CN1132578C - 降低哺乳动物血糖水平的二肽基肽酶iv效应物的用途 - Google Patents

降低哺乳动物血糖水平的二肽基肽酶iv效应物的用途 Download PDF

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CN1132578C
CN1132578C CN97194017A CN97194017A CN1132578C CN 1132578 C CN1132578 C CN 1132578C CN 97194017 A CN97194017 A CN 97194017A CN 97194017 A CN97194017 A CN 97194017A CN 1132578 C CN1132578 C CN 1132578C
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H－U·德姆思
F·罗施
J·施密德
R·P·帕里
C·H·S·麦克恩多什
R·A·佩德逊
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Abstract

本发明涉及一种方法的用途，其中，通过施用效应物来降低哺乳动物血液中二肽基肽酶(DP IV)-以及DP IV类似物-酶活性，将导致内源(或者外源施用)的促胰岛素肽(肠促胰岛素)、抑胃多肽1-42(GIP1-42)以及高血糖素样肽酰胺-17-36(GLP-17-36)(或类似地GLP-17-37或这些肽的类似物)降解至一个较低的含量。由此这些肽激素或其类似物的浓度降低(导致由DP IV和DP IV类似物-酶降解)将被减少或者延迟。由于DP IV效应物的作用，由内源性或外源性施用可得的肠促胰岛素或其类似物的提高了的稳定性改变了内源胰岛素的能力并由此刺激在被处理有机体中碳水物质的代谢。因此被处理有机体血清中血糖水平降低至低于表征高血糖的葡萄糖浓度之下。与在血中长时间高葡萄糖浓度相关的代谢异常例如糖和脂代谢的异常、葡糖尿和严重代谢性酸中毒以及糖尿病得以防止或减轻。本发明是一种降低高血糖浓度的新方法。它简单，有商业应用前景，并且它适用于治疗尤其是由高于平均血糖水平引起的人疾病的药物中。

Description

降低哺乳动物血糖水平的二肽基肽酶IV效应物的用途
本发明涉及一种降低血糖浓度的简单的方法，该方法借助对与二肽基肽酶IV的酶促活性有类似或相同的活性的酶进行抑制的效应物(底物、假底物、抑制剂、结合蛋白、抗体和其类似物)来降低血糖浓度。
除了与非特异蛋白酶解的蛋白酶有关以外，导致蛋白质特异性降解的蛋白酶为大家所熟知，这与内源性肽的功能调节(活化、失活或调节)有关[KIRSCHKE，H.，LANGNER，J.RIEMANN，S.，WIEDERANDERS，B.，ANSORGE，S.和BOHLEY，P.，溶酶体半胱氨酸蛋白酶．Excerpta，Medica(Ciba基础专题研讨75)，15(1980)；KRUSSLICH，H.-G.和WIMMER，E.，病毒蛋白酶．生物化学年度综述57，701(1987)]。
在免疫系统研究和神经肽研究中已经发现了所谓的转化酶、信号肽酶或脑腓肽酶[GOMEZ，S.，GLUSCHANKOF，P.，LEPAGE，A.，MARRAKCHI，N.和COHEN，P.美国国家科学院院报85，5468(1988)；ANSORGE，S.和SCHN，E.，组织化学82，41(1987)]。
由于氨基酸脯氨酸在许多肽激素中非常丰富且由此决定这些肽的一定结构性质，因此将脯氨酸特异的肽酶当作一种对信号肽酶的有类似功能的酶讨论[YARON，A.，在生物活性肽的蛋白水解调节中脯氨酸的作用。生物高聚物(1987)26，215；WALTER，R.，SIMMONS，W.H.和YOSHIMOTO，T.，脯氨酸特异性内肽酶和外肽酶，分子细胞生物化学30，111(1980)；VANHOOF，G.，GOOSSENS，F.，DEMEESTER，I.，HENDRIKS，D.和SCHARP S.，脯氨酸基元和它们的生物加工。FASEB期刊9，736(1995)]。由于它的例外结构，在这种肽中脯氨酸决定着它们的构象和稳定性，以阻止由非特异蛋白酶导致的降解。[KESSLER，H.，构象和生物活性。应用化学94，509(1982)]。相对地，对脯氨酸包含的序列(包括HIV-蛋白酶，cyclophylin等等)具有高度特异性能力的酶是药物化学的具有吸引力的靶。尤其是，将后脯氨酸切割的肽酶(如脯氨酰内肽酶(PEP)和二肽基肽酶IV(DP IV)的活性)与天然肽底物的生物活性的调节和它们的由这些酶的选择性切割联系起来。有人指出PEP与记忆和学习有关，并且DPIV在免疫应答期间参与信号转导[ISHIURA，S.，TSUKAHARA，T.TABIRA，T.SHIMLZU，T.，ARAHATAK和SUGITA，H.，FEBS-通讯(1990)260，131；HEGEN，M.，NIEDOBITEK，G.，KLEIN，C.E.，STEIN，H.和FLETSCHER，B.，免疫学杂志144，2908(1990)]。
除它们有突出的相似于高脯氨酸的特异性之外，在这些酶的底物的典型识别区中有能够选择性地识别氨基酸丙氨酸的高选择性。据此，人们认为含丙氨酸的肽在结构上可采用与结构类似的含脯氨酸的肽类似的构象。前不久，含脯氨酸的肽链的这类性质已通过基因点突变(脯氨酸交换丙氨酸)[DODGE R.W.和SCHERAGA，H.A.，牛胰核糖核酸酶A的脯氨酸-向-丙氨酸突变体的折叠和解折叠动力学，生物化学35(5)1548(1996)]。
在由生物活性肽的N端释放高活性二肽的地方，当脯氨酸或丙氨酸是序列中N-末端氨基酸的相邻残基时，血液循环中存在的DP IV-或DP IV类似物-的活性(例如胞质DP II具有与DP IV的几乎同样的底物特异性)是高度特异性的。因此，这种酶参与了体内多肽的活性调节[VANHOOF，G.，COOSSENS，F.，DE MEESTER，I.，HENDRIKS，D.和SCHARP
Figure C9719401700041
，S.，脯氨酸基元和它们的生物加工，FASEB期刊9，736(1995)]。
糖依赖性胰岛素释放肽：抑胃多肽1-42(GIP1-42)和胰高血糖素样肽酰胺-17-36(GLP-17-36)-它们是刺激从胰腺(肠促胰岛素)分泌葡萄糖诱导的胰岛素的激素-是DP IV的底物，因为它们分别在体外和体内从这些肽的N-末端序列释放二肽酪氨酰-丙氨酸和组氨酰-丙氨酸[MENTLEIN，R.，GALLWITZ，B.，和SCHMLDT，W.E.：二肽基肽酶IV水解抑胃多肽、胰高血糖素样肽-1(7-36)酰胺、肽组氨酸甲硫氨酸，并且在人血清中对它们的降解负责，欧洲生物化学杂志214，829(1993)]。
在哺乳动物中，在实验室条件和病理状态下，在体内降低由DPIV-或DPIV类似物-酶活性对这种底物的切割可能用于有效抑制不合乎需要的酶促活性[DEMUTH，H.-U.，在丝氨酸和半胱氨酸蛋白酶的不可逆抑制方面的最新进展，酶抑制杂志，3，249-278(1990)；DEMUTH，H.-U.和HEINS，J.，在二肽基肽酶IV(CD 26)的代谢和免疫应答中二肽基肽酶IV的催化机理(B.Fleischer，编著)R.G.Landes，生物药物出版社，Georgetown，1-35(1995)]。例如，II型真性糖尿病(以及老年性糖尿病)是基于胰岛素分泌受阻或受体功能的紊乱，除了其它因素外，这是酶解决定的分泌物浓度异常的原因[BROWN，J.C.，DAHL，M.，KWAWK，S.，MCINTOSH，C.H.S.，OTTE，S.C和PEDERSON，R.A.肽2，241(1981)；SCHMLDT，W.E.SIEGEL，E.G.，GALLWITZ，B.KUMMEL，H.，EBERT，R和CREUTZFELDT，W.，从抑胃多肽衍生的片段的促胰岛素活性的鉴定，糖尿病生理学29，591A(1986)；ADELHORST，K.，HEDEGAARD，B.B.，KNUDSEN，L.B.和KIRK，O.，胰高血糖素样肽的结构活性研究，生物化学杂志296，6275(1994)]。
按照现有技术，通过利用不同的施用形式给患者施用胰岛素(例如从牛或猪胰分离的或者由基因工程获得的材料)来治疗高血糖和与此有关的病因和后遗症。至今已知的以及较现代的治疗方法表现出高耗费以及对患者身体状况的强烈损害。经典的方法(每日进行静脉内胰岛素注射，从三十年代就已经利用)处理急性症状，但是在应用较长时间后将导致血管变形(动脉硬化)和神经性损伤[LACY，P.，脉间区细胞移植的状态，糖尿病护理16(3)76(1993)]。
更现代的方法，如皮下贮存植入物的安装(成功地计量胰岛素释放，取消每日注射)以及在功能紊乱的胰腺或其它器官和组织中植入朗氏细胞完整脉间区(移植)正在试验中。然而，这样的移植昂贵。另外，它们表示出高风险的外科手术排斥反应，并且在采用移植方法时要求进行免疫抑制或者避开免疫应答。[LACY，P.，用移植细胞治疗糖尿病，美国科学273(1)40-46(1995)]。
与上述疗法相比，尽可能地口服高效的低分子量酶抑制剂是在处理病理现象时的、一种对于例如侵害性的外科手术方法的非常有效的替代选择方案。这类酶抑制剂找到了在治疗中的用途，以用作抗高血压药物、免疫抑制药物以及抗艾滋病毒剂。通过对分子的稳定性、转录和裂变性质进行化学设计，可以改进它们的功效，并且使它们在有机体之间适应个体的区别。[SANDLER，M.和SMLTH，H.J.，编著，作为药物的酶抑制剂的设计，牛津大学出版社，牛津大学(1989)；MUNROE，J.E.，SHEPHEAD，T.A.，JUNGHEIM，L.N.，HORNBACK，W.J.，HATCH，S.D.，MUESTNG，M.A.，WISKERCHEN，M.A.，SU，K.S.，CAMPANALE，K.M.，BAXTER，A.J.和COLACINO，J.M.，包含非编码的D-氨基酸的有效的口服的HIV-1蛋白酶抑制剂，生物药物化学通讯5(23)2987(1995)]。
本发明的目的是提供一种降低血糖水平的简单的并且新的方法，其中通过给哺乳动物服用酶的效应物，使所说酶的效应物诱导DP IV-酶的或者DPIV类似物-酶的活性降低，这将导致内源的(或外源施用的)促胰岛素肽抑胃多肽1-42(GIP1-42)和胰高血糖素样肽酰胺-17-36(GLP-17-36或这些肽的类似物)的降解减少。因此，将阻止或者延迟这些肽激素或它们类似物在浓度上的减少。
本发明基于这样一个惊人的发现：在血液循环中，二肽基肽酶DPIV酶的或者DPIV类似物-酶的活性降低将导致改进的葡萄糖耐受性。我们观察到：
1.降低二肽基肽酶DPIV-或DPIV类似物-酶活性导致葡萄糖刺激的内源释放的或外源施用的肠降血糖素(或其类似物)稳定性相对地提高，因此通过服用DPIV-或DPIV类似物-蛋白质的活性抑制效应物，可以控制肠降血糖素在血液中的降解。
2.肠降血糖素(或其类似物)的提高了的生物降解稳定性导致胰岛素作用效果改进。
3.由降低二肽基肽酶DPIV-或DPIV类似物-酶活性引起的肠降血糖素稳定性的升高将导致葡萄糖诱导的胰岛素作用随后改变，且借此导致一种可借助DPIV效应物控制性调节的血糖水平。
因此，本发明涉及二肽基肽酶DPIV-或者DPIV类似物-酶活性的活性抑制效应物的用途，用于将血糖水平降低至哺乳动物血中表征高血糖水平的葡萄糖浓度之下。本发明尤其涉及DPIV-或DPIV类似物-酶活性效应物在预防或者减轻哺乳动物代谢中的病理变态如葡糖尿、超脂血症、代谢性酸中毒和糖尿病中的应用。在一个更优选的实施方案中，本发明涉及降低哺乳动物血中血糖浓度至表征高血糖水平的葡萄糖浓度之下的方法。其特征在于，给哺乳动物服用治疗有效量的二肽基肽酶DPIV-或DPIV类似物-酶活性的效应物。
在第二个优选的实施方案中，本发明涉及二肽基肽酶DPIV-或DPIV类似物-酶活性的活性抑制效应物，它用于降低哺乳动物血中血糖浓度至表征提高血糖葡萄糖浓度之下的方法中。
按照本发明，施用的DPIV-和DPIV类似物-酶的活性抑制效应物作为酶抑制剂、底物、假底物、DPIV-表达物的抑制剂、结合蛋白或所说的酶蛋白的抗体或者作为这些不同化合物的组合体用于可用作药物的配方复合体中，这些效应物减少在哺乳动物中DPIV-和DPIV类似物-蛋白质的浓度。按照本发明的效应物例如是DPIV-抑制物如二肽衍生物或如丙氨酰-吡咯烷酰胺(pyrolidid)、异亮氨酰-四氢噻唑之类的二肽模仿物，以及假底物N-结氨酰-脯氨酰，O-苯甲酰羟胺。这些化合物从文献中是已知的[DEMUTH，H.-U.，在丝氨酸以及半胱氨酸蛋白酶的不可逆抑制方面的最新进展，酶抑制杂志3,249(1990)]，或者可以按照文献所描述的方法进行合成。
按照本发明的方法是一种降低哺乳动物血液中升高了的血糖浓度的新方法。本方法简单、制药学上有用，并且适用于制备治疗尤其是人类疾病的药物，这些疾病是基于超过正常血糖水平引起的。
将效应物以药物制剂形式进行施用，该制剂包含有效成分和常规的、从现有技术已知的载体材料。例如将它们以肠胃外(静脉内，以生理盐溶液)或经肠道(口服，与通常的载体材料形成配方)施用。
取决于效应物的内源稳定性和生物利用率，要进行一次或多次给药，以达到所预期的血糖浓度正常化。例如在用氨基酰基-四氢噻唑的情况下，剂量可以在1.0-10.0mg效应物物质/kg的范围内变化。
实施例
实施例1.在体内肠促胰岛素GIP-1-42和GLP-17-36的DPIV-催化水解的抑制作用
体内利用纯化的酶或现场利用混合人血清可以证明，由DPIV-和DPIV类似物-酶促活性引起的肠促胰岛素的水解、或借助抑制剂可对它进行抑制(图1)。
按照本发明，在体内通过温育30μM GIP1-42或30μM GLP-17-36和20μM异亮氨酰-四氢噻唑(1a)，在24小时内实现对两种肽激素的酶催化水解的完全抑制(1b和1c，各见上面谱图)，上述温育物在pH7.6和30℃下是在20％混合血清中的可逆DP IV-抑制物。在pH7.6和30℃下，将合成的抑胃多肽GIP1-42(5μM)和合成的GLP-17-36(15μM)用在0.1mM TRICINE缓冲液中的人血清(20％)温育24小时。在不同时间间隔之后，取出温育分析样品(对于GIP1-42 2.5pmol，对于GLP-17-367.5pmol)。将样品利用2′，6′-二羟乙酰苯酮作为基质进行共结晶，并且通过MALDI-TOF-质谱分析法进行分析。谱图(图l)显示，每样品中有250个单个激光激发的积累。
(1b)在范围m/z 4980.1±5.3中的信号对应于GIP1-42(M4975.6)，并且在范围m/z 4745.2±5.5中的信号对应于DPIV-水解产物GLP-13- 42(M4740.4)。
(1c)信号m/z 3325.0±1.2对应于GLP-17-36(M3297.7)，并且信号m/z 3116.7±1.3对应于DPIV-水解产物GLP-19-36(M3089.6)。
在不包含任何抑制剂的参照分析试样中，在这种时间内肠促胰岛素几乎完全降解(图1b和1c，各见下面的谱图)。
实施例2.通过体内的DPIV-抑制剂异亮氨酰-四氢噻唑抑制GLP-17-36的降解
与一个对照样相对照，跟踪分析鼠血清中天然肠促胰岛素(此处为GLP-17-36)的代谢对DPIV-抑制剂异亮氨酰-四氢噻唑(静脉内注射包含1.5μM抑制剂的0.9％食盐溶液)的依赖关系。在用抑制剂处理过的供试动物(N＝5)中，以浓度为每千克供试鼠用0.1mg抑制剂异亮氨酰-四氢噻唑试验时，促胰岛素肽激素GLP-17-36在实验期间没有观察到发生了降解(图2)。
在存在和不存在DPIV-抑制剂时，为了检测肠促胰岛素的代谢物，在开始静脉内施用抑制剂或食盐水20分钟后，将供验和参照动物进一步静脉内注射50-100pM125I-GLP-17-36(大约1μCi/pM比活)。温育2-5分钟后收集血样，并且利用20％乙腈提取原生质。随后，在RP-HPLC上分离所说的肽提取物并且在γ-计数器上分析样品的放射活性。将实测数据表达为相对于最大值的每分钟计数次数(cpm)。实施例3.在体内静脉内施用DPIV-抑制剂异亮氨酰-四氢噻唑后胰岛素作用的调节和血糖水平的下降。
在通过对十二指肠内(i.d.)注射葡萄糖刺激的鼠身上，可通过体内施用不同的DPIV-效应物例如每千克鼠重0.1mg异亮氨酰-四氢噻唑，观测到归因于抑制剂效果的、时间上延迟发生作用的葡萄糖水平下降。这种效果取决于剂量，且在停止注射每千克鼠重0.05mg/分钟DPIV-抑制剂异亮氨酰-四氢噻唑后，效果是可逆的。与十二指肠内葡萄糖刺激的供试动物相反，将抑制剂处理的和对照用的动物作静脉内施用相同量的葡萄糖后，没有观察到可比的作用。图3显示了这些抑制剂依赖性的原生质参数的改变：A-DPIV-活性、B-原生质-胰岛素水平、C-血糖水平。
试验动物(N＝5，雄性Wistar-鼠，200-225g)最初获得含于0.9％食盐溶液中的1.5μM异亮氨酰-四氢噻唑(▲)或不含抑制剂的相同体积0.9％食盐溶液(■)(对照组，n＝5)。试验组在30分钟实验时间内另外获得0.75μM/分钟的抑制剂注射(*)。将对照组在相同的时间间隔期间注入0.9％的无抑制剂的食盐溶液。在开始时间T＝0时，将所有动物十二指肠内施用葡萄糖剂量为1g/kg  40％的葡萄糖溶液(w/v)。
在10分钟时间间隔内收集所有试验动物的血样。当在原生质中的DPIV-活性和胰岛素浓度被分析时，利用全血(Lifescan One Touch II分析器)分析葡萄糖含量。
所采用的胰岛素测定法在10至160mU/ml的范围内是敏感的[PEDERSON，R.A.，BUCHAN，A.M.J.，ZAHEDI-ASH，S.，CHEN，C.B.和BROWN，J.C.Reg.Peptides.3，(1982)]。通过光谱分析法确定DPIV-活性[DEMUTH，H.-U.和HEINSIJ.，二肽基肽酶IV(CD26)在代谢和免疫应答中二肽基肽酶IV的催化机理，(B.Fleischer，编)R.G.Landes，生物医学出版社，Georgetown，1-35(1995)]。所有数据以平均值加标准偏差给出。

Claims (4)

1.二肽基肽酶IV或二肽基肽酶IV样-酶活性的活性抑制效应物用于制备药物的用途，所述药物用于将哺乳动物血清中的血糖水平降低至表征高血糖的葡萄糖浓度之下。
2.按照权利要求1的用途，其特征在于，所述药物用于预防或者减轻下列哺乳动物代谢病理变态：葡糖尿，高脂血症，代谢性酸中毒和糖尿病。
3.按照权利要求1的用途，其特征在于，其中所述能够抑制二肽基肽酶IV或二肽基肽酶IV样-酶活性的效应物可采用所述酶的抑制剂、底物、假底物、二肽基肽酶-表达物抑制剂、这些酶蛋白的结合蛋白质或者抗体、或者所说效应物的组合物。
4.按照权利要求1的用途，其特征在于，所述效应物是异亮氨酰-四氢噻唑。
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