CN1466456A - 用作诊断和治疗靶点的sgk2和sgk3 - Google Patents
用作诊断和治疗靶点的sgk2和sgk3 Download PDFInfo
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- CN1466456A CN1466456A CNA018163351A CN01816335A CN1466456A CN 1466456 A CN1466456 A CN 1466456A CN A018163351 A CNA018163351 A CN A018163351A CN 01816335 A CN01816335 A CN 01816335A CN 1466456 A CN1466456 A CN 1466456A
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Abstract
本发明涉及可检测sgk2和/或sgk3的物质用于诊断与离子通道活性、尤其是钠通道和/或钾通道活性有关之疾病的用途。本发明还涉及活性成分用于治疗上述疾病的用途，所述活性成分可以影响sgk2和/或sgk3的表达和/或功能，从而调节Na+和/或K+的消除。优选的活性成分是星形孢菌素和/或白屈菜红碱。
Description
本发明涉及用于诊断性检测血清和糖皮质激素依赖性激酶2和/或3(sgk2和/或sgk3)的物质的用途，并且涉及作用于sgk2和/或sgk3的活性成分用于治疗性处理与离子通道尤其是与钠离子和/或钾离子通道活性紊乱有关的疾病的用途。所涉及的sgk代表受到转录和转录后调控的丝氨酸/苏氨酸蛋白激酶家族。
细胞受到多种外部信号的作用，这些外部信号引起细胞内部的磷酸化/去磷酸化级联反应，从而使得可快速、可逆地将所涉及的信号从质膜及其受体向细胞质到细胞核传递。对参与这些级联反应的个体蛋白质的调节一开始是高特异性的，且细胞的柔性使得它们可快速对胞外信号反应。血清和糖皮质激素依赖性激酶(sgk)最初是从大鼠的乳房癌细胞中克隆得到(Webster等人，1993a，1993b)。人的血清和糖皮质激素依赖性激酶(hsgk)以细胞容量调节基因的形式克隆自肝细胞(Waldegger等人，1997)。据发现(Chen等人，1999；Naray-Fejes-Toth等人，1999)大鼠激酶刺激上皮Na+通道(ENaC)。另据显示(Warnock，1998)高血压伴随着ENaC的活性升高。
hsgk也在脑中表达(Waldegger等人，1997)，其中电压依赖性K+通道Kv1.3在神经兴奋性调节中起了决定性的作用(Pongs，1992)。Kv1.3在调控细胞增殖(Cahalan和Chandy，1997)和程序性细胞死亡(Szabo等人，1996；Lang等人，1999)也起了主要作用。Kv1.3对淋巴细胞的增殖和功能的调控也很重要(Cahalan和Chandy，1997)。两个血清和糖皮质激素依赖性激酶家族的其他成员sgk2和sgk3最近也被克隆(Kobayashi等人，1999)。与sgk1一样，sgk2和sgk3也是由胰岛素和IGFI经由PI3激酶途径激活。但是到目前为止，还没有得知这两种新激酶的其他特征和其功能性的用途。
因此，本发明提出了使sgk2和sgk3这两种激酶可用于诊断性和治疗性目的的问题。
在运用双电极电压夹的实验中，出乎意料地发现hsgk2或hsgk3的共表达引起上皮Na+通道(EnaC)活性的大幅提高。上皮Na+通道在肾脏排除Na+的过程中起着决定性的作用，从而影响着血压的变化。激酶sgk3也在大脑中表达，在运用双电极电压夹的实验中，同样显示hsgk2或hsgk3的共表达可以大幅提高K+通道Kv1.3的活性。因为K+通道的活化引起神经兴奋性降低，获得的这些功能性数据指示出sgk3的功能有助于降低神经元兴奋性。Sgk3的表达或功能紊乱因此可能是引起癫痫发作的原因。反过来，可穿过血脑屏障的sgk3表达或活性刺激物可成功地用于癫痫发作的结论得到证明。最后，发现在心脏中表达的K+通道minK被sgk1、sgk2和sgk3激活。因此这些激酶在心脏兴奋性调节上起作用。
鉴于此，本发明所提出的问题可由独立权利要求1、2、13和17的主题解决。优选的实施方案在从属权利要求3-12、14-16和18-23中阐述。所有权利要求的内容均通过引用的方式构成说明书内容不可分割的一部分。
根据本发明，至少有一种物质可用于检测sgk2或sgk3在真核细胞中的表达和/或功能，具体地讲，该物质还可以诊断那些与离子通道例如钠通道和钾通道活性紊乱有关的疾病。这种物质可以是如直接抗sgk2或sgk3的抗体，并可用于本领域技术人员众所周知的检测方法，如酶联免疫吸附试验(ELISA)。在此类免疫测定中，直接抗待检测抗原(sgk2和sgk3)的特异性抗体(或者，在抗体鉴定的情况下，为同源试验抗原)结合至载体物质(如纤维素或聚苯乙烯)上，孵育后，与样本在载体物质上形成免疫复合体形式。在下一步，这些免疫复合体与一个经过标记的抗体结合。向此基础反应物中加入生色底物可以使连接在这些免疫复合体上的酶—底物复合体显色，或者通过与具有已知的酶催化活性的标准品比较，由光度测量法确定与这些免疫复合体结合的标记物酶的浓度而确定出样本中的抗原浓度。其它可用于诊断—检测目的的物质是寡核苷酸，其在聚合酶链反应(PCR)的协助下，运用分子遗传学方法，适于定量检测sgk2和sgk3，在这种方法下，特定DNA片断得到选择性的扩增。其它用于定量检测已知目的蛋白质的方法是本领域技术人员众所周知的。
根据本发明，要求对以治疗与离子通道尤其是钠通道和/或钾通道活性紊乱有关的疾病为目的的、用于影响尤其是抑制或激活sgk2和sgk3在真核细胞中的表达和/或功能的活性成分享有专利权。因为sgk2和sgk3是激酶，故已知的激酶抑制剂如星形孢菌素(staurosporine)、白屈菜红碱等物质以及其它物质代表了活性成分的候选物质。本领域技术人员知道这类抑制剂，且它们中的一部分可以从Sigma或Merck等公司购买到。遗传改变的sgk2和/或sgk3突变体可例如用作活化剂。
根据本发明，所涉及的离子通道可为ENaC亚型的钠通道，其中sgk2和/或sgk3的抑制或活化优选影响Na+通过该通道的转运，这可以影响例如血压。sgk2和/或sgk3的过度表达或过度活化会引起肾脏钠潴留，从而引起高血压的发生。因此血压可由相关激酶的活化或去活化得到调节。
在优选的实施方案中，所涉及的离子通道为Kv1.3亚型的钾通道。具体地讲，其作用涉及到sgk2和/或sgk3的抑制或活化，优选影响K+通过Kv1.3亚型钾通道的转运。在其它优选的实施方案中，所涉及的离子通道为minK亚型的钾通道，在这此情况下，抑制或激活sgk1、sgk2和/或sgk3将影响K+通过minK亚型钾通道的转运。
在本发明的优选实施方案中，活性成分直接对抗sgk2和/或sgk3本身。所涉及的活性成分因此可为反义序列、称为“激酶缺陷型突变体”的物质或激酶抑制剂，例如星形孢菌素和/或白屈菜红碱或其类似物。也可使用那些能够影响sgk2和/或sgk3表达的所谓“小分子化合物”或编码肽的多聚核苷酸。
在本发明的另一个优选实施方案中，活性成分直接对抗sgk2和/或sgk3的激活物、抑制物、调节物和/或生物学前体。这些sgk2和/或sgk3的激活物、抑制物、调节物和/或生物学前体可为sgk信号转导级联反应的上游和下游成员、影响sgk2和/或sgk3表达水平的转录因子、或者至今不知道的受活性成分影响并且参与sgk2和/或sgk3的表达和/或功能的分子。
本发明允许运用已知的或至今未知的活性成分。在一个特别优选的实施方案中，活性成分为所谓的“小分子化合物”，尤其是其分子量(MW)小于1000的化合物。所涉及的“小分子化合物”可为激酶抑制剂，例如分子量为377.4的咪唑衍生物SB203580或分子量为331.3的咪唑衍生物SB202190，它们都是已知的激酶表达抑制剂并且由美国的Calbiochem.SanDiego，CA上市销售。
本发明可用于治疗与钠通道和/或钾通道活性紊乱有关的所有疾病。尤其值得注意的是动脉高血压以及与Liddle综合征相应的症状，其中所述Liddle综合征是一种罕见的、遗传性的ENaC过度活化，并且因此为伴有血压大幅升高的疾病。
就目前所了解的，可通过本发明的方法治疗的与钾通道活性尤其是Kv1.3和/或minK亚型的钾通道活性紊乱有关的疾病包括癫痫症、神经变性、自身免疫性疾病和免疫缺陷。具体地讲，mink通道紊乱可以造成心律波动。
本发明也涉及以诊断与离子通道，尤其是钠通道和/或钾通道紊乱有关的疾病为目的的包含至少一种适合于检测sgk2和/或sgk3的表达和/或功能的物质的诊断试剂盒。这样的试剂盒也可以用于诊断与sgk2和/或sgk3过量表达、低表达、功能亢进或功能不足有关的疾病。这样的诊断法可与诊断试剂盒结合用来检测疾病，例如动脉高血压、Liddle综合征、自身免疫性疾病和免疫缺陷。在后一种情况下，疾病也是通过检测sgk2和/或sgk3的表达和/或功能紊乱而检测的。
本发明也包括含有至少一种影响、尤其是抑制或激活sgk2和/或sgk3表达和/或功能的活性成分的药物组合物，并且如果需要，优选还含有药物载体。所涉及的活性成分可为激酶抑制剂，例如前面提到的星形孢菌素、白屈菜红碱、SB203580、SB202190及它们的类似物之一或一些其它物质。所涉及的活性成分也可为编码影响、优选抑制或激活sgk2和/或sgk3表达的肽、优选多肽的多聚核苷酸。这种多肽例如可为所谓的“激酶缺陷型突变体”。所涉及的活性成分也可为所谓的“小分子化合物”，优选分子量小于1000的小分子。最后，所涉及的活性成分也可为反义序列，即可以与mRNA结合形成双链结构从而阻止mRNA翻译成多肽的序列。也可使用sgk2和sgk3序列本身，以通过例如掺入含有强启动子的载体来引起这些激酶的过量表达。关于该组合物的其他特征，可以参见本说明书上文的相关部分。
最后，本发明包括含有至少一种有效量的活性成分的药物组合物，其中活性成分可以影响、尤其是抑制或激活sgk2和/或sgk3的激活物、抑制物、调控物和/或生物学前体的表达和/或功能。所述药物组合物优选还包含药物载体。sgk2和/或sgk3的这些激活物、抑制物、调控物和/或生物学前体可以是诸如其它参与调控或激活sgk2和/或sgk3的激酶。转录因子影响着sgk2和/或sgk3以及sgk2和/或sgk3信号转导级联中其它已知或仍然未知的成员的表达水平。该组合物也可含有编码影响、尤其是抑制或激活sgk2和/或sgk3的激活物、抑制物、调控物和/或其生物学前体表达的肽的多核苷酸。也可使用所谓的“小分子化合物”，其分子量(MW)优选小于1000并且可直接作用于sgk2和/或sgk3的激活物、抑制物、调控物和/或其生物学前体，从而抑制或激活那些激酶的表达或功能。
可以从以下对优选实施方案的描述并结合权利要求及附图看出本发明现存的特点和其它特点，其中的各单个特点可以独立或相互组合而实现。
附图描述：图1：用hsgk2和hsgk3刺激Na+通道γ-ENaC。图2：用hsgk2和hsgk3刺激K+通道Kv1.3。图3：抑制K+通道Kv1.3对人胚肾细胞(HEK-细胞)存活的影响。
材料和方法
爪蟾的解剖和以及卵母细胞的获得和处理在以前已经详细描述过(Busch等人，1992)。对各卵母细胞注射1ng来自α-ENaC、β-ENaC和γ-ENaC、Kv1.3或minK的cRNA，同时向其中注射或不注射激酶hsgk1、hsgk2和hsgk3。在注射后2至4天内进行双电极电压夹和电流夹实验。在10赫兹滤出Na+电流(在EnaC的情况下)和K+电流(在Kv1.3和minK的情况下)并用记录仪记录。实验通常在注射cRNA后的第二天进行。槽液含有96mM NaCl、2mM KCl、1.8mM CaCl2、1mM MgCl2和5mM HEPES，pH为7.5，持续电位-80毫伏。在所有实验中，槽液的pH值用HCl或NaOH滴定确定。槽液流速设定为20毫升/秒钟，可在10至15分钟内完全更换溶剂。所有数据以算术平均值±SEM的形式给出。结果
为了研究hsgk1、hsgk2或hsgk3的作用，将各个激酶的mRNA分别与上皮Na+通道、α-ENaC、β-ENaC和γ-ENaC或电压依赖性K+通道Kv1.3或minK通道的mRNA一起注入非洲爪蟾的卵母细胞并随后测定阿米洛利敏感性Na+电流INa和电压激活的K+电流IK。从下表1以及图1和图2中可以看出，hsgk2和hsgk3都可刺激ENaC和Kv1.3的活性。hsgk1可刺激minK的活性(表1)。它们的刺激作用完全被蛋白激酶抑制剂星形孢菌素和白屈菜红碱阻止。
表1：
表1：在卵母细胞中注入(去离子)水、注入α-ENaC、β-ENaC和γ-ENaC、注入Kv1.3或minK，含或不含hsgk1、hsgk2或hsgk3的Na+电流(INa)[μA]和K+电流(Ik)[μA]实验1：
| 无激酶 | hsgk1 | hsgk2 | hsgk3 | N | |
| α-ENaC、β-ENaC和γ-ENaC INa | 2.5±0.3 | 5.9±1.0 | 9.4±1.7 | 4.5±0.8 | 7 |
| Kv1.3 IK | 3.1±0.6 | 8.4±1.8 | 6.5±0.6 | 8.2±0.7 | 7 |
| MinK IK | 0.67±0.07 | 1.16±0.11 | 0.97±0.1 | 1.1±0.11 | 7 |
可以从图1中看出，在注入来自hsgk2和hsgk3的mRNA后，由于hsgk2和hsgk3的共表达，通过Na+通道γ-ENaC的阿米洛利抑制性电流Iamil显著增大。激酶抑制剂星形孢菌素和白屈菜红碱可抑制Na+通道的激活(参见图1)。由于hsgk2和hsgk3对ENaC通道的刺激作用可以被激酶抑制剂星形孢菌素和白屈菜红碱阻止，因此，(a)诊断性检测sgk2或sgk3的表达或功能的紊乱代表了发现诸如高血压发生原因的主要测量方法，并且(b)Sgk2和sgk3的抑制剂例如星形孢菌素、白屈菜红碱或其它的激酶抑制剂可用于上述疾病的治疗。实验2：
在联合注射来自于hsgk1、hsgk2或hsgk3的mRNA与来自K+通道Kv1.3或minK的mRNA后，可以显示通过这些通道的电流I可以升高(参见表1)。图2代表在hsgk2和hsgk3的mRNA与来自于Kv1.3的mRNA同时注射后，第一天(d1，最左边的条)和第五天(d5，最右边的条)的实验结果。由于钾通道的活化会引起神经兴奋性的降低，因此，这些功能性的数据表明，对脑中表达的hsgk3的影响可用于降低神经元的兴奋性。sgk3的表达或功能的紊乱因此可能引起癫痫发作。反过来，可穿过血脑屏障的sgk3的表达或功能的刺激物可用于癫痫发作。基于同样的考虑，可以通过刺激或抑制激酶、尤其是hsgk1来影响心脏兴奋性的紊乱。实验3：
根据图3，从人胚肾细胞(HEK-细胞)中除去胎牛血清(FCS)(Lewis等人(1984)；Phillips等人(1982))会由于细胞死亡而引起细胞总数的减少，这可以从黑色条和点状条的比较看出，图3描绘了24小时和48小时后的情况。这种减少可以通过加入胰岛素样生长因子(IGF1)而减弱，如图中的白色条所示。同时用玛格毒素(MT)抑制K+通道可以消除胰岛素样生长因子1的作用，在图中用带阴影线的条表示。这些数据表明，胰岛素样生长因子IGF1在K+通道受到抑制时会失去其抑制细胞死亡的作用。因此由sgk2和sgk3介导的Kv1.3通道的激活有抗细胞凋亡效应，并且缺乏sgk2和sgk3的作用会引起细胞死亡率的增加，就像在神经变性时所发生的一样。反过来，sgk2和sgk3的激活物可能用于阻止神经变性时的程序性细胞死亡。由于Kv1.3在淋巴细胞增殖和功能的调控中也起重要作用，这些激酶的抑制剂或激活物可在患有例如自身免疫性疾病或免疫缺陷的个体中用于影响免疫系统。
参考文献：1、A.E Busch，M.P.Kavenaugh，J.P.Adelman和R.A.North：“第二信使对在非洲爪蟾卵母细胞中产生的慢活化电压依赖性钾电流的调节”J.Physiol.Lond.450(1992)，491-502页。2、M.D.Cahalan和K.G.Chandy：“在免疫系统中离子通道作为免疫抑制的靶点”Cur.Opin.Biotech.8(6)(1997)，749-756页。3、S.Y.Chen，A.Bhargava，L.Mastroberardino，O.C.Mejier，J.Wang，P.Buse，G.L.Firestonea，F.Verrey和D.Pearce：“醛固酮诱导的蛋白sgk对上皮钠通道的调节”Proc.Nat.Acad.Sci.USA 96(1999)，2514-2519页。4、T.Kobayashi，M.Deak，N.Morrice和P.Cohen：“两种新同工型血清和糖皮质激素诱导的蛋白激酶的结构和调节特征”Biochem.J.344(1999)，189-197页。5、F.Lang，I.Szabo，A.Lepple-Wienhues，D.Siemen和E.Gulbins：“受体介导的淋巴细胞凋亡的生理学”News Physiol. Sci.14(1999)，194-200页。6、M.L. Lewis，D.R.Morrison，B.J.Mieszkuc和D.L.Fessler：“在生物鉴定来自培养的HEK细胞产物纤溶酶原激活物中的问题”Adv.Exp.Med.Biol，172(1984)，241-267页。7、A.Naray-Fejes-Toth，C.Canessa，E.S.Cleaveland，G.Aldrich和G.Fejes-Toth：“sgk是在肾集合管中作用于上皮Na+通道的醛固酮诱导的激酶。”J.Biol.Chem.274(1999)16973-16978页。8、S.G.Phillips，S.L. Liu和D.M.Phillips：“上皮细胞与外源凝集素包被表面的结合”In Vitro 18(1982)，727-738页。9、O.Pong：“电压依赖性钾通道的分子生物学”Physiol.Rev.72(1992)，S69-S88页。10、I.Szabo，E.Gulbins，H.Apfel，X.Zhan，P.Barth，A.E.Busch，K，Schlottmann，O.Pong和F.Lang：“Fas刺激后，对T淋巴细胞的电压控制开闭的K+通道酪氨酸磷酸化依赖性的抑制”J.Biol.Chem.271(1996)，20465-20469页。11、S.Waldegger，P.Barth，G.Raber和F.Lang：“在不等渗和等渗改变细胞容量过程中推定的转录修饰的人丝氨酸/苏氨酸蛋白激酶的克隆和特征”Prof.Nat.Acad.Sci.USA 94(1997)，4440-4445页。12、D.G.Warnock：“Liddle综合征：人类高血压的一种常染色体显性形式”Kideny Ind.53(1998)，18-24页。13、M.K.Webster，L.Goya和G.L. Firestone：“推定的丝氨酸/苏氨酸蛋白激酶的立即早期转录调控和mRNA快速转换”J.Biol.Chem.268(16)(1993a)，11482-11485页。14、M.K.Webster，L.Goya，Y.Ge，A.C.Maiyar和G.L.Firestone：“一个由糖皮质激素和血清诱导转录的丝氨酸/苏氨酸蛋白激酶家族新成员sgk的特征”Mol.Cell Biol.13(4)(1993b)，2031-2040页。
Claims (23)
1、一种用以检测sgk2和/或sgk3在真核细胞中表达和/或功能的物质用于诊断与离子通道活性、尤其是钠通道和/或钾通道活性紊乱有关之疾病的用途。
2、一种用于在真核细胞中影响、尤其是抑制或激活sgk2和/或sgk3的表达和/或功能的活性成分用于治疗与离子通道活性、尤其是钠通道和/或钾通道活性紊乱有关之疾病的用途。
3、据权利要求2的用途，其中，对sgk2和/或sgk3的影响、尤其是抑制或激活，可以影响和/或控制Na+和/或K+的清除。
4、根据以上权利要求中任意一项所述的用途，其中的离子通道是ENaC亚型的钠通道。
5、根据以上权利要求中任意一项所述的用途，其中的离子通道是Kv1.3亚型的钾通道。
6、根据权利要求2-5中任意一项所述的用途，其中的活性成分直接针对sgk2和/或sgk3。
7、根据权利要求2-6中任意一项所述的用途，其中的活性成分直接针对sgk2和/或sgk3的激活物、抑制物、调节物和/或生物学前体。
8、根据权利要求2-7中任意一项所述的用途，其中的活性成分是激酶抑制剂，优选星形孢菌素和/或白屈菜红碱或它们类似物。
9、根据权利要求2-8中任意一项所述的用途，其中的活性成分是编码肽、优选多肽的多核苷酸，其中所述的肽可以影响、优选抑制或激活sgk2和/或sgk3的表达。
10、根据权利要求2-9中任意一项所述的用途，其中的活性成分是一种“小分子化合物”，优选分子量MW小于1000的“小分子化合物”。
11、根据以上权利要求中任意一项所述的用途，其中所述的疾病、尤其是与钠通道活性紊乱有关的疾病是动脉高血压或与Liddle综合征有关的症状。
12、根据以上权利要求中任意一项所述的用途，其中所述的疾病、尤其是与钾通道活性紊乱有关的疾病是癫痫症、神经变性、自身免疫性疾病或免疫缺陷。
13、用于诊断与离子通道活性、尤其是钠通道和/或钾通道活性紊乱有关的疾病的、包含至少一种用于检测sgk2和/或sgk3的表达和/或功能的物质的诊断试剂盒。
14、根据权利要求13的诊断试剂盒，其用于诊断与sgk2和/或sgk3过量表达和/或低表达有关的疾病。
15、根据权利要求13或权利要求14的诊断试剂盒，其用于诊断动脉高血压或与Liddle综合征有关的症状。
16、根据权利要求13或权利要求14的诊断试剂盒，其用于诊断癫痫症、神经变性、自身免疫性疾病或免疫缺陷。
17、包含有效量的至少一种活性成分的药物组合物，其中所述的活性成分可以影响、尤其是抑制或激活sgk2和/或sgk3的表达和/或功能，且根据需要，该药物组合物还可包含药物载体。
18、根据权利要求17的药物组合物，其中的活性成分是激酶抑制剂，优选星形孢菌素和/或白屈菜红碱或它们的类似物。
19、根据权利要求17的药物组合物，其中的活性成分是编码肽、优选多肽的多核苷酸，其中所述的肽可以影响、优选抑制或激活sgk2和/或sgk3的表达。
20、根据权利要求17的药物组合物，其中的活性成分是一种“小分子化合物”，优选分子量MW小于1000的“小分子化合物”。
21、根据权利要求17的药物组合物，其包含有效量的至少一种活性成分，其中的活性成分影响、尤其是抑制或激活sgk2和/或sgk3的激活物、抑制物、调控物和/或生物学前体的表达和/或功能，且根据需要，该药物组合物还可包含药物载体。
22、根据权利要求21的药物组合物，其中的活性成分是编码肽、优选多肽的多核苷酸，其中所述的肽可以影响、优选抑制或激活sgk2和/或sgk3的激活物、抑制物、调控物和/或生物学前体的表达。
23、根据权利要求21的药物组合物，其中的活性成分是一种“小分子化合物”，优选分子量MW小于1000的“小分子化合物”。
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