如溃疡性结肠炎和哮喘。
发明背景
尿鸟苷蛋白、鸟苷蛋白和细菌ST肽是在结构上相关的肽，它们与鸟苷酸环化酶受体结合并刺激细胞内产生环化鸟嘌呤核苷单磷酸(cGMP)(1-6)。这导致了囊性纤维化跨膜传导调节蛋白(CFTR)的激活，CFTR是一个顶端膜通道，用于氯从沿肠道排列的肠细胞外排(1-6)。CFTR的激活以及随后的氯的跨上皮分泌的增加导致激发钠和水向肠腔内的分泌。因此，cGMP受体激动剂通过作为CFTR的旁分泌调控因子，可以调控胃肠道内液体和电解质的运输(1-6，美国专利5，489，670)。
上皮的更新过程包括胃肠道细胞在胃肠腔内的增殖、迁移、分化、衰老以及最终的丧失(7，8)。根据上皮细胞的增殖指数，胃肠粘膜可以分为三个明显的区带。其中的一个区带--增殖区带，由未分化的干 细胞组成，这些干细胞提供新生细胞的持续来源。干细胞向肠腔方向迁移，并被挤压进入肠腔。在迁移时，细胞失去其分裂的能力，并分化为执行胃肠粘膜特异功能的细胞(9)。胃肠粘膜的更新非常迅速，其在24到48小时以内完全更新一次(9)。在这一过程中，突变的和不需要的细胞被新的细胞补充。因此，胃肠粘膜的稳态由增殖速率和细胞凋亡速率之间的平衡的连续维来调控(8)。
消化道上皮细胞的细胞增殖速率和凋亡速率可以由于多种不同的情况被增加或降低，例如对于生理刺激如衰老、炎症信号、激素、肽、生长因子、化学物质和饮食习惯的反应。除此以外，提高的增殖速率常常与全更新时间的减少和增殖区带的扩张有关(10)。据观察，增殖指数在溃疡性结肠炎和其他胃肠疾病的病理情况下要高很多(11)。因此，肠增生是胃肠炎症和癌症发生的主要促进原因。
尿鸟苷蛋白和鸟苷蛋白除了具有对肠内液体和离子分泌的调节作用以外，这些肽还可能参与胃肠道粘膜的持续更新。以前在wO01/25266中公开的数据提示，具有尿鸟苷蛋白活性结构域的肽可能具有结肠息肉生长抑制剂的功能，并可能成为结肠癌的一种治疗方法。但是，该功能出现所依据的机制还不能确定，因为wO01/25266中教导尿鸟苷蛋白拮抗肽与称为GC-C的鸟苷酸环化酶受体特异结合，该鸟苷酸环化酶受体最早被描述为大肠杆菌(E.coli)中热稳定的肠毒素(ST)受体(4)。缺失这个鸟苷酸环化酶受体的基因敲除小鼠在肠内对ST表现出抗性，但在肾脏体内实验中，尿鸟苷蛋白和ST的作用没有受到影响(3)。这些结果受到下面事实的进一步支持：鸟苷蛋白引起的膜的去极化被酪氨酸激酶抑制剂--染料木黄酮(5，7，4′-三羟基异黄酮)阻断，而尿鸟苷蛋白引起的膜的超极化不受影响(12，13)。这些数据一起，提示尿鸟苷蛋白也与一个目前还不清楚的、与GC-C不同的受体结合。
另外一些文章也报道了在癌变早期的结肠息肉和肿瘤组织中，尿鸟苷蛋白和鸟苷蛋白的产量显著降低(14-17)。除此以外，还发现编码尿鸟苷蛋白和鸟苷蛋白的基因定位在常常与人结肠肿瘤中杂合性的丧 失有关的基因组区域内(18-20)。这些发现一起表明尿鸟苷蛋白、鸟苷蛋白以及其他有相似活性的肽可以用于结肠异常性生长的预防和治疗。这个提议得到了最近一项研究的支持，该研究证明了鸟苷蛋白的口服给药抑制了小鼠中息肉的形成(15，16)。
尿鸟苷蛋白和鸟苷蛋白肽看起来也通过控制细胞的离子流而促进细胞凋亡。细胞凋亡的改变与肿瘤发展为转移性表型有关。原发性的胃肠癌只限于小肠、结肠和直肠，但癌变可以转移并扩张至骨、淋巴结、肝脏、肺、腹膜、卵巢、大脑等部位。通过提高钾离子的外流和钙离子的内流，尿鸟苷蛋白和相关肽可以促进转化细胞的死亡，从而抑制癌变转移。
降低的CFTR活性的一项临床表现是呼吸道的炎症(21)。这一结果可能归因于CTFR调控NF-kB、趋化因子和细胞因子的表达(22-25)。最近的报道也提示CFTR通道与还原型谷胱甘肽的运输和维持有关。还原型谷胱甘肽是抗氧化剂，在防止因氧化胁迫而产生的炎症方面起着重要作用(39)。通过激活鸟苷酸环化酶或抑制cGMP特异的磷酸二酯酶这两条途径而产生的细胞内cGMP水平的提高，可预计对这些炎症刺激有减量调节的作用。因此，尿鸟苷蛋白型的激动剂应该在肺(如哮喘)、肠[如溃疡性结肠炎和节段性回肠炎(克罗恩氏病)]、胰腺和其他器官炎症的预防和治疗中有用。
总之可以得出结论，鸟苷酸环化酶受体的激动剂如尿鸟苷蛋白，在多种炎症、癌症(特别是结肠癌)的治疗中以及作为抗转移药物，都具有潜在的治疗价值。因此，新型激动剂的开发在临床上具有实质的重要性。
发明概述
本发明基于新型鸟苷酸环化酶受体激动剂的开发和天然存在的激动剂的新用途。这些激动剂是尿鸟苷蛋白的类似物，其中许多具有很优良的性质，在低pH下具有提高的受体激活能力、稳定性、活性或者降低的副作用。这些肽可以用于治疗任何对细胞内提高的cGMP水平反 应的情况。提高细胞内cGMP的产量和/或通过cGMP特异的磷酸二酯酶抑制cGMP的降解都可以提高细胞内的cGMP水平。在能够被预防或治疗的具体情况中有炎症、癌症、息肉和癌转移。
首先，本发明针对基本由SEQ ID NO：2-21中任意一个氨基酸序列组成的肽以及含有这些肽的治疗用组合物。术语“基本由...组成”包括肽，其序列与上面列举的带有标识序号的序列相同以及在结构或功能上与这些序列没有根本区别的其他序列。对于本申请的目的，如果一个肽在结构上相对于SEQ ID NO：2-21中的肽有三个以上氨基酸的变化，或者其激活细胞内cGMP产生的能力有50％的增加或减少，则该肽有根本的区别。优选，基本相似的肽不应该有两个以上氨基酸的差异，并且在激活cGMP产生方面的差异不应该大于25％。最优选的肽是具有SEQ ID NO：20序列的双环肽。
这些肽可以与一或多种赋形剂一起，以单位剂量形式出现在药物组合物中。术语“单位剂量形式”指一个单一给药实体，如片剂、胶囊、溶液或吸入制剂。加入的肽量应该为在给患者用药时，足以产生有效的治疗作用(一般在100微克与3克之间)。“有效的治疗作用”的建立取决于被治疗的特定情况，而且包括本领域技术人员容易识别的状况的任何显著改善。例如，有效的治疗作用可以包括炎症的减少、息肉或肿瘤的缩小、转移性损害的减少等等。
本发明还包含了联合疗法，使用鸟苷酸环化酶受体激动剂单独给药或与cGMP依赖的磷酸二酯酶的抑制剂、抗炎症药剂或抗癌药剂一起给药。这些药剂的量应当是本领域内已知的给患者服用后有治疗效果的量。抗肿瘤药剂可以包括烷基化试剂、表鬼臼毒素、亚硝基脲、抗代谢物、长春花生物碱、蒽环类抗生素、氮芥试剂以及类似的物质。具体的抗肿瘤药剂可以包括三苯氧胺(它莫西芬)、紫杉醇、表鬼臼毒素吡喃葡糖苷和5-氟尿嘧啶。在设计适合于患者具体需要的治疗方案时，抗病毒和单克隆抗体疗法可以与包括至少一种鸟苷酸环化酶受体激动剂的化疗组合物联合使用。
另一方面，本发明针对通过给患者服用含有效量鸟苷酸环化酶受 体激动剂--优选合成的鸟苷酸环化酶受体激动剂的组合物来预防、治疗或减缓受治疗者的癌症，特别是上皮细胞癌症或息肉发作的方法。术语“有效量”是指能够可测量地提高细胞内cGMP水平的足量的激动剂。术语“合成的”是指制造的与鸟苷酸环化酶受体结合的肽，但该肽含有某些在已知的内源鸟苷酸环化酶激动剂--如尿鸟苷蛋白中不存在的氨基酸序列替换。该激动剂应当选自由SEQ ID NO：2-21限定的，并且列在表2和表3中的肽。本发明还包括了通过给患者服用有效剂量的选自尿鸟苷蛋白、鸟苷蛋白和大肠杆菌ST肽的肽来治疗原发性癌症而非原发性结肠癌的方法。尽管优选使用人类的肽，但是任何已知形式的尿鸟苷蛋白或鸟苷蛋白都可以用于此目的。
本发明还包括预防或治疗来源于原发性肿瘤块的肿瘤转移。依据本发明产生的肽可以靶向具有鸟苷酸环化酶受体的转移性肿瘤细胞。在优选的实施方案中，在胃肠癌细胞上和源自这些癌的转移细胞上，会发现被靶向的受体。这种受体一般是跨膜蛋白，具有细胞外配基结合结构域，跨膜结构域和具有鸟苷酸环化酶活性的胞内结构域。尽管本发明没有任何特殊作用机制的限制，但是一般认为这些肽通过与这些细胞受体相结合并引发细胞凋亡而发生作用。转移性的肿瘤也可以通过给药任意已知形式的尿鸟苷蛋白或鸟苷蛋白(优选人源的)或给药大肠杆菌ST肽进行治疗。
肽可以单独给药或者与一或多种cGMP依赖的磷酸二酯酶的抑制剂一起给药。cGMP依赖的磷酸二酯酶的抑制剂的例子有suldinac砜，苯氮嘌呤酮和motapizone。可以治疗的癌症形式包括乳腺癌、直肠癌，肺癌、卵巢癌、胰腺癌、前列腺癌、肾癌和睾丸癌。可以施用根据本发明的组合物通过抑制癌变早期直肠息肉的发育而预防结肠癌的发生。可以认为这些肽对治疗结肠癌和预防结肠肿瘤转移应该非常有效。
第三方面，本发明针对通过施用含有可以提高细胞内cGMP产量的鸟苷酸环化酶受体激动剂的组合物来治疗、防治或延缓受治疗者器官炎症(如与胃肠道、哮喘、肾炎、肝炎、胰腺炎、支气管炎或囊肿性纤维化有关的炎症)发作的方法。优选的肽激动剂选自表2和表3所 示的SEQID NO：2-21定义的肽，或者是尿鸟苷蛋白、鸟苷蛋白或大肠杆菌ST肽。这些肽可选与一或多种cGMP依赖的磷酸二酯酶的抑制剂，如suldinac砜，苯氮嘌呤酮或motapizone一起给患者服用。在一个优选的实施方案中，本发明针对治疗哺乳动物的胃肠道炎症的方法。炎症可以归为发炎性肠部疾病，更为具体地可以是节段性回肠炎(克罗恩氏病)或溃疡性结肠炎。给药方式可以是肠溶性的，并使用适于靶向肠细胞的制剂。
从更广义的意义上讲，本发明包括通过给患者施用有效量的具有SEQ ID NO：2-21中任一序列的肽，或者尿鸟苷蛋白、鸟苷蛋白或大肠杆菌ST肽来诱导细胞凋亡的方法。在这一意义上，“有效量”的肽所指足以在目标组织中提高细胞凋亡的量。例如，在肿瘤生长中可以给予足量的肽以诱导提高速率的细胞死亡。
最优选用于上述方法的肽是SEQ ID NO：20所限定的肽。其序列如下(也请参见表3)：
Asn1Asp2Glu3Cys4Glu5Leu6Cys7ValsAsn9Val10Ala11Cys12Thr13Gly14Cys15Leu16
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且其中在第4位的半胱氨酸和第12位的半胱氨酸之间有一个二硫键；第二个二硫键位于第7位的半胱氨酸和第15位的半胱氨酸之间(SEQ ID NO：20)。已经发现由于该肽对于鸟苷酸环化酶受体提高的结合常数，作为cGMP产生的激动剂，它具有增强的生物活性。在温度和蛋白酶稳定性方面以及在大肠中生理适宜pH值(pH6-7)时的生物活性方面，该肽优于尿鸟苷蛋白。
上述方法中使用的鸟苷酸环化酶受体激动剂可以口服、全身或局部方式给药。剂量形式包括吸入或注射的制剂、溶液、悬浮液、乳剂、片剂、胶囊、局部软膏和洗剂、透皮组合物，其他已知的肽剂型和pegylated肽类似物。组合物的有效剂量一般在约1微克到约10毫克每千克体重之间，优选在约10微克到5毫克每千克体重之间。使用本领域的常规方法并依据具体的组合物和临床的考虑调整剂量。激动剂可以以单一活性药剂的形式给药，或者与其他药物如cGMP依赖的磷酸二酯酶的抑制剂一起给药。在所有情况下，其他药物的给药剂量应当 以本领域现有技术为指导的治疗有效剂量。可以以单一组合物或逐一给药的方式给药。
发明详述
本发明建立在多种原理上。首先是依赖cGMP的机制，其调控细胞增殖和细胞凋亡之间的平衡，并且由于尿鸟苷蛋白/鸟苷蛋白的缺乏和/或cGMP特异的磷酸二酯酶的激活而导致的cGMP水平的降低，这是肿瘤转化中早期且至关重要的一步。第二个原理是花生四烯酸从膜磷脂上的释放将导致在发炎过程中cPLA2、COX-2及可能还有5-脂氧合酶的激活，该释放受到依赖cGMP机制的负调控，这会导致前列腺素和白三烯水平的降低，并且提高胞内的cGMP水平因此可以产生抗炎症反应。除此以外，依赖cGMP的机制被认为参与促炎过程的调控。因此，升高胞内cGMP水平可以用作治疗和控制肠部发炎性疾病如溃疡性结肠炎和节段性回肠炎(克罗恩氏病)及其他器官炎症(例如与哮喘、肾炎、肝炎、胰腺炎、支气管炎、囊肿性纤维化有关的炎症)的一种方法。
并非局限于任何理论，预想离子跨细胞膜的运输可以被证明是细胞增殖和凋亡之间平衡的重要调控因子，这个平衡会受到能够改变cGMP浓度的组合物的影响。已有证据显示尿苷蛋白刺激胃肠道中钾离子外流，钙离子内流以及水的运输(3)。此外，已发现心房肽(ANP)，一个也可以与特异的鸟苷酸环化酶受体结合的肽，诱导大鼠血管系膜细胞的凋亡，并通过依赖cGMP的机制诱导心肌细胞的凋亡(26-29)。可以认为本发明的激动剂与鸟苷酸环化酶受体的结合刺激cGMP的产生。这种配基-受体相互作用，通过激活依赖cGMP的蛋白激酶和CFTR的级联作用，预期会诱导目标细胞的凋亡。因此，施用如表2和表3中所示的SEQ ID NO：2-21所限定的新型肽，或者尿鸟苷蛋白、或鸟苷蛋白或大肠杆菌ST肽，预期会消除，或至少延缓，胃肠道炎症的发作和普通器官发炎(如哮喘、肾炎、肝炎、胰腺炎、支气管炎和囊肿性纤维化)。
在第二方面，本发明针对通过施用含有有效量的鸟苷酸环化酶受 体激动剂的组合物，优选合成的鸟苷酸环化酶受体激动剂，来治疗、防治或延缓受治疗者的癌症，特别是上皮细胞癌症发作的方法。术语“有效量”指可以使胞内cGMP水平产生可测量增加的足量的激动剂。术语“合成的”指制造出来与鸟苷酸环化酶受体结合的肽，却含有某些已知的内源鸟苷酸环化酶激动剂--如尿鸟苷蛋白中不存在的氨基酸序列替换。该激动剂应当是选自SEQ ID NO：2-21所限定的，及在表2和表3中列出的肽。本发明还包括了通过施用有效剂量的选自尿鸟苷蛋白、鸟苷蛋白和大肠杆菌ST肽的肽，来治疗除原发性结肠癌以外的原发癌症的方法。尽管优选使用人源的肽，但是任何已知形式的尿鸟苷蛋白或鸟苷蛋白都可以用于此目的。
调控转移性肿瘤细胞中细胞增殖和凋亡之间平衡的依赖cGMP的机制可以作为靶向和治疗转移性肿瘤的机制。肝脏是最常见的从原发性结直肠癌转移的位置。在癌症的后期，结直肠的转移性细胞也可以侵袭身体的其他部位。应重点注意的是来源于胃肠道中原发位点的转移性细胞一般会继续表达鸟苷酸环化酶受体，因此，这些细胞应当对由肠部鸟苷酸环化酶受体介导的凋亡疗法敏感。具有尿鸟苷蛋白活性的肽，在单独使用或与cGMP-磷酸二酯酶的特异抑制剂一起使用时，也会通过cGMP介导的机制，恢复细胞增殖和凋亡间的健康平衡，而延缓消化道上皮的癌症发生。
这里使用的术语“鸟苷酸环化酶受体”指位于任何细胞类型上的鸟苷酸环化酶受体，在此所述的发明的激动剂肽或天然激动剂与这些受体结合。
这里使用的术语“鸟苷酸环化酶受体-激动剂”指与鸟苷酸环化酶受体结合并刺激cGMP产生的肽和/或其他化合物。该术语还包括所有这样的肽，它们具有与包含SEQ ID NO：1的3-15号氨基酸残基结合结构域的至少一部分基本上相同的序列。该术语还涵盖了与鸟苷酸环化酶受体结合并刺激cGMP产生的片段和前肽。术语“基本上相同”指具有与结合结构域相同氨基酸序列的肽，序列中某些残基可以被删除，或被其他氨基酸替代而不影响该肽结合鸟苷酸环化酶受体并刺激 cGMP产生的能力。
新型鸟苷酸环化酶受体激动剂的策略和设计
尿鸟苷蛋白由杯状突和其他排列为胃肠粘膜的上皮细胞以功能上无活性的尿鸟苷蛋白原的形式分泌。人类的肽原随后在肠腔内通过内源蛋白酶的作用被转变为功能上有活性的，由SEQ ID NO：1所表示的16氨基酸肽(人尿鸟苷蛋白序列，参见表2)。因为尿鸟苷蛋白是一种耐热、耐酸和耐蛋白酶水解的肽，在治疗方法中可以有效地采用这种肽和/或其他与SEQ ID NO：1的序列相似的功能上有活性的16氨基酸肽的口服或全身性给药。
下面讨论与尿鸟苷蛋白相似但不同的肽，包括一些具有优异的cGMP增强性质，和/或其他与以前知道的尿鸟苷蛋白肽相比有利的性质。这些肽可以用于抑制胃肠炎症，以及治疗或预防与消化道炎症有关的息肉形成。也可以治疗易于形成癌细胞的上皮组织。这里描述的鸟苷酸环化酶受体激动剂具有表2和3中所示的氨基酸序列。激动剂-受体相互作用的“结合结构域”包含SEQ ID NO：1的3-15号氨基酸残基。
应用分子模拟设计新型的鸟苷酸环化酶受体激动剂，具体方法见(30)。分子模拟设计包括对三个已知与鸟苷酸环化酶受体相互作用的化合物的能量计算，这三个化合物为人尿鸟苷蛋白，双环[4，12；7，15]
Asn1-Asp2-Asp3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Glv14-Cys15-Leu16(UG，SEQ ID NO：1)、人鸟苷蛋白，双环［4，12；7，15］
Pro1-Gly2-Thr3-Cys4-Glu5-Ile6-Cys7-Ala8-Tyr9-Ala10-Ala11-Cys12-Thr13-Gly14-Cys15(GU，SEQ ID NO：22)、和大肠杆菌小的热稳定肠毒素，三环[6，10；7，15；11-18]Asn1-Ser2-Ser3-Asn4-Tyr5-Cys6-Cys7-Glu8-Leu9-Cys10-Cys11-Asn12-pro13-Ala14-Cys15-Thr16-Gly17-Cvs18--Thr19-(ST，SEQ ID NO：23)。对这三个化合物所有可能的低 能量构象进行几何比较，以揭示出作为生物活性构象(即在与受体相互作用的过程中GU，UG和ST所采用的构象)“模板”的共有的3-D结构。分子模型设计允许在以其他低能量构象为代价的情况下，通过选择对于多种氨基酸残基的单独替代，设计具有生物活性构象显著增加的构象群体的新型类似物。
利用堆积(build-up)步骤进行能量计算(30)。用平面顺式肽键(包括ST中的Prol3的平面顺式肽键)用刚性化合价几何结构，使用ECEPP/2势场(31，32)。Pro13的ω角允许变动。脂肪族和芳香族的氢-般被包括在CHn类型的联合原子中心中；对α氢原子和酰胺的氢进行明确的描述。
主要的计算方案涉及许多相连续的步骤。首先要考虑两个单环的模型片段(对于ST是三个片段)，Ac-环(Cysi-...-Cysj)-NMe的序列，其中除了Cys、Gly和Pro以外的所有残基都由丙氨酸替代；i和j的值与GU、UG和ST的序列对应。在这一步，要考虑每一个氨基酸残基对肽骨架的局部最小量的所有可能组合，即对Ala残基，E，F，C，D，A和A*类型[按照(33)中的符号系统]的Rama chandran图中的最小量；对Gly残基，E*，F*，C*，D*，A，E，F，C，D，和A*类型的Rama chand ran图中的最小量；对P ro残基，F，C和A类型的Rama chandran图中的最小量。对于每一个骨架构象，通过检查D-Cy s残基沿二面角x1旋转的能量性质，找到使用ECEPP/2力场内在的抛物线势能函数关闭环的最适可能性。
总计，对每一个环部分，至少考虑大约180，000个构象。然后，满足E-Emin＜△E=15kcal/mol标准，且在任意骨架二面角的至少一个值上有40°以上差异的构象(对不同的模型片段，从约3000到8000个构象中)被挑选出来。在下一步，将相配的单环片段中所选出来的构象进行叠加，以产生双环模型片段的可能构象(对于ST是三环片段)。这一步一般得到20，000到30，000个构象。所有这些构象进入新一轮能量计算的循环，产生出对于ST模型片段满足E-Emin＜△E=20kcal/mol标准的191个构象和对于GU/UG模型片段满足同样条件 的6，965个构象。此后，恢复在模型片段中漏掉的侧链，再次进行能量计算，在能量最小化之前，利用前述算法(34)，对侧链基团的二面角值(除了Cys残基的x1角以外)和骨架末端基团的二面角值进行优化，以达到这些基团最适宜的空间排列。对于UG4-15片段，632个构象满足△E=20kcal/mol的标准；其中162个满足更为严格的△E=12kcal/mol的标准，这符合已接受的1kcal/mol/残基的标准(30)。接下来由UG4-15片段向3-16片段的延长，以及延长为整个UG分子，以同样的堆积步骤进行。最终找到满足△E=16kcal/mol标准的31个UG的骨架构象。
用以下方法对每一个构象进行几何比较。根据(35)，确定一个构象对中原子中心重叠的最适度，以检查两个构象之间几何相似性的水平。几何相似性的标准是rms值，对于一对构象A和B，rsm值计算如下：
rns=(1/N)∑N i=1[(xA i-xB i)2+(yA i-yB i)2+(zA i-zB i)2］1/2，
其中N是选择用于重叠的α碳原子对的数目，x、y和z是笛卡尔坐标。根据rms＜2.0
的几何相似性标准，刚性构象片段UG4-15的低能量构象归入七个构象家族。其中的一个家族由与1UYA和1ETN都相似的相同的六个构象组成；该家族还包含UG的最低能量构象。(1UYA和1ETN由实验限定为UG和ST分别的3D结构，已知它们具有高生物活性(36，37)；从蛋白质数据库中可以获得3D结构。)
表1在UG的“模板”构象中，肽骨架的二面角(用度表示)值
确定这个UG片段总体3D形状的二面角和ψ的值是相似的(表1)。它允许进行新型类似物的初级设计，其目的是利用已知的由于多种类型氨基酸施加的局部构象限制，稳定这个特殊的构象家族。
例如，已知Gly与其他L-氨基酸残基相比，由于可以采用
和ψ的四种符号组合中的任意一种，即-，+；-，-；+，+；和+，-，因此在构象上更灵活。最后一种组合对于L-氨基酸如Ala来说，是空间上禁止的。因此，用Ala14替代Gly14会限制14位的构象灵活性，保持表1所描述构象。但是，用Aib(α-Me-Ala，双α甲基丙氨酸)替代，只会在两个区域，即-，-和+，+，限制局部构象的灵活性，第一个区域(-，-)与表1中Ala11的构象相容。因此，另一个合意的替代是 Aib11。在Pro中，ψ的值固定在-75°；该残基与缬氨酸具有相似的疏水性质。因此，val10可以用Pro10替代，向表1中的UG构象加入了更多的局部构象限制。被Pro替代还要求它的前一个残基只具有正ψ值；表1中的Asn9满足这个要求。Pro残基已经存在于ST的相应位置处。下面表示的SEQ ID NO：1内所有建议的替代(如Pro10，Aib11或Ala14)并不改变非脂肪族氨基酸(如Asn，Asp或Thr)的化学性质，这些性质在与受体的实际相互作用中非常重要。前述的替代应该只导致使UG的构象平衡向所建议的“模板”3-D结构方向移动的构象限制。
根据表1中限定的3D结构，对尿鸟苷蛋白定义了一个三维的药效团，使得可能确定被认为直接与受体相互作用的尿鸟苷蛋白官能团之间的距离。那些被认为与受体直接相互作用的官能团是位于骨架序列3，5，9和13位的残基侧链基团。这些残基优选是Glu3，Glu5，Asn9和Thr13，如SEQ ID NO：2和SEQ ID NO：20所示。因此，描述出尿鸟苷蛋白的三维药效团，其中在3，5，9和13位残基的四条侧链的空间排列可以产生为使得这些侧链之间的距离使可选的生物活性成为可能。那些距离(用相应残基的β碳原子之间的距离来量度)如下：对于3-5的距离从5.7到7.6
；对于3-9的距离从4.0到6.0
；对于3-13的距离从7.7到8.3
；对于5-9的距离从9.4到9.5
；对于5-13的距离从9.4到9.5
；且对于9-13的距离从5.8到6.3；
以上距离只取决于蛋白骨架的构象。但在某些情况中，侧链自身的构象也同样重要。例如，计算显示出在低能量构象方面，UG(SP301)，[Glu2]一UG(SP303)，[Glu3]-UG(SP304)，和[Glu2，Glu3]-UG(SP302)的骨架之间没有构象差异。但是，在第三位Asp的β羧基和Glu的γ羧基之间，在空间位置上有显著的差异。即第三位Glu残基的γ羧基明显比相应Asp残基的β羧基向分子堆积“以外”伸出得更远。以上的观察强烈暗示第三位上带有负电的羧基基团与受体上带有正电的结合位点之间有特异的相互作用；因此，含有Glu3而不是Asp3的类似物活性应该更高。同时，为了保证这种特殊相互作用的有效性，配基 和受体之间的远程静电相互作用的整体系统必须保持十分平衡。因为与Asp2侧链相比，Glu2侧链呈现出更多的构象可能性，所以与SP304(Asp3单替换为Glu3)相比，这一平衡在SP302(两个Asp被替换为Glu)中可能有微小的改变。
能够采用表1中所述低能量构象的化合物列在表2中。所有的化合物都是[4，12；7，15]双环。
表2
1.母体化合物：尿鸟苷蛋白
SEQ ID NO：1
Asn1-Asp2-Asp3-Cys4-Glus-Leu6-Cys7-Vals-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Leu16
2.没有半胱氨酸修饰的化合物：
共有序列(SEQ ID NO：2)：
Asn1-Aaa2-Bbb3-Cys4-Glus-Leu6-Cys7-Vals-Asn9-Xxx10-yyy11-Cys12-Thr13-Zzz14-Cys15-Leu16
其中Aaa=Asp，Glu；Bbb=Asp，Glu
例外：同一分子中，Aaa和Bbb不同时都是Asp
且其中Xxx=Val，Pro；Yyy=Ala，Aib；Zzz=Gly，Ala
3.第七位的半胱氨酸被替代为巯基脯氨酸的化合物：
共有序列(SEQ ID NO：3)：
Asn1-Aaa2-Bbb3-Cys4-Glu5-Leu6-Mpt7-Val8-Asn9-Xxx10-Yyy11-Cys12-Thr13-Zzz14-Cys15-Leu16
其中Aaa-Asp，Glu；Bbb=Asp，Glu
其中Xxx=Val，Pro；Yyy=Ala，Aib；Zzz=Gly，Ala
4.半胱氨酸被替代为霉胺（β，β-二甲基半胱氨酸，Pen)的化合物：
共有序列(sEQ ID NO：4)：
Asn1-Aaa2-Bbb3-Kkk4-Glu5-Leu6-Lll7-Val8-Asn9-Xxx10-Yyy11-Mmm12-Thr13-Zzz14-Nnn15-Leu16
其中Aaa=Asp，Glu；Bbb=Asp，Glu
其中Xxx=Val，Pro；Yyy=Ala，Aib；Zzz=Gly，Ala
且Kkk，Lll，Mmm和Nnn是Cys，或Pen(例外：同一分子中，所有的这些残基不能都是Cys)
5.二硫键被内酰胺键替代的化合物：
共有序列(SEQ ID NO：5)：
Asn1Aaa2-Bbb3-Kkk4-Glu5-Leu6-Lll7-Val8-Asn9-Xxx10-Yyy11-Mmm12-Thr13-Zzz14-Nnn15-Leu16
其中Aaa=Asp，Glu；Bbb=Asp，Glu
其中Xxx=Val，Pro；Yyy=Ala，Aib；Zzz=Gly，Ala
以及所有下面的组合(Dpr是二氨基丙酸)：
Kkk是Dpr，且Mmm是Asp或Glu
Kkk是Asp或Glu，且Mmm是Dpr
Lll是Cys或Pen
Nnn是Cys或Pen
或：
Lll是Dpr，且Nnn是Asp或Glu
Lll是Asp或Glu，且Nnn是Dpr
Kkk是Cys或Pen
Mmm是Cys或Pen
表2所示的一些肽含有16个氨基酸残基，其中在Cys4和Cys13以及Cys7和Cys15半胱氨酸残基之间分别形成二硫键。这些肽与WO01/25266中描述的肽不同，而且是根据肽构象和能量计算设计的。
除此以外，表3所示的长度在13到16个氨基酸变化的肽，根据能量计算和三维结构设计，以促进生物活性构象的稳定性，并向消除生物学上无活性构象的互变现象或使其最小化。这些肽的设计目的还在于增加对于蛋白酶水解和较高温度的稳定性。这些肽的设计包括了氨基酸的修饰，这些氨基酸含有在较低pH值时带有离子电荷，如谷氨酸和天冬氨酸。
表3
x1到x9可以是任意氨基酸。在4和12以及7和15位的半胱氨酸残基之间分别形成二硫键。SEQ ID NO：18代表了使这些肽与鸟苷酸环化酶受体结合时的最小长度要求。
药物组合物和制剂
本发明的鸟苷酸环化酶受体激动剂(表2；sEQ ID NO：2-5和表3；SEQ ID NO：6-21)，以及尿鸟苷蛋白、鸟苷蛋白和/或细菌肠毒素ST，可以联合使用或与不同的赋形剂、载体或佐剂一起配制，用于口服、局部或全身的给药。肽组合物可以以溶液、粉末、悬浮液、乳剂、片剂、胶囊、透皮胶布、药膏或其他制剂形式给药。制剂和剂型形式，可以使用本领域内众所周知的方法制得。(参见，例如，Remington，sPharmaceut icalSciences，16th版，A.Oslo编，Easton，PA(1980))
依赖cGMP的磷酸二酯酶的抑制剂可以是小分子、肽、蛋白质或其他特异阻止cGMP降解的化合物。抑制性化合物包括suldinac砜、苯氮嘌呤酮、motapizone和其他阻断cGMP特异的磷酸二酯酶的酶活性的化合物。这些化合物中的一或多个可以与SEQ ID NO：2-21所示例的鸟苷酸环化酶受体激动剂、尿鸟苷蛋白、鸟苷蛋白和大肠杆菌ST肽联合使用。
载体(如磷酸缓冲盐溶液或PBS)以及其他可用于组合物组分的选择，完全处于本领域技术水平以内。除了含有一或几种鸟苷酸环化酶受体激动剂以外，这种组合物还可以结合已知能帮助给药和/或提高药物吸收的药学可接受的载体和其他成分。其他制剂，如微球体、纳米颗粒、脂质体、pegylated蛋白或肽，以及以免疫为基础的系统也可以使用。实例包括使用聚合物(例如20％w/v聚乙二醇)或纤维素的制剂、或内服制剂和pegylated肽类似物，以提高在全身的半寿期和稳定性。
治疗方法
术语“治疗”指减少或减轻受治疗者的症状，防止症状的恶化或发展，或防止疾病的发展。对于给定的受治疗者，症状的改善、恶化、恢复或发展可以由本领域技术人员通常采用的主或客观测量方法来确定。对于治疗癌症的功效可以用发病率或死亡率的改善(例如对所选群体的存活曲线的延长)来量度。因此，有效的治疗应该包括对已有疾病的治疗、通过减缓疾病的发展或使其停止来控制疾病、预防疾病的出现、降低症状数量或严重程度或其组合。使用一或多个统计上显著的标准，治疗效果可以在有对照的研究中表现出来。
具有一项或多项内科/外科的程序和/或至少一种其他化疗药剂的联合疗法可以与本发明一起实施。其他在组合疗法中有用的合适药剂包括抗炎药物如类固醇，或非类固醇抗炎症药物(NSA I DS)如阿司匹林或类似物。防治或降低复发率的预防方法也被认为是治疗。
预期对于组合物有反应的癌症包括乳腺癌、结直肠癌、肺癌、卵巢癌、胰腺癌、前列腺癌、肾癌、胃癌、膀胱癌、肝癌、食道癌和睾丸癌。更多的涉及癌变组织或者早期癌变组织、应当对至少含有一种鸟苷酸环化酶受体激动剂的治疗产生反应的疾病包括：肿瘤(例如基底细胞、嗜碱性鳞状细胞(basosquamous)、Brown-Pearce、管道(ductal)、艾利希氏肿瘤、原位、克雷布斯、梅克尔细胞、小型或非小型细胞肺、燕麦细胞、乳头状的、细支气管、鳞状细胞、移行细胞、沃克)、白血病(例如B细胞、T细胞、HTLV、急性或慢性淋巴细胞的、肥大细胞、骨髓的)、组织细胞瘤、多发性组织细胞瘤、何杰金氏疾病、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、血管角皮瘤、具嗜曙红性细胞增多的淋巴增生、硬化性血管瘤、多发性血管瘤、胺前体摄取脱羧细胞瘤、鳃瘤、恶性生长类癌综合征、类癌心脏疾病、乳腺癌肉瘤、牙骨质瘤、胆管瘤、胆脂瘤、软骨肉瘤、成软骨细胞瘤、软骨肉瘤、脊索瘤、迷芽瘤、颅咽管瘤、软骨瘤、圆柱瘤、囊腺癌、囊腺瘤、叶状囊肉瘤、无性细胞瘤、室管膜细胞瘤、尤文氏肉瘤、纤维瘤、纤维肉瘤、巨大细胞肿瘤、节状神经瘤、成胶质细胞瘤、血管球瘤、颗粒性细胞肿瘤、成雌雄嵌合细胞瘤、错构瘤、血管内皮瘤、血管瘤、血管外皮肉瘤、血管肉瘤、肝细胞瘤、岛细胞肿瘤、卡波西肉瘤、平滑肌瘤、平滑肌肉瘤、白细胞肉瘤、莱迪希氏细胞肿瘤、脂瘤、脂肪肉瘤、淋巴管瘤、淋巴管肌瘤、淋巴管肉瘤、成神经管细胞瘤、脑膜瘤、问充质细胞瘤、中肾瘤、间皮细胞瘤、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、神经上皮细胞瘤、神经纤维瘤、多发性神经纤维瘤、牙瘤、骨瘤、骨肉瘤、乳头状瘤、副神经节瘤、非嗜铬性副神经节瘤、松果体瘤、横纹肌瘤、横纹肌肉瘤、足细胞肉瘤、畸胎瘤、卵泡膜细胞肿瘤，以及其他细胞变得发育异常、永生化或转化的疾病。
发明的组合物的大丸(片)剂可以在短时间内给药。一天一次是很方便的给药计划，特别是治疗以上提到的疾病时。另一种方法是，
为给药目的，有效的日剂量可以分为多重剂量，例如每天2至12剂量。选择使用的剂量水平取决于化合物的生物有效性、活性和稳定性，给药途径，被治疗疾病的严重程度，以及需要接受治疗的受治疗者的情况。预期日剂量一般在约10微克到约2毫克(例如约100微克到1毫克)化合物每千克体重。施用的组合物的量取决于本领域技术人员所知道的因素，例如组合物的化学性质、给药途径、癌症的位置和类型及其他类似因素。接受治疗的哺乳动物可以是任何动物或人类患者。因此，根据本发明包括既有兽医的又有医疗的治疗。
本发明将在下面的非限制性实施例中作进一步描述。
实施例
材料与方法
细胞培奍：人T84结肠肿瘤细胞从美国典型培养物保藏所(ATCC)获得，在通道52。细胞生长在Ham′s F一12培养基和Dulbec co′s改良Eagle′s培养基(DMEM)的1：1混合物中，混合物添加了10％胎牛血清、100单位每毫升的青霉素、100微克每毫升的链霉素。每隔两天更换新鲜培养基，在铺满率大约为80％时分瓶。
基于T84细胞的砺定胞内cGMP水平的测定法：肽类似物由MultiplePeptideSystems，San Diego，CA和PrincetonBiomolecules La nghorne，PA定制合成。合成肽的生物活性根据以前的报道(15)测定。简要步骤如下，24孔培养板中铺满的单层细胞用250微升含50mM HEPES(pH7.4)的DMEM洗两次，在37℃用250微升含50mMHEPES(pH7.4)和1mM异丁基甲基黄嘌呤(I BMX)的DMEM预温浴10分钟，接下来用肽类似物(0.1nM到10μM)温浴30分钟。将培养基重悬，用3％的高氯酸终止反应。离心后用0.1N氢氧化钠中和，上清直接用ELISA试剂盒(Caymen Chemical，Ann Arbor，MI)测定cGMP含量。
结果
表4所示的肽定制合成，并用已发表的步骤(38)纯化(大于95％的纯度)。在基于T84细胞的测定中，对肽类似物提高细胞内cGMP 水平的能力进行测定。如表4所示，在所有被检测的类似物中，SP304(SEQ ID NO：20)使胞内cGMP的含量增加得最多。SP316(SEQ ID NO：21)的有效性排在第二，而SP301、SP302和SP303的生物活性全部较弱。在该测定中，肽类似物SP306和SP310没有活性。这些结果表明SP304是增加cGMP最有效的肽。这些结果还提示在第7位的甲硫氨酸参与[7，15]二硫键的形成，不能被青霉胺替换，且第9位的天冬酰胺残基不能替换为谷氨酰胺。
表4：在T84细胞生物测定中评价肽激动剂的生物活性。
*SP301、SP304和SP316的序列的标识所表示的序列就是与文中给出的这些类似物的氨基酸序列。
**在用1μM相应的肽激动剂处理30分钟后，观察到的T84细胞的胞内cGMP水平。SP304的数值在统计上显著，其p大于0.5。
为了检查热稳定性，10μM的肽类似物溶液在95℃加热达90分钟。在处理过程中的特定时刻，用T84细胞测定法检测样品的生物活性。加热60分钟后，SP301、SP302、SP303和SP304的生物活性没有明显改变。90分钟后，SP301、SP302和SP303的生物活性降低至他们原有活性的80％，而SP304的生物活性保持不变。这表明，与其他被检测 的肽相比，SP304对于热变性更为稳定。根据能量计算和3D结构，我们预期SEQ ID NO：1第三位带负电的侧链羧基基团，与受体上带有正电的结合位点特异地相互作用。在这种相互作用可以被增强的情况中，含有Glu3而非Asp3的类似物的活性应更高，这正是SP304的情况。同时，为了保证这种特殊相互作用的有效作用，配基和受体之间的远程静电相互作用的整体系统必须保持良好的平衡。因为与Asp2侧链相比，Glu2侧链呈现出更多的构象可能性，所以与SP304(Asp3单替换为Glu3)相比，这一平衡在sP302(两个Asp被替换为Glu)中可能有微小的改变。的确，在测定的类似物中，SP304的生物活性最好。
用T84细胞测定法，还检测了合成的肽SP301、SP302、SP303和sP304在不同pH值时的活性。尽管所有这些肽在pH值5和7之间时都使胞内cGMP产量增加，但是SP304在pH6.5和7之间使cGMP的增加最大。应重点引起注意的是大肠的生理pH也处于相似的范围内，因此预期sP304对于结肠癌的治疗应非常有效。
我们还评价了单独使用肽或者与依赖cGMP的磷酸二酯酶的抑制剂(如苯氮嘌呤酮或sulindac砜)联合使用在T84细胞测定法中提高胞内cGMP水平的量。在这些实验中，sP304与依赖cGMP的磷酸二酯酶抑制剂联合使用，对于cGMP水平的增加具有强烈的效果。与只有苯氮嘌呤酮或sulindac砜单独存在时cGMP的水平相比，合成肽SP304显著提高了cGMP水平。SP304与苯氮嘌呤酮或sulindac砜联合使用处理细胞，会导致胞内cGMP的协同性增加。这些增加在统计上显著，p值小于0.5。这些数据表明鸟苷酸环化酶受体的肽激动剂和一或多种依赖cGMP的磷酸二酯酶抑制剂联合使用，会得到比加和性增加值更高的cGMP的浓度。
尽管对于本发明已经进行了详细描述，并且提供了关于本发明的具体实施方案，但是对于本领域内那些具有一般技术的技术人员，在不脱离本发明的本质精神和范围的前提下，显然可以作多方面的改动和调整。
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Claims (6)
1.由SEQ ID NO：20的氨基酸序列组成的肽。
2.单位剂量的组合物，其包含由SEQ ID NO：20的氨基酸序列组成的鸟苷酸环化酶受体激动剂肽。
3.单位剂量形式的组合物，其包含：
a)由SEQ ID NO：20的氨基酸序列组成的鸟苷酸环化酶受体激动剂肽；和
b)选自如下组的至少一种化合物，所述组由依赖cGMP的磷酸二酯酶抑制剂、抗炎药剂、抗病毒药剂和抗癌药剂组成。
4.权利要求2或3的组合物，其中所述单位剂量形式选自如下组，所述组由片剂、胶囊、溶液和吸入剂型组成。
5.权利要求2或3的组合物，进一步包含一或多种赋形剂。
6.肽偶联物，其包含连接于由氨基酸序列SEQ ID NO：20组成的肽的聚乙二醇(PEG)。
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