CN1822851A - 肽和多肽药物的稳定类似物 - Google Patents
肽和多肽药物的稳定类似物 Download PDFInfo
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- CN1822851A CN1822851A CNA2004800198500A CN200480019850A CN1822851A CN 1822851 A CN1822851 A CN 1822851A CN A2004800198500 A CNA2004800198500 A CN A2004800198500A CN 200480019850 A CN200480019850 A CN 200480019850A CN 1822851 A CN1822851 A CN 1822851A
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- CN
- China
- Prior art keywords
- peptide
- analog
- protease
- polypeptide
- disease
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000000034 method Methods 0.000 claims abstract description 84
- 238000002360 preparation method Methods 0.000 claims abstract description 29
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Abstract
本发明涉及抗蛋白酶水解的肽和多肽类似物的组合物、其药学用途及其制备方法。
Description
发明背景
多肽和肽药物被广泛应用于医疗实践中,它们易于制备(或用重组DNA技术或肽合成的方法),保证了它们在未来的数年内仍然能够在各种情况下使用。多肽药物,如激素、细胞因子和生长因子是治疗性药物的重要组成部分。然而,某些天然多肽在体内会因蛋白水解和异构化作用迅速失活。当人们期待药物一段时间内在血中保持在一个恒定并持久的水平时,这种失活将带来很大不便,因为必须反复给药。在某些情况下,多肽的一个或多个水解产物还可能成为完整多肽活性的拮抗剂,在这种情况下,单纯补充给药是不足以克服水解产物的拮抗作用的。
进一步说,有一类肽类激素在血中存在较长时间是很有益处的,这类激素包括胰高血糖素样肽1和肽2(GLP-1和GLP-2)、葡萄糖依赖的促胰岛肽(GIP)、神经肽Y(NPY)、胰多肽(PP)和肽YY(PYY)。GLP-1是在葡萄糖代谢和胃肠道分泌和代谢中发挥调节功能的重要多肽激素,目前的研究表明GLP-1是胰腺β细胞生长因子,或许还与其他器官中的细胞分化有关。GLP-2是一个由33个氨基酸组成的肽,对胃肠道疾病有治疗作用,特别是已知GLP-2是一种营养因子,有加强和维持胃肠道正常功能的作用,同时还能促进肠道组织的生长(见,例,美国专利序号5,834,428;5,789,379;和5,990,077;和国际公开号WO 98/52600)。GIP是由小肠内分泌细胞合成并分泌的含42个氨基酸的肽(见R.A.Pederson,等,Endocrinology 99,780-785(1976)and T.B.Usdin,等,Endocrinology 133,2861-2870(1993)),灌注试验显示,GIP可抑制胰高血糖素对肝的作用而加强胰岛素的作用。另外,GIP对肝脏血流有双重作用,即增强门静脉血流,抑制肝动脉血流。神经肽Y是胰多肽家族中的一员,含36个氨基酸,在哺乳动物的中枢和周围神经系统中呈高浓度存在,是已知的最强有力的增加食量的物质,可能还与II型糖尿病有关(见美国专利6410701、6075009、5026685、5328899和K.Tatemoto,Proc.Natl.Acad.Sci.USA 79,5485-5489(1982))。肽YY(PYY)和胰多肽(PP)是结构上相关的肽类激素,与记忆力丧失、抑郁、焦虑、癫痫、疼痛、高血压及睡眠和饮食障碍有关。
此类多肽激素和其他多肽类因子相信是由丝氨酸蛋白酶的脯氨酸后(post-proline)切割组成员降解的,如二肽基肽酶IV(DPP IV)。DPPIV是膜相关丝氨酸肽酶,切割肽链上N端二肽,肽链次末(P1)位最好是脯氨酸残基,或如果N端(P2)是组氨酸或一个大芳香族氨基酸如酪氨酸、色氨酸或苯丙氨酸时,次末(P1)位最好为丙氨酸残基。GLP-1、GIP和GLP-2的氨基端序列分别为His-Ala-Glu、Tyr-Ala-Glu和His-Ala-Asp。NPY、PP和PYY的氨基端序列分别为Tyr-Pro-Ser、Ala-Pro-Leu和Tyr-Pro-Ile。由此,提示了DPP IV在体内对这类多肽类激素和其他多肽的调节作用。
DPP IV介导从上述有生物活性的肽激素的N端切除Xaa-Ala或Xaa-Pro二肽(这里Xaa为一个氨基酸残基)导致激素失活或变为拮抗剂。丝氨酸蛋白酶导致的肽类激素被切割和失活是蛋白水解过程极大限制治疗性多肽使用的一个例子。找到能够在蛋白水解,如DPP IV介导的失活作用下仍保持稳定的肽类药物的类似物将有很大意义,也即是说,本领域有着对蛋白水解抗性肽类激素的需求。
发明概述
本发明总的来说提供了抗蛋白酶切割(如抗蛋白水解)的肽或多肽类似物(P′1类似物)的组合物。
本发明的一个方面关系到一个发现,即对脯氨酸后切割蛋白酶底物的P′1位置(酰胺切割位点的羧基端一侧的残基)进行修饰后,产生的底物类似物与天然底物相比,对酶介导的切割的敏感性有很大程度的降低,但却保留了天然底物的生物学活性。例如,用一个氨基酸类似物修饰脯氨酸后切割丝氨酸蛋白酶DDP IV底物的P′1位残基(具DPP IV切割位点),得到一个对DDP IV的切割不敏感,但又保留了天然底物的生物学活性的底物类似物。
本发明的另一个方面关系到一个更普遍的观察,即用一个具有四取代的Cβ碳的氨基酸类似物修饰蛋白酶底物的P′1位残基(具切割位点),得到的底物类似物在体内的半衰期明显延长,相对天然底物来说,其生物有效期可能延长和/或清除可能减缓。基于此发现及它对多种蛋白酶切割底物的适用性,本发明提供了一个制备这些蛋白酶如丝氨酸蛋白酶、金属蛋白酶、天冬氨酸蛋白酶和半胱氨酸蛋白酶底物的P′1类似物的方法。
本发明还提供了含有一个或多个的题述P′1类似物的药用组合物,示例性药用组合物含一个或多个用药学上可接受的载体或赋形剂配制的P′1类似物。
本发明的另一个方面是治疗受试者疾病的方法,包括给予治疗有效剂量的一个或多个的P′1类似物,该题述P′1类似物可以单独给药,也可作为包括适于治疗特殊疾病适应症的其他疗法的治疗方案的一部分来用药。例如,P′1类似物可单独用于治疗糖尿病,也可在使用时结合饮食控制和运动,和/或联合使用胰岛素。更进一步,示例性的联合治疗方法包括给予P′1类似物的同时,也给予切割其天然多肽的特定酶的抑制剂,这样的抑制剂可能是某种特殊的酶特异性的(如DDP IV特异性抑制剂)或更宽泛地针对一类酶(如,丝氨酸酶抑制剂)。
本发明的另一个方面是关于题述P′1类似物在诊断方面的用途。
本发明的另一个方面是关于题述P′1类似物在生产提供蛋白酶抗性肽的药物方面的用途。
本发明的另一个方面是P′1类似物在生产治疗性药物方面的用途。
本发明还有的一个方面是关于实施商业计划的方法,包括P′1类似物及其药用组合物、和/或含有P′1类似物的试剂盒的鉴别、生产、推销、发放和给予准许。
在上述诸方面中,本发明料想到P′1类似物作为多肽类激素类似物,如胰高血糖素样肽、NPY、PPY、肠泌素、GLP-1、GLP-2和GIP的类似物的组合物和方法,本发明认识到可以在任何可被蛋白酶切割的多肽或肽类激素的切割位点上进行修饰而生成一个具有蛋白酶抗性的P′1类似物。更进一步,本发明认识到根据我们对酶的切割位点的认识和本申请中提供的方法,能够很容易地设计出具有多种多样蛋白酶抗性的P′1类似物。这类蛋白酶的例子包括金属蛋白酶、天冬氨酸蛋白酶、半胱氨酸蛋白酶和丝氨酸蛋白酶。
附图简述
图1为天然GLP-1被DPP IV降解的图解。
图2为两个不同的GLP-1(7-37)类似物抵抗DDP IV切割的HPLC/MS结果概述。
图3显示出3-二甲基-天冬氨酸取代的GLP-1类似物保持天然GLP-1的功能活性。左边的图形显示GLP-1和GLP-1(3-DMA)以相似但不相同的亲和力与其受体结合。右边的图形显示GLP-1和GLP-1(3-DMA)具有基本相同的信号转导能力,这一点是暴露于GLP-1和GLP-1类似物后,通过测定cAMP的产生得出的。
图4显示3-丁基-甲基-甘氨酸取代的GLP-1(GLP-1(BM))类似物保持天然GLP-1的功能活性。图形显示GLP-1和GLP-1(BM)具有基本相同的信号转导能力,这一点是暴露于GLP-1和GLP-1类似物后,通过测定cAMP的产生得出的。图5显示GLP-1(7-37)酰胺用人DDP IV处理2小时后(下)与未处理过的肽(上)的HPLC/MS结果比较。注意GLP-1(7-37)被DDP IV处理后出现时间依赖的肽损失。
图6显示含有叔-亮氨酸(TLE)残基替代P′1谷氨酸的GLP-1类似物用人DDP IV处理2小时后(下)与未被DDP IV处理过的肽(上)的HPLC/MS结果比较。注意该TLE-GLP-1类似物对DPP IV的降解有抗性。
图7显示叔-亮氨酸(TLE)在一个丝氨酸蛋白酶凝血酶的模型底物的P′1位置上的取代导致了一个具有凝血酶抗性的肽类似物的生成。
图8显示使用三个不同剂量(40μg、4μg、0.4μg)的毒蜥外泌肽-4的糖尿病小鼠与生理盐水对照的糖尿病小鼠体内不同时间血糖变化的百分比。
图9显示使用40μg剂量的GLP-1(TPA1B4)类似物的糖尿病小鼠与生理盐水对照或GLP-1对照的糖尿病小鼠体内不同时间血糖变化的百分比。
图10显示使用三个不同剂量(800μg、80μg、8μg)的GLP-1(TPA1B4)类似物的糖尿病小鼠与生理盐水对照的糖尿病小鼠体内不同时间血糖变化的百分比。
图11显示使用20mg/kg剂量的GLP-1(TPA1B4)类似物的糖尿病小鼠与生理盐水对照或GLP-1对照的糖尿病小鼠体内不同时间血糖变化的百分比。
图12显示使用20mg/kg剂量的GLP-1(TPA1B4)类似物的糖尿病小鼠与生理盐水对照或GLP-1对照的糖尿病小鼠体内不同时间的血糖水平。
图13显示使用三个不同剂量(8μg、0.8μg、0.08μg)的毒蜥外泌肽-4的糖尿病小鼠与生理盐水对照的糖尿病小鼠体内不同时间血糖变化的百分比。
图14显示使用800μg剂量的GLP-1的糖尿病小鼠与生理盐水对照的糖尿病小鼠体内不同时间血糖变化的百分比。
图15显示使用8μg和0.8μg两个剂量的GLP-1类似物(P1732)的糖尿病小鼠与生理盐水对照的糖尿病小鼠体内不同时间血糖变化的百分比。
图16显示式(II)的示例性实施方案,其中天然存在的氨基酸在β-位(3-位)用R1和R2修饰。
发明详述
I.概况
本发明总的来说涉及肽和因对蛋白水解酶的切割敏感性降低而体内半衰期延长,且保留了天然底物的活性的P′1类似物。本发明中的P′1类似物包括其活性和/或体内半衰期通常由蛋白水解调节的生长因子、细胞因子、肽类激素和其他多肽和肽的类似物。
本发明的一个方面涉及发现对脯氨酸后切割蛋白酶底物的P′1位(酰胺切割位点羧基端的一侧的氨基酸残基)进行修饰能产生较之天然底物对酶切割的敏感性大大降低了的底物类似物,而且天然底物的生物活性仍然存在。例如,用一个氨基酸类似物对脯氨酸后切割丝氨酸蛋白酶DPP IV底物的P′1位(DPP Ive切割位点)进行修饰,生成一个极大降低了对DDP IV切割敏感性的底物类似物,而且天然底物活性还被保留了下来。
用另一个天然氨基酸替代P′1位氨基酸残基是一种选择,在优选实施方案中,取代P′1位氨基酸残基是一个非天然的氨基酸类似物,甚至更优选的,是用一个保留了与其相似的立体构型和/或电荷性状的结构类似物来取代。本发明的某些实施方案提供了一个修饰过的多肽,经修饰后该多肽对脯氨酸后切割蛋白酶,如对二肽基肽酶IV(DPP IV)水解作用的敏感性降低,该多肽在P′1位的残基被一个氨基酸或式I的氨基酸类似物所修饰。
其中,R1和R2独立选自低级烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基、烷氧基、羧基、氨基甲酰基(carboxamide)、羰基、卤素、羟基、胺或氰基,或R1和R2也可一起形成一个4-7元的环;
R3选自低级烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基、氨基、烷氧基、卤素、羧基、酰胺基、羰基、氰基、硫代烷基(thioalkyl)、酰基氨基、酰氨基、氰基、硝基、叠氮基、硫酸酯基、磺酸酯基、亚磺酰氨基、-(CH2)mR4、-(CH2)mOH、-(CH2)mCOOH、-(CH2)mO-低级烷基、-(CH2)mO-低级烯基、-(CH2)nO(CH2)mR4、-(CH2)mSH、-(CH2)mS-低级烷基、-(CH2)mS-低级烯基、-(CH2)nS(CH2)m-R4、(CH2)mNH2、(CH2)mNC(=NH)NH2、-(CH2)mC(=O)NH2或-(CH2)mNH2;
R4每次出现独立代表芳基、芳烷基、环烷基、环烯基或杂环;
m为0、1或2;
n为0、1或2。
在某些优选实施方案中,R1和R2各自独立地代表一个小疏水基团,如一个低级烷基(优选甲基、乙基或丙基,更优选的是甲基)、卤素或一个卤化的低级烷基。
在某些优选实施方案中,R3代表低级烷基,更优选甲基、乙基或丙基,甚至更优选的是甲基。在另一个优选实施方案中,R3代表一个芳基,如苯基或羟苯基(优选对羟基)。在其他的优选实施方案中,R3代表一个羟基基团。在还有的优选实施方案中,R3代表-(CH2)mCOOH,优选的m为0或1。
在某些优选实施方案中,n为0。
在某些底物类似物的优选实施方案中,P′1位是具有四取代的Cβ碳的氨基酸类似物,如式式II表示的那样:
其中R1和R2独立代表一个低级烷基或卤素;R3代表一个低级烷基、芳基、羟基、-(CH2)mCOOH、-(CH2)mNH2、-(CH2)mNC(=NH)NH2、-(CH2)mC(=O)NH2、-SH或-(CH2)m-S-CH3;m为0、1或2。
在某些优选实施方案中,R1和R2独立地选自甲基、乙基或丙基,甚至更优选的是甲基。
在某些优选实施方案中,R3代表一个低级烷基,更优选为甲基、乙基或丙基,甚至更优选的是甲基。在其它优选实施方案中,R3代表芳基,如苯基、羟苯基(优选对羟基)、吲哚或咪唑。在又一个优选实施方案中,R3代表一个羟基。在某些优选实施方案中,R3代表-COOH或-CH2COOH。在再一个优选实施方案中,R3代表-CH2CH2NC(=NH)NH2、-CH2C(=O)NH2、-CH2CH2C(=O)NH2、-SH或-CH2SCH3。
本发明的另一个方面涉及一个更普遍的观察,即用一个具有四取代的Cβ碳的氨基酸类似物修饰蛋白酶底物的P′1位残基(具酶切位点),得到的底物类似物在体内的半衰期明显延长,相对野生型多肽来说,其生物有效期可能较长,清除可能较缓。基于此发现及它对多种蛋白酶切割底物的适用性,本发明提供了一个制备这些蛋白酶底物的P′1类似物的方法,这些蛋白酶包括丝氨酸蛋白酶、金属蛋白酶、天冬氨酸蛋白酶和半胱氨酸蛋白酶。
在某些优选实施方案中,P′1为氨基酸类似物,具四取代的Cβ碳,如式II中表示的那样:
其中R1和R2各自独立地代表一个低级烷基或卤素;R3代表低级烷基、芳基、羟基基团、-(CH2)mCOOH、-(CH2)mNC(=NH)NH2、-(CH2)mC(=O)NH2、-(CH2)mNH2、-SH、-(CH2)mSCH3;m为0、1或2。
在某些优选实施方案中,R1和R2各自独立代表甲基、乙基或丙基,甚至更优选的是甲基。
在某些优选实施方案中,R3代表低级烷基,更优选甲基、乙基或丙基,甚至更优选的是甲基。在另一个优选实施方案中,R3代表芳香基团,如苯基、羟苯基(优选对羟基)、吲哚或咪唑。在另有的优选实施方案中,R3代表一个羟基基团。在某些优选实施方案中,R3代表-COOH或-CH2COOH。在还有的优选实施方案中,R3代表-CH2CH2NC(=NH)NH2、-CH2C(=O)NH2、-CH2CH2C(=O)NH2、-SH或-CH2SCH3。修饰天然氨基酸的优选实施方案的例子见图16。
II.
定义
术语“底物”指被酶催化并发生化学转变而生成产物的酶底物。
肽底物的结合位点由一系列分布在酶表面的“特异性亚位点”组成,术语“特异性亚位点”指酶分子上能够与该酶的底物的某部分相互作用的口袋或其他位点。
在讨论肽和蛋白底物与蛋白酶如丝氨酸和半胱氨酸蛋白酶等相互作用时,本发明采用了Schechter and Berger命名法[(1967)Biochem.Biophys.Res.Commun.27:157-162]]。底物或抑制剂上的各氨基酸残基被标示为-P2-P1-P′1-P′2等,酶分子上的对应亚位点被标示为S2、S1、S′1、S′2等。底物上易裂的键为连接P1和P′1残基的酰胺键。
“P′1残基”指底物多肽的氨基酸主链经过蛋白酶切割以后形成的产物多肽上的新氨基端的氨基酸残基,为了进一步阐明,底物多肽包括用以下通式来代表的对蛋白水解反应敏感的酰胺骨架键。
术语“氨基酸残基”指氨基酸,这里所用的命名天然氨基酸的缩写是以IUPAC-IUB Commission on Biochemical Nomenclature(seeBiochemistry(1972)11:1726-1732)的推荐为依据的。例如Met、Ile、Leu、Ala和Gly分别代表甲硫氨酸、异亮氨酸、亮氨酸、丙氨酸和甘氨酸残基。用残基来表示对应的α-氨基酸的羧基上失去了一个OH,氨基上失去了一个H后衍生而来的基团。
术语“氨基酸侧链”是指氨基酸残基除了主链的部分,正如Kopple在,″Peptides and Amino Acids″,W.A.Benjamin Inc.,New York andAmsterdam,1966,第2和33页中定义的。例如,普通氨基酸的侧链为:CH2CH2SCH3(甲硫氨酸侧链)、-CH2(CH3)-CH2CH3(异亮氨酸侧链)、-CH2CH(CH3)2(亮氨酸侧链)或H-(甘氨酸侧链)。这些侧链连在主链的Cα碳上。
术语“四取代的Cβ碳”指一个碳原子,该碳原子(i)是直接连在氨基酸主链的Cα碳上;(ii)含4个侧取代基(包括Cα碳在内),其中没有一个是氢。
这里所用的“蛋白质”指基本由20种氨基酸中的任何氨基酸组成的多聚体,虽然多肽常被用来指相对较大的蛋白质,肽用于指较小的蛋白质,这些术语在本领域的使用是重叠的和变化的。如果内容上没特别表明,这里的“肽”、“蛋白质”和“多肽”是混用的。
正如这里所用,术语“核酸”指多核苷酸,如脱氧核糖核酸(DNA)和核糖核酸(RNA)。应该明白,该术语同样包括由核苷类似物生成的RNA或DNA类似物,同时也适用于方案中描述的单链(正义或反义)或双链多核苷酸。
The International Union of Biochemistry and Molecular Biology(1984)推荐用“肽酶”来称呼肽键水解酶(亚类E.C 3.4)的亚类。广泛应用的术语“蛋白酶”是“肽酶”的同义词,它们在此是混用的。肽酶包括两组酶:内切肽酶和外切肽酶。内切肽酶从蛋白的内部某点切割肽键,外切酶从蛋白的N端或C端连续切除氨基酸。
术语“蛋白酶”也是内切肽酶的同义词。蛋白酶根据其催化机理分类,The International Union of Biochemistry and Molecular Biology已经认可了四类不同机理的酶:丝氨酸蛋白酶、半胱氨酸蛋白酶、天冬氨酸蛋白酶和金属蛋白酶。
“丝氨酸蛋白酶”类包括两个独特的家族,一为糜蛋白酶家族,包括哺乳动物酶如糜蛋白酶、胰蛋白酶、弹性蛋白酶或激肽释放酶,另一为枯草蛋白酶家族,包括了细菌酶如枯草蛋白酶。两个家族有着不同的总体三维结构但其活性位点的几何构型相同,通过相同的机理发挥催化作用。该丝氨酸蛋白酶展现不同的底物特异性,这和与底物残基相互作用的各种酶的亚位点上的氨基酸取代有关(见,thenomenclature of Schechter and Berger)。形成催化三联体的三个残基为催化过程所必须,它们是His-57、Asp-102和Ser-195(糜蛋白酶原上的位数)。
“半胱氨酸”家族包括植物肽酶如木瓜蛋白酶、猕猴桃碱或菠萝蛋白酶,几个哺乳动物溶酶体组织蛋白酶,胞质钙蛋白酶(钙激活的),和一些寄生虫肽酶(如锥虫,血吸虫)。木瓜蛋白酶是这类酶中的天然类型,也是研究得最透彻的一个。
大多数“天冬氨酸蛋白酶”属于胃蛋白酶家族,该胃蛋白酶家族包括消化酶如胃蛋白酶和凝乳酶,同时还有溶酶体组织蛋白酶D,加工酶如肾素,和某些真菌肽酶(青霉天冬酰蛋白酶、根酶蛋白酶(rhizopuspepsin)、内座壳蛋白酶(endothiapepsin))。第二个家族包括病毒蛋白酶如爱滋病毒肽酶,又叫反转录肽酶(retropepsin)。
“金属蛋白酶”在细菌、霉菌和较高级的生物体中均有发现,它们在序列和结构上大不相同,但大多数此类酶都含有一个具有催化活性的锌原子,许多酶含有HEXXH序列,该序列为锌提供了两个组氨酸配体,第3个配体要么为谷氨酸(嗜热芽胞菌蛋白酶、中性溶酶、丙氨酰氨基肽酶)要么为组氨酸(虾红素)。
术语“激动剂”在这里指一种肽或P′1类似物,该肽或P′1类似物保留了天然目的底物的生物活性,当用于动物体后能产生相似的生物效应。
术语“拮抗剂”指一种肽或P′1类似物,该肽或P′1类似物不再具有原有目的底物的生物活性,或至少相对天然底物来说活性水平有所降低,并抑制天然底物的生物学活性。
术语“类似物”指一个在功能上与一个完整的受体分子或其片段基本相似的分子。
关于母体化合物的“微小修饰的衍生物”的术语,用于指化学性状与母体化合物相似的化合物,例如一个氨基酸类似物。最好,微小修饰衍生物在结构上有微小修饰,这样可被认为是原有化合物的“结构类似物”。
“心脏相关疾病”包括任何涉及到心脏和/或相关组织(如心包膜、主动脉、和其他相关血管)的慢性或急性病理变化,包括缺血-再灌注损伤;充血性心衰;心脏骤停;心肌梗死;由化合物如药物(盐酸多柔比星、赫赛汀、盐酸硫利达嗪和西沙必利)引起的心脏毒性;由于寄生虫感染(细菌、真菌、立克次氏体,病毒,例如梅毒,慢性克氏锥虫(Trypanosoma cruzi)感染)引起的心脏损害;暴发性心脏淀粉样变性、心脏外科手术;心脏移植;心脏外伤(如穿透性或钝性心外伤和动脉瓣破裂);胸主动脉瘤外科修复、肾上腺动脉瘤;由心肌梗塞或心衰引起的心源性休克;神经源性休克和过敏反应。
这里所用的“说明书”指描述涉及试剂盒或封装的药品使用方法和材料相关的产品标签和/或文件。这些材料可包括下述任何内容的组合:背景信息、内容物清单、推荐剂量、可能的负作用警告、用药说明,技术支持和其他任何相关文件。
短语“药学上可接受的”用在这里指那些配体、材料、组合物和/或剂型。在一个良好的医学判断所及的范围内,适合于用来与人或动物组织接触,而基本无热原反应,无过量毒性、刺激、过敏反应,无其他问题和/或并发症,与合适的效益/危险比相称。
用于这里的短语“药学上可接受的载体”指药学上可接受的涉及到携带或运输目标化学物质从身体的一个器官或部位到另一个器官或部位的材料、组合物或媒介物,如液体或固体的填充剂、稀释剂、赋形剂、溶剂或胶囊化材料。各种载体必须在可与制剂中的其他成份配伍,不伤害病人,基本无热原的概念上可接受。药学上可接受的材料的例子包括:(1)糖类,如乳糖、葡萄糖和蔗糖;(2)淀粉,如玉米淀粉和土豆淀粉;(3)纤维素及其衍生物,如羧甲基钠纤维素、乙基纤维素和乙酸纤维素;(4)粉状西黄蓍胶;(5)麦芽;(6)明胶;(7)滑石粉;(8)赋形剂,如可可缓冲液和支撑蜡;(9)油,如花生油、棉籽油、葵花油、芝麻油、橄榄油玉米油和豆油;(10)甘醇,如丙二醇;(12)酯,如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,如氢氧化镁和氢氧化铝;(15)藻酸;(16)无热原水(17)等渗盐;(18)Ringer’s溶液;(19)乙醇;(20)磷酸盐缓冲液;和(21)其他用于药物制剂中的无毒相容物质。在某些实施方案中,本发明中的药物组合物是无热原的,即用于病人后不会引起病人体温升高。
术语“药学上可接受的盐”:指抑制剂的无毒的、无机和有机的酸加成盐,这些盐可在分离或纯化该抑制剂的过程中在原位制备,也可用该纯化的抑制剂的游离碱与合适的有机或无机酸进行反应,再分离生成的盐。代表性的盐包括氢溴化物、氢氯化物、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、乙酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、延胡索酸盐、琥珀酸盐、酒石酸盐、萘酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐和月桂基磺酸盐等等(见,例,Bergeet al(1977)″Pharmaceutical Salts″,J.Pharm.Sci.66:1-19)。
在其他情况下,本发明中的抑制剂可以含一个和/或多个酸性功能基团,能够与药学上可接受的碱形成药学上可接受的盐。在这些例子里术语“药学上可接受的盐”指抑制剂的相对无毒的无机和有机碱加成盐。这些盐同样能够在最后分离和纯化抑制剂的过程中原位制备而成,或另行用纯化的游离酸形式的抑制剂与合适的碱反应,如一种药学上可接受的金属离子的氢氧化物、碳酸盐或碳酸氢盐与氨或与药学上可接受的有机一级、二级或三级胺反应。碱或碱土盐的代表包括锂、钠、钾、钙、等镁和铝盐等。用于形成碱加成盐的有机胺包括乙基胺、二乙基胺、乙二胺、乙醇胺、二乙醇胺哌嗪等(见,例,Berge等,supra)。
术语“预防”是本领域认可的,当用于涉及如局部复发(疼痛)的病症、如癌症等疾病、如心衰等复合综合征、或其他任何医学症状时,其意义在本领域是人尽皆知的。预防包括将一种药物组合物用于一个受试者,使用过该组合物的受试者相对未用过该组合物的受试者来说,其医学症状发生的频率降低,发作时间延迟。由此,预防癌症包括,例如,接受过预防措施的病人群体相对未接受过预防措施的病人群体,可检测出的癌细胞生长被降低到有统计学或临床意义的量,或接受过预防措施的病人群体较之未接受过预防措施的病人群体,可检测到的癌性生长的出现被延迟到有统计学或临床意义的量。预防感染包括,例如,接受过治疗的群体相对未接受过治疗的群体,被确诊为感染的人数降低,或接受过治疗的群体相对未接受过治疗的群体,感染症状的发作被延迟。预防疼痛包括,例如,接受过治疗的群体相对未接受过治疗的群体,其疼痛的程度降低,痛感的出现延迟。
一种化合物,如本发明中的多肽或肽的类似物的“治疗有效量”,应用在治疗方面指制剂中的多肽或肽,作为理想剂量方案(用于哺乳动物,优选人体)的一部分使用时,根据临床上可以接受的对疾病或病症进行治疗的标准或美容目的的标准,能减轻症状,改善状况,或延迟疾病发作,如有一个适合于各种医疗治疗的合理的效益/危害比。
术语“烷基”指完全饱和的指明有若干碳原子的含侧链或不含侧链的碳链基,或如果没有特别指明碳链可长达30个碳原子。例如,“低级烷基”指含1到10个碳原子的烷基,如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基,及这些烷基的位置异构体。含有10到30个碳原子的烷基包括癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基、二十烷基、二十一烷基、二十二烷基、二十三烷基和二十四烷基。在优选实施方案中,直链或支链烷基在其主链上有30或少于30个碳原子(如直链1到30个,支链3到30个),更优选的为20个或少于20个碳原子。同样,优选环烷基在其环状结构上有3到10个碳原子,更优选的为5、6、或7个碳原子。
此外,贯穿于本说明和权利要求的术语“烷基”(或“低级烷基”)有意把未取代的和取代的烷基链均包含于其中,取代的烷基链指烷基的烃主链上的一个或多个碳原子上的氢被取代基取代。这些取代基包括,如卤素、羟基、羰基(如羧基、烷氧羰基、甲酰基或酰基)、硫代羰基(如硫代酸酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、磷酰基、磷酸酯基、膦酸酯基、次膦酸酯基、氨基、酰氨基、脒、氰基、硝基、硫氢基、烷硫基、硫酸酯基、磺酸酯基、氨磺酰、磺酰氨基、磺酰基、杂环基、芳烷基、或芳香或杂芳香基团。那些本领域的技术人员知道,如果合适,烃链上的取代基团本身也可被取代。例如,被取代烷基上的取代基可以包括取代和未取代形式的氨基、叠氮基、亚氨基、酰氨基、磷酰基(包括膦酸酯基和次膦酸酯基)、磺酰基(包括硫酸酯基、亚磺酰氨基、氨磺酰和磺酸酯基)和甲硅烷基基团,还有醚、烷硫基、羰基(包括酮、醛、羧酸盐和酯)、-CF3、-CN等。示例性的取代烷基在下面描述。环烷基可进一步被烷基、烯基、烷氧基、烷硫基、氨基烷基、羰基取代的烷基、-CF3、-CN等取代。
除非特别指明碳原子数,这里所用的“低级烷基”,指一个烷基基团,正如以上定义的,含1到10个碳原子,更优选的含1到6个碳原子在其主链结构上,如甲基、乙基、正丙基、异丙基、二级丁基、三级丁基。类似,“低级烯基”和“低级炔基”有着相似的链长度。贯穿整个申请,优选的烷基基团是低级烷基。在优选实施方案中,指明的烷基取代基为低级烷基。
这里所用的术语“碳环”指环中的各个原子均为碳原子的芳香或非芳香环。
这里所用的术语“芳基”包括5-、6-和7元单环芳基,这些芳基可含有0到4个杂原子,例如,苯、吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、三唑、吡唑、吡啶、吡嗪、哒嗪、嘧啶等。在环结构上含有杂原子的芳基又被称为“芳基杂环”或“杂芳基”。芳环在其环上一个或更多的位置可被以上描述的取代基取代,例如,卤素、叠氮化物、烷基、芳烷基、烯基、炔基、环烷基、羟基、烷氧基、氨基、硝基、硫氢基、亚氨基、酰氨基、膦酸盐根、次膦酸酯基、羰基、羧基、甲硅烷基、醚、烷硫基、磺酰基、亚磺酰氨基、酮、醛、酯、杂环基、芳基或杂芳基、-CF3、-CN等。术语“芳基”也包括含有两个或多个环状结构的多环系统,该多环系统的两个相邻的环共用两个或更多的碳原子(“稠环”),其中至少一个环是芳香环,如其他环可以是环烷基、环烯基、环炔基、芳基和/或杂环基。
“烯基”指任何支链或直链的不饱和碳链基,其碳原子数可以是已指定的,如未特别指明,碳原子数可多达26个,且含有一个或更多的双键。典型的6个至26个碳原子的烯基的实例为己烯基、庚烯基、辛烯基、壬烯基、癸烯基、十一烯基、十二烯基、十三烯基、十四烯基、十五烯基、十六烯基、十七烯基、十八烯基、十九烯基、二十烯基、二十二烯基、二十三烯基和二十四烯基,和它们的各种异构体,其不饱和键可以位于基团的任何位置,其可形成关于双键的(Z)或(E)构型。
术语“炔基”指与烯基范围一样的烃基,但是,炔基含有一个或多个三键。
这里所用的术语“烷氧基”指一个如以下定义的含有一个与之相连的氧基的烷基基团。代表性的烷氧基团包括甲氧基、乙氧基、丙氧基、丁氧基等。“醚”由两个烃基与一个氧原子共价结合而成。因此,使烷基成为醚的取代基是或者类似于烷氧基,如-O-烷基、-O-烯基、-O-炔基、-O-(CH2)m-R1的其中之一,这里m和R将在下面描述。
术语“杂环”或“杂环基团”指3到10元环结构,优选的是3到7元环,其环结构上包括1到4个杂原子。杂环也可以是多环。杂环基团包括,例如,噻吩、噻蒽、呋喃、吡喃、异苯并呋喃、色烯、呫吨、氧硫杂蒽(phenoxathiin)、吡咯、咪唑、吡唑、异噻唑、异噁唑、吡啶、吡唑、嘧啶、哒嗪、吲嗪、异吲哚、吲哚、吲唑、嘌呤、喹嗪、异喹啉、喹啉、酞嗪、萘啶、喹喔啉、喹唑啉、噌啉、蝶啶、咔唑、carboline、菲啶、吖啶、嘧啶、菲咯啉、吩嗪、吩砒嗪、吩噻嗪、呋喃、吩噁嗪、吡咯烷、氧杂环戊烷、硫杂环戊烷、噁唑、哌啶、哌嗪、吗啉、内酯、内酰胺如氮杂环丁烷酮和吡咯烷酮、磺内酰胺、磺内酯等。杂环基团可以在一个或更多的位置被以上描述过的取代基取代,例如,被卤素、烷基、芳烷基、烯基、炔基、环烷基、羟基、硫氢基、亚氨基、酰氨基、磷酸盐、磷酸酯、膦酸盐、羰基、羧基、硅烷基、氨磺酰基、亚硫酰基、醚、烷硫基、甲酮、醛、酯、杂环、芳香和杂芳香基团、-CF3、-CN等。
术语“烷硫基”指一个以上定义的烷基,含有一个与之结合的硫基。在优选实施方案中,烷硫基基团以-(S)-烷基、-(S)-烯基、-(S)-炔基和-(S)-(CH2)m-R1中的一个为代表,其中m和R1将在下面定义。代表性的烷硫基基团包括甲硫基、乙硫基等。
如这里所用,术语“硝基”指-NO2;术语“卤素”指氟、氯、溴、碘;术语“巯基”指-SH;术语“羟基”指-OH;术语“磺酰基”指-SO2-。
术语“胺”和“氨基”是本领域认可的术语,指无取代和取代的胺,例如一个可用以下式表示的基团:
其中,R3、R5和R6分别独立地代表氢原子、烷基、烯基、-(CH2)m-R1,或R3和R5与连接它们的氮原子一起形成4到8个原子的杂环结构,R1代表烯基、芳基、环烷基、环烯基、杂环基或多环基。M为零或1到8的整数。在优选实施方案中,R3或R5中只有一个是羰基,如R3、R5和氮原子一起不形成二酰亚胺。在甚至更优选的实施方案中,R3和R5(任选R6)各自独立地代表氢原子、烷基、烯基、-(CH2)m-R1。这样,术语“烷基胺”在这里指一个胺基,如上面所定义的,含有一个取代的或未取代的烷基与之结合在一起,即至少R3和R5中的一个是烷基。在某些实施方案中,氨基或烷基胺是碱性的,意味着其PKa≥7.00,这些功能基团的质子化形式溶与水时Pka都在7.00以上。
术语“羰基”是本领域认可的,包括可用以下通式表示的基团:
其中X是键,或代表一个氧或一个硫。R7代表氢原子烷基、烯基、-(CH2)m-R1或其药学上可接受的盐。R8代表氢原子、烷基、烯基、-(CH2)m-R1,此处的m和R1如以上所定义。当X是氧,R7、R8不是氢,该式代表“酯”。当X是氧,R7如以上所定义,该基团这里指羧基,特别是当R7是氢时,该式代表“羧酸”。当X是氧,R8是氢,该式代表“甲酸酯”。一般来说,当上述式的氧原子被硫取代,该式代表“硫代羰基”基团。当X是硫,R7和R8不是氢,该式代表“硫酯”基团。当X是硫,R7和R8是氢,该式代表“硫代羧酸”基团。当X是硫,R8是氢,该式代表“硫代甲酸酯”基团。另一方面,当X是一个键,R7不是氢,上述式代表“酮”基团。当X是一个键,R7是氢,上述式代表“醛”基团。
如这里所用,术语“取代”涵盖所有允许的有机化合物的取代基,广义地说,允许的取代基包括有机化合物的无环和环状,支链和直链,碳环和杂环,芳香和非芳香取代基。说明性的取代基包括以上描述的那些。对合适的有机化合物,取代基可以有一个或多个、可以是相同的也可以是不同的。为了本发明的目的,杂原子,如氮,可以有氢取代基和/或任何这里描述的能满足杂原子的化合价的有机化合物的允许取代基。不能以任何方式用化合物的允许取代基限制本发明。应该明白,“取代”或“被取代”包括了未明讲的限制性条文,即这样的取代应该与被取代原子和取代基的化合价相对应,取代应该导致生成一个稳定的化合物,即该化合物不应该如通过重排、环化和消除等发生自发的转化。
术语“氨磺酰”是本领域认可的,包括一个能被以下通式表示的基团:
其中R3和R5如以上所定义。
术语“硫酸酯基”是本领域认可的,包括一个能被以下通式表示的基团:
其中R7如以上定义。
术语“磺酰氨基”是本领域认可的,包括一个能被以下通式表示的基团:
其中R2和R4如以上定义。
术语“磺酸酯基”是本领域认可的,包括一个能被以下通式表示的基团:
其中R7是电子对、氢、烷基、环烷基或芳基。
这里所用的术语“亚砜基”或“亚硫酰基”,指一个能被以下通式表示的基团:
其中R12选自氢、烷基、烯基、炔基、环烷基、杂环基、芳烷基或芳基。
可以对烯基和炔基基团进行类似取代而生成氨基烯基、氨基炔基、酰氨基烯基、酰氨基炔基、亚氨基烯基、亚氨基炔基、硫代烯基、硫代炔基、羰基取代的烯基或羰基取代的炔基。
如这里所用,各种表达的定义,如烷基、m、n等,当其在任何结构中出现一次以上时,表示其独立于在同一结构的其他地方的定义。
为了本发明,化学元素根据CAS version,Handbook of Chemistryand Physics,67th Ed.,1986-87,内封面的元素周期表鉴别。也为了本发明,术语“烃”基意在包括所有的含有至少一个氢原子和一个碳原子的化合物。更广泛地讲,允许的烃基包括非环状和环状、支链和直链、碳环和杂环、芳香和非芳香的有机化合物,它们可以是取代的或未取代的。
III.示例性实施方案
(a)P′1类似物
本发明提供了抗蛋白酶介导的切割的肽和P′1类似物的生产和使用方法。天然的多肽通常能被某种特殊的蛋白酶(如,金属蛋白酶、半胱氨酸蛋白酶、天冬氨酸蛋白酶或丝氨酸蛋白酶)切割,人们能很容易地确定天然多肽上酶切割的位置(切割位点)。一旦酶切位点被确定,就可根据本发明的方法很容易地制备P′1类似物。随着对酶学领域理解的深入,大量蛋白酶的优选酶切位点已经被鉴别。要鉴别一个天然多肽的酶切位点,通过对其氨基酸序列进行分析就可很快很容易地完成。
在一个特殊多肽的酶切位点未知的情况下,或简单地分析氨基酸序列难以确定的情况下,可以通过将该多肽与蛋白酶共孵育,使切割反应发生,分离被切割的多肽(如,用电泳法),对切割后的多肽片段进行序列分析,并将测得的片段的序列与天然多肽的全序列进行比较,这样,人们就能快速、轻易地鉴别和确认蛋白酶作用在天然多肽上的切割位点。
另一个快速确定蛋白酶的底物特异性的典型方法在PCT公开号第WO0061789号上有公开。
本发明提供了构建蛋白酶抗性P′1类似物的一般方法。本发明涉及抗金属蛋白酶、半胱氨酸蛋白酶、天冬氨酸蛋白酶和丝氨酸蛋白酶的P′1类似物的设计和用法。例如,可以使目标类似物可以获得针对选自下述蛋白酶的切割的抗性:氨肽酶(EC3.4.11.-)、二肽酶(EC3.4.13.-)、二肽基肽酶或三肽基肽酶(EC3.4.14.-)、肽基二肽酶(EC3.4.15.-)、丝氨酸型羧基肽酶(EC3.4.16.-)、金属蛋白羧基肽酶(EC3.4.17-)、半胱氨酸型羧基肽酶(EC 3.4.18.-)、Ω肽酶(EC3.4.19.-)、丝氨酸蛋白酶(EC3.4.21.-)、半胱氨酸蛋白酶(EC3.4.22.-)、天冬氨酸蛋白酶(EC 3.4.23.-)、金属蛋白酶(EC 3.4.24.-)或机理未知的蛋白酶(EC3.4.99.-)。各类蛋白酶后面的EC为International Union of Biochemistryand Molecular Biology(1984)推荐的标识,在这里用作参考。
为了进一步阐明蛋白酶抗性P′1类似物所针对的示例性的蛋白酶,无尽数的蛋白酶可以列举,包括亮氨酰氨肽酶、膜丙氨酸氨肽酶、半胱氨酸氨肽酶、三肽氨肽酶、脯氨酰氨肽酶、氨肽酶B、谷氨酰氨肽酶、Xaa-Pro氨肽酶、细菌亮氨酸氨肽酶、梭菌氨肽酶、细胞溶胶丙氨酰氨肽酶、赖氨酰氨肽酶、Xaa-Trp氨肽酶、色氨酰氨肽酶、甲硫氨酰氨肽酶、D-立体特异性氨肽酶、氨肽酶Ey、液泡氨肽酶I、Xaa-His二肽酶、Xaa-Arg二肽酶、Xaa-甲基-His二肽酶、Cys-Gly二肽酶、Glu-Glu二肽酶、Pro-Xaa二肽酶、Xaa-Pro二肽酶、Met-Xaa二肽酶、非立体特异性二肽酶、细胞溶胶非特异性二肽酶、膜二肽酶、β-Ala-His二肽酶、二肽基肽酶I(DPP I)、二肽基肽酶II(DPP II)、二肽基肽酶III(DPP III)、二肽基肽酶IV(DPP IV)、二肽基二肽酶、三肽基肽酶I、三肽基肽酶II、Xaa-Pro二肽基肽酶、肽基二肽酶A、肽基二肽酶B、肽基二肽酶Dcp、溶酶体Pro-X羧基肽酶、丝氨酸型D-Ala-D-Ala羧基肽酶、羧基肽酶C、羧基肽酶D、羧基肽酶A、羧基肽酶B、赖氨酸(精氨酸)羧基肽酶、Gly-X羧基肽酶、丙氨酸羧基肽酶、胞壁酰五肽羧基肽酶、羧基肽酶H、谷氨酸羧基肽酶、羧基肽酶M、胞壁酰四肽羧基肽酶、锌D-Ala-D-Ala羧基肽酶、羧基肽酶A2、膜Pro-X羧基肽酶、微管蛋白-Tyr羧基肽酶、羧基肽酶T、热稳定羧基肽酶1、羧基肽酶U、谷氨酸羧基肽酶II、金属蛋白羧基肽酶D、半胱氨酸型羧基肽酶、酰基氨酰基-肽酶、肽基-甘氨酰胺酶、焦谷氨酰肽酶I、β-天冬氨酰-肽酶、焦谷氨酰肽酶II、N-甲酰甲硫氨酰肽酶、蝶酰聚-γ-谷氨酸羧基肽酶、γ-谷氨酰水解酶、γ-D-谷氨酰-内消旋-二氨基庚二酸-肽酶I、糜蛋白酶、糜蛋白酶C、metridin、胰蛋白酶、凝血酶、凝血因子Xa、纤溶酶、肠肽酶、顶体素、α-裂解-内肽酶、谷氨酰内肽酶、组织蛋白酶G、凝血因子VIIa、凝血因子IXa、黄瓜素、脯氨酰寡肽酶、凝血因子XIa、brachyurin、血浆激肽释放酶、组织激肽释放酶、胰腺弹性蛋白酶、白细胞弹性蛋白酶、凝血因子XIIa、胃促胰酶、补体成份Clr、补体成份Cls、经典补体旁路C3/C5转化酶、补体因子I、补体因子D、选择性补体旁路C3/C5转化酶、干酵母菌、下丘泌素C、赖氨酰内肽酶、内肽酶La、γ-肾素、venombin AB、亮氨酰内肽酶、类胰蛋白酶、scutelarin、kexin、枯草蛋白酶、oryzin、蛋白激酶K、嗜热霉菌素、thermitase、内肽酶So、T-血纤溶酶原激活物、蛋白C(激活的)、胰腺内肽酶E、胰腺弹性蛋白酶II、IgA-特异的丝氨酸内肽酶、U-血纤溶酶原激活物、venombin A、弗林蛋白酶、成髓细胞蛋白酶、semenogelase、颗粒酶A、颗粒酶B、sreptogrisin B、谷氨酰内肽酶、寡肽酶B、鲎凝血因子B、鲎凝集酶、omptin、阻抑物LexA、信号肽酶I、togavirin、flavirin、内肽酶Clp、前蛋白转化酶1、前蛋白转化酶2、蛇毒因子V激活物、lactocipin、组织蛋白酶B、木瓜蛋白酶、ficain、糜木瓜蛋白酶、萝蛋白酶、梭菌蛋白酶、链霉菌蛋白酶、actinidain、组织蛋白酶L、组织蛋白酶H、钙蛋白酶、组织蛋白酶T、甘氨酰内肽酶、肿瘤前凝血物、组织蛋白S、picornain3C、picornain2A、caricai、nananain、干菠萝蛋白酶、果菠萝蛋白酶、legumain、溶组织素、胱冬酶-1、gingipainR、组织蛋白酶K、胃蛋白酶A、胃蛋白酶B、胃亚蛋白酶、凝乳酶、组织蛋白酶D、neopenthesin、肾素、反转录肽酶、阿片黑皮质素前体转化酶、曲霉蛋白酶I、曲霉蛋白酶II、青霉天冬蛋白酶、根酶蛋白酶、内座壳蛋白酶、毛霉肽酶(mucoropepsin)、念珠菌肽酶(candidapepsin)、糖肽酶、rhodotorulapepsin、似绒泡菌蛋白酶(physaropepsin)、acrocylindropepsin、多孔菌蛋白酶(polyporopepsin)、pycnoporopepsin、小柱孢肽酶(scytalidopepsin)A、小柱孢肽酶B、黄杆菌蛋白酶(xanthomonapepsin)、组织蛋白酶E、barrierpepsin、信号肽酶II、假单孢菌蛋白酶、plasmepsin I、plasmepsin II、phytepsin、atrolysin A、微生物胶原酶、溶白细胞素、间质胶原酶、neprilysin、envelysin、IgA-特异的金属蛋白内肽酶、前胶原N-内肽酶、甲拌磷寡肽酶、溶神经素、溶基质素1、meprin A、前胶原C-内肽酶、肽基-Lys金属蛋白内肽酶、虾红素、溶基质素2、matrilysin、明胶酶A、气单孢菌蛋白酶、pseudolysin、嗜热菌蛋白酶、芽孢杆菌蛋白酶、aureolysin、coccolysin、溶真菌酶(mycolysin)、β-裂解金属蛋白内肽酶、肽基-Asp金属蛋白内肽酶、中性白细胞胶原酶、明胶酶B、利什曼蛋白酶、糖蛋白酶、自溶素、deuterolysin、serralysin、atrolysin B、atrolysin C、atroxase、atrolysin E、atrolysin F、adamalysin、horrilysin、ruberlysin、bothropasin、bothrolysin、ophiolysin、trimerelysin I、trimerelysin II、mucrolysin、pitrilysin、insulysin、O-唾液糖蛋白、内肽酶、russellysin、线粒体中间肽酶、dactylysin、nardilysin、magnolysin、meprin B、线粒体加工肽酶、噬菌体弹性蛋白酶、绒毛膜蛋白酶L、绒毛膜蛋白酶H、tentoxilysin、bontoxilysin、寡肽酶A、内皮素转化酶1、蛇毒溶栓酶、jararhagin、fragilysin和多催化内肽酶复合物。
本发明的一个方面是编码多肽类激素的蛋白酶抗性类似物的多肽序列,该序列的N末端选自NH2-Xaa-Ala-Yaa-和NH2-Xaa-Pro-Yaa-,这里Xaa和Yaa各自代表一个氨基酸残基。在某些实施方案中,Xaa为带有一个芳香族侧链的氨基酸。在某些实施方案中,Xaa选自组氨酸、酪氨酸、色氨酸和苯丙氨酸。在某些实施方案中,Yaa是一个带有酸性侧链的氨基酸残基。在某些实施方案中,Yaa选自天冬氨酸和谷氨酸。
通过举例,在某些实施方案中,蛋白酶是丝氨酸蛋白酶。在某些实施方案中,蛋白酶是二肽基肽酶。示例性的二肽基肽酶的二肽基肽酶IV(DPP IV)。DPP IV活性改变大量生物活性蛋白和生物活性多肽的生物学活性。除美国专利6,090,786中公开的DPP IV的潜在底物外,本发明还涉及GLP-1、GLP-2和GIP的类似物。在某些实施方案中,该肽类激素是哺乳动物体内发现的天然存在变种。在某些实施方案中,该肽类激素是天然的、或天然存在的肽类激素(野生型)的人工突变变种。因此,天然和合成的肽类激素都在考虑被修饰的肽类激素的范围之内。于是在某些实施方案中,本发明提供上述肽类激素的DPP IV蛋白水解抗性类似物。
为了进一步说明具有蛋白酶抗性的P′1类似物,表1提供了几种作为DPP IV底物的人类激素清单。各肽类激素的P′1氨基酸用星号标记。代表性类似物也被列于表1中,其中X为带有以上式II代表的侧链的氨基酸类似物。人们能轻易地建立一个含其他丝氨酸蛋白酶底物的类似表格,并轻易地鉴别P′1氨基酸。同样,人们能轻易地建立一个含天冬氨酸蛋白酶、半胱氨酸蛋白酶、或金属蛋白酶的底物的表格,并鉴别P′1氨基酸。
表1:示例性DPP IV底物类似物
天然序列 | 示例性类似物 |
人胰高血糖素样肽GLP-1(7-37) | HAE*GTFTSDVSSYLEGQAAKEFIAWLVKGR | HAXGTFTSDVSSYLEGQAAKEFIAWLVKGRG |
人胰高血糖素样肽1:GLP-1(7-36) | HAE*GTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 | HAXGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 |
人胰高血糖素样肽2,GLP-2 | HAD*GSFSDEMNTILDNLAARDFINWLIQTKITD | HAXGSFSDEMNTILDNLAARDFINWLIQTKITD |
人葡萄糖依赖性促胰岛素多肽,GIP | YAE*GTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ | YAXGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ |
人神经肽Y,NPY | YPS*KPDNPGEDAPAEDMARYYSALRHYINLITRQRY | YPXKPDNPGEDAPAEDMARYYSALRHYINLITRQRY |
人胰腺肽pp | APL*EPVYPGDNATPEQMAQYAADLRRY | APXEPVYPGDNATPEQMAQYAADLRRY |
人肽YY | YPI*KPEAPGEDASPEELNRYYASLRHYLNLVTRQRY | YPXKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY |
毒蜥外泌肽-4(GLP-1类似物) | HGE*GTFTSDLSKEMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 | HGXGTFTSDLSKEMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 |
毒蜥外泌肽-3(GLP-1类似物) | HSD*GTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS | HSXGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS |
在GLP-1(7-37)、GLP-1(7-36)NH2、GLP-1(7-36)-毒蜥外泌肽尾-NH2、GLP-2、GIP和毒蜥外泌肽-3类似物的某些方案中,X为式II的氨基酸类似物,其中R1和R2独自代表甲基、乙基或丙基。在最优选的实施方案中,X为式II的氨基酸类似物,其中R1和R2均为甲基,R3选自-COOH或-CH2-COOH。
在某些NPY类似物的优选实施方案中,X为式II的氨基酸类似物,在优选实施方案中,X为式II的氨基酸类似物,其中R1和R2各自独立地代表甲基、乙基、或丙基。在最优选的实施方案中,X为式II的氨基酸类似物,其R1和R2二者均为甲基,R3代表-OH。
在某些胰腺多肽PP和肽YY(PYY)类似物的优选实施方案中,X为式II的氨基酸类似物。在优选实施方案中,X为式II的氨基酸类似物,其中R1、R2和R3各自独立地代表甲基、乙基、或丙基。在最优选实施方案中,X为式II的氨基酸类似物,其中R1和R2为甲基,R3代表-CH(CH3)2或-CH2CH3。
在某些毒蜥外泌肽-4类似物的优选实施方案中,X为式II代表的氨基酸类似物。在优选实施方案中,X为式II的氨基酸类似物,其中R1和R2各自独立地代表甲基、乙基、或丙基,R3代表-(CH2)m-C(=O)NH2(其中m为0、1或2)。在最优选的方案中,X为式II的氨基酸类似物,其中R1和R2均为甲基,R3代表-CH2-C(=O)NH2。
更通常的,本发明特别着重于制备含有Xaa-Ala-Yaa-R或Xaa-Pro-Yaa-R′氨基酸序列的肽和多肽因子类似物。
其中Xaa和Yaa代表氨基酸残基,R和R’相互独立地代表含1到100个氨基酸残基的多肽链,其中在类似物序列的Yaa被式I或式II的代表的氨基酸残基置换。本发明进一步着重于修饰序列不同于野生型多肽的多肽变种,以制备变种P′1类似物。这些变种至少与野生型多肽有80%、85%、90%、95%、97%、99%,或大于99%相同。
在某些实施方案中,R是含有选自下列序列的多肽:
GTFTSDVSSYLEGQAAKEFIAWLVKGR,
GTFTSDVSSYLEGQAAKEFIAWLVKGRPSSGAPPPS-NH2,
GTFTSDVS SYLEGQAAKEFIAWLVKGR-NH2,
GSFSDEMNTILDNLAARDFINWLIQTKITD,and
GTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ,
或与以上序列有5个或少于5个的残基不同的序列,甚至更优选的是不同残基少于4个、3个或2个的序列。
在某些优选实施方案中,R是含有选自下列序列的多肽:
KPDNPGEDAPAEDMARYYSALRHYINLITRQRY,
EPVYPGDNATPEQMAQYAADLRRY,
KPEAPGEDASPEELNRYYASLRHYLNLVTRQRY,
或与以上序列有5个或少于5个的不同残基的序列,甚至更优选的是不同残基少于4个、3个或2个的序列。
蛋白酶抗性的GHRH类似物是对本发明的一般方法和组合物的进一步说明。生长激素途径的调节性表达为最佳线性生长所必需,也是保持碳水化合物、蛋白和脂肪代谢稳定所必需。生长激素释放激素(GHRH)刺激生长激素的合成和从垂体前叶脉冲式地分泌,而促生长素抑制素抑制其合成和释放,这两者均为下丘脑激素。生长激素增强胰岛素样生长因子-I(IGF-I)的产量,主要在肝脏,也在其他靶器官。
线性增长的速度和身体组分对GH或GHRH替代疗法的反应在人体和家畜均有许多不同的情况,这些情况出现的原因各不相同。50%的人GH缺陷其GHRH-GH-IGF-I轴在功能上是完好的,但却不能在其靶组织诱导出合适的生物学反应。GH轴不同环节上的基因缺陷产生的表现相似,在非GH缺陷的矮小症也同样。几种以生长受阻为特征且其GHRH-GH-IGF-I轴功能正常的状况,如Turner’s综合症、软骨发育欠缺、节段性回肠炎(Crohn’s病)、宫内生长迟缓、或慢性肾功能不全的情况,用GHRH或GH治疗显示可促进生长。
在老年人,GHRH-GH-IGF-I轴的功能大大减低,导致GH分泌减少和IGF-I产量降低。这些变化与骨骼肌组织丧失(少肌症)、骨质疏松、脂肪集聚和瘦肌肉组织流失有关。已有证据表明,用重组GH治疗可抵消这些变化。
然而现有的GH治疗有几个缺陷,包括频繁的皮下或静脉注射、胰岛素抗性和糖耐受受损。儿童使用GH易引起骨骺过早闭合和股骨头骨骺滑脱。对牲畜,GHRH和GH刺激奶产量、提高从饲料到奶的转化率、维持生长、主要增加瘦肉组织、提高整个喂养的效益。GHRH增加热和冷胴体重量,降低胴体脂肪(软组织百分比)。
虽然GHRH蛋白疗法诱导和刺激GH的正常周期性分泌且几乎无负作用,但该激素在体内短暂的半衰期使其必须频繁(每天1到3次)的静脉、皮下和鼻内(高出300倍的剂量)用药。所以,作为慢性治疗,重组GHRH是不适用的。
GHRH的天然序列如下,其R’氨基酸(为天冬氨酸)为黑体并用星号标示。
YAD*AIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL
GHRH被脯氨酸后切割酶脯氨酰内肽酶切割(PEP)。PEP为胞质内肽酶,该酶切割大量的底物,除GHRH以外还有神经活性肽,如精氨酸加压素、黄体生成激素释放激素、促甲状腺激素释放激素、α-黑色素分泌激素、底物P、缩宫素、缓激肽、神经降压素、血管紧张素(Ag)I和II。
所以,在某个方案中,本发明着重于含以下式代表的氨基酸序列的GHRH类似物。
Tyr-Ala-Yaa-R
其中Yaa代表含有式I或式II代表的侧链序列的氨基酸,R代表含有以下序列的多肽链
AIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL,或与其序列有5个或少于5个的不同残基的序列,甚至更优选的是不同残基少于4个、3个或2个的序列。在某些优选实施方案中,R1和R2各自独立地代表甲基、乙基或丙基,更为优选的为甲基。R3代表-COOH或-CH2COOH。
另一个例子是血管紧张素(ANG)-(1---7),血管紧张素(ANG)-(1---7)的主要作用部位是微血管系统和肾,ANG-(1---7)最初在肺膜被水解为ANG-(1---5)。ANG转化酶(ACE)抑制剂赖诺普利阻断ANG-(1---5)和其更小的代谢物生成。因此,抗切割的ANG-(1---7)肽类似物与ACE抑制剂有着相同和/或相似的作用。换句话说,这样的肽类似物将增加ANG-(1---7)的有效浓度和/或半衰期。
对生产治疗疾病的药物有着重要应用价值的另一个例子是IGFBP-3,血清和其他体液中的IGFBP-3被蛋白酶水解,被水解后的产物对IGF的结合力大大降低或完全丧失。在多种临床和生理状况包括怀孕和某些癌症时均观察到IFGBP-3的水解增强。因此,设计出蛋白酶抗性的IGFBP-3类似物可能在维持IGFBP-3的正常水平,如在癌症引起IGFBP-3水解加强的情况下有特殊作用。
上述引用的例子只是为了说明问题。本发明提供了一个一般性的方法,根据该方法,基本上所有的蛋白酶底物都能通过在其酶切割位点的四取代修饰而产生蛋白酶抗性的P′1类似物。示例性的蛋白酶底物且经修饰其酶切位点后可产生蛋白酶抗性的P′1类似物的包括但不限于:脑啡肽、Leu-脑啡肽、Met-脑啡肽、血管紧张素I、血管紧张素II、血管加压素、内皮素、血管活性肠肽、神经降压素、内啡肽、胰岛素、gaarnicidin、paracelsin、δ-睡眠诱导肽、促性腺激素释放激素、甲状旁腺激素(1-34)、Wrighton等描述的红细胞生成素的截断类似物(Wrighton等,1996,Science 273:458-463)、特殊的EMP-1、心钠肽(ANP、ANF)、人脑钠肽(hBNP)、抗菌肽、运动升压素、europhysins、弹力素、guamerin、心房肽I、心房肽II、心房肽III、δ啡肽I、δ啡肽II、血管升压素、缓激肽、强啡肽、强啡肽A、强啡肽B、生长激素释放因子、生长激素、生长激素释放肽、缩宫素、降钙素、降钙素基因相关肽、降钙素基因相关肽II、生长激素释放肽、速激肽、促肾上腺皮质激素(ACTH)、脑钠多肽、胆囊收缩素、促肾上腺皮质激素释放因子、diazeparn结合抑制剂片段、FMRF-酰胺、甘丙肽、胃肠释放多肽、胃肠抑制多肽、胃泌素、胃泌素释放肽、胰高血糖素、胰高血糖素样肽-1、胰高血糖素样肽-2、LHRH、黑色素聚集激素、促黑素(MSH)、α-MSH、吗啡调节肽、促胃动素、神经激肽-A、神经激肽-B、神经介素13、神经介素C、神经介素K、神经介素N、神经介素U、神经肽K、神经肽Y、垂体腺苷酸环化酶激活多肽(PACAP)、胰多肽、肽YY、肽组氨酸-甲硫氨酸酰胺(PHM)、肠泌素、生长抑素、底物K、促甲状腺激素释放激素(TRH)、京都啡肽、促黑素抑制素(MIF-1)、血小板生成素类似物、特别是AF 12505、胰岛素样生长因子I(57-70)、胰岛素样生长因子I(30-41)、胰岛素样生长因子I(24-41)、胰岛素样生长因子II(33-40)、胰岛素样生长因子II(33-40)、胰岛素样生长因子II(69-84)、生长激素(GH)-释放肽-6(GHRP-6)、β-白介素1(163-171)、β-白介素II(44-56)、白介素II(60-70)、表皮生长因子、双价水蛭素(水蛭肽)、水蛭肽-I、C-型利尿钠肽、鸟氨酸加压素(也称8-鸟氨酸-加压素)、奥曲肽、eptifibatide、降钙素基因相关肽(CGRP)、内吗啡肽-1;内吗啡肽-2、伤害感受肽、血管紧张素原、肾上腺髓质素、抗心律失常肽(AA-P)、拮抗剂G、indolicidin、骨钙蛋白、cortistatin 29、cortistatin 14、PD-145065、PD-142893、纤维蛋白原结合抑制肽、瘦体素、GR 83074、副甲状腺激素相关多肽、血管紧张素原、亮抑酶肽、以及它们的任何修饰的或截断的类似物。
在许多实施方案中,会选择保留类似物的天然底物在体内或体外的一个或多个功能。测定体内或体外功能可用任何一个可用的适合于各特殊多肽的技术方法。确定P′1类似物是否保留了相同或相似活性的可测定的典型功能活性包括:在细胞实验或非细胞实验中该多肽与其受体的结合能力、该多肽在与其反应的细胞中诱导变化的能力(如,增生、分化、存活、生长、迁移)、该多肽在与其反应的细胞中调节一个多个基因或蛋白表达的能力。
在某些实施方案中,该类似物与天然多肽的活性基本相似(如是天然多肽活性的80%、90%、100%、110%、120%)。在一些方案中,类似物的活性不如天然多肽(如与天然多肽约50%、60%、70%、75%活性相同)。我们注意到,如在体内或细胞培养物中,活性稍低可能无碍,如果降低了的活性仍然能够在足够的时间内提供一个足够的局部浓度,蛋白酶抗性引起的半衰期延长可能能够弥补因为构建类似物而造成的活性下降。在另一些方案中,类似物的活性较天然多肽更高(如是天然多肽活性的130%、150%、175%、200%、300%、500%、800%或甚至1000%)。在任何前述内容中,“活性”指天然多肽的一个或多个功能。例如,多肽的活性(如生物功能)可以是受体结合,协同因子反应、结合DNA的能力、作为转录激活物或抑制物的能力、参与某个特殊的信号传导途径的能力和影响细胞行为(如增殖、分化、存活或迁移)的能力。
这些活性可以被表示为,例如,相对结合常数(如对受体结合而言)、有效浓度(EC50)和/或有效剂量(ED50)。
示例性的P′1类似物因对通常可以切割天然多肽的蛋白酶产生了抗性,与天然多肽相比(体外和体内)半衰期延长。但是,各种P′1类似物具有不同的半衰期(与天然多肽相比半衰期有不同变化)是可以接受的。本领域的技术人员可很容易地用标准方法对体外和/或体内半衰期进行测定。某些方案中,在相似测定条件下,类似物的体外或体内半衰期可以是天然多肽的0.5、0.6、0.7、0.8、.09、1.0、1.3、1.5、2、3、5、10、25、30、50、75、100或甚至超过100倍。
(b)肽类激素类似物的合成
本发明中的肽可用标准的固相合成方法制备。参见,例如Stewart,J.M.等.,Solid Phase Synthesis(Pierce Chemical Co.,2d ed.1984)。
本发明中的肽可用标准固相肽合成技术制备。众所周知,一定长度的多肽可用商业化的仪器和试剂,并根据厂家提供的说明书,通过阻断干扰基团、保护拟反应的氨基酸、连接、去保护和戴帽未反应的残基的步骤来制备。合适的仪器可以从,例如,AppliedBioSystems in Foster City,Calif.,或Biosearch Corporation in SanRaphael,Calif.获得。
在一个优选方法中,采用标准的自动固相合成方法,用带有合适侧链保护的叔丁氧羰基-α氨基酸进行肽合成。已完成的肽从固相支撑上取下,并用氟化氢的标准方法进行同步侧链去保护。粗制的肽进一步用0.1%三氟乙酸(TFA)配制的乙腈梯度洗脱液在半制备的反相HPLC(Vydac C18)上纯化,合成的肽用真空干燥的方法去除乙腈,然后溶于0.1%三氟乙酸水溶液中冻干。纯度用分析用RP-HPLC确定。合成的肽可被冻干,然后用水或0.01M的乙酸溶解制成1-2mg/ml浓度的溶液。
当肽含有非编码氨基酸或D-氨基酸时,前述合成方法是必需的。然而,对于基因编码的肽,可以借助重组技术,用合成的DNA序列在商业化的表达系统表达。
本发明的一个方面是制备多肽类似物的方法,其中所说的多肽对选自金属蛋白酶、丝氨酸蛋白酶、天冬氨酸蛋白酶和半胱氨酸蛋白酶的一组蛋白酶有抗性。在一个方案中,该丝氨酸蛋白酶是一个二肽基肽酶,如一个脯氨酸后切割二肽基肽酶。在另一个方案里,该二肽基肽酶是DPP IV。在任何上述描述中,制备蛋白酶抗性肽类似物可包括用以上式I或式II代表的氨基酸残基取代该肽类激素的一个或多个残基。
本发明的另一个方面是制备肽类激素类似物的方法,其中该肽类激素的氨基端序列为Xaa-Ala-Yaa-R,或Xaa-Pro-Yaa-R’,序列中的Xaa和Yaa代表氨基酸残基,R和R’各自独立地代表1到100个氨基酸残基(优选为约<90、<80、<70、<60、<50、<40、<30、<20或甚至<10个氨基酸残基),类似物上的Yaa被以上式I或式II代表的氨基酸残基所取代。
正如这里所详细概括的,本发明提供一个通用的制备蛋白酶抗性P′1类似物的方法,根据对已知底物上的某个特殊酶的酶切位点的了解,根据这里提供的制备蛋白酶抗性类似物的指导原则,可以很容易地构建出大量的抗切割P′1类似物,例如,抗丝氨酸蛋白酶、抗金属蛋白酶、抗天冬氨酸蛋白酶、和抗半胱氨酸蛋白酶切割的类似物。一旦制备出候选P′1类似物、可很容易地对其活性(如是否能作为蛋白酶的底物)进行测定并与天然多肽活性进行比较。
本领域有众多测定候选P′1类似物是否抗蛋白水解的方法,例如,特殊蛋白酶切割P′1类似物的能力可以在体外用无细胞系统进行测定。在一个这样的无细胞测定系统方案中,用可检测到的标记物,如放射性物质,对候选底物(如P′1类似物和/或天然多肽)进行末端标记,标记过的底物与蛋白酶一起孵育。一段时间后,终止反应取样品进行电泳,其发射性条带大小的改变提示该多肽已被蛋白酶切割,这种改变发生的比率提示了该多肽被蛋白酶切割的比率。可以将该比率与用天然多肽观察到的比率进行比较。
为进一步说明,测试P′1类似物的典型实验可以涉及到以下方法,天然多肽与认定的P′1类似物各自用放射性物质标记(注意:标记的目的是使多肽被切割后产生与标记的全长多肽在大小上有所不同的放射性片段),标记后的天然多肽与P′1类似物与某种特殊的蛋白酶共孵育,继共孵育后,用电泳的方法对天然多肽和P′1类似物进行分离,并分析被标记片段的迁移。人们可期待看到天然多肽(与蛋白酶共孵育前和后)的标记片段在大小上的变化,其较小的片段为被酶切割后的产物。然而,如果P′1类似物抗蛋白水解,在与酶进行共孵育后,要么不发生这种迁移改变,要么与天然多肽相比迁移改变的速度要慢得多。
也可用体外细胞实验来测定蛋白酶切割P′1类似物与切割天然多肽的相对能力。在一个这样的细胞实验中,在表达已知蛋白酶的细胞中加入天然多肽或P′1类似物,使天然多肽或P′1类似物进入细胞中,与以上描述的无细胞实一样,天然多肽与P′1类似物已被标记,对天然多肽或P′1类似物的切割的检测和对比可通过提取细胞蛋白、测定标记蛋白的迁移来进行。
在另一个细胞实验的例子里,在一种不表达已知蛋白酶的细胞中加入天然多肽或P′1类似物,使天然多肽或P′1类似物进入细胞中,在该细胞中进一步加入某种特殊蛋白酶,使该酶进入细胞内,通过对提取的细胞蛋白中标记蛋白的迁移的检测和对比来检测天然多肽或P′1类似物被切割的情况。
在任何以上提到的细胞实验中,本发明着重于使用各种原代细胞或细胞系中的任何一种,在某些例子里,选择一种特殊的细胞或细胞系来进行体外分析可能会有优势,例如,在某些例子里选用一个与P′1类似物拟应用于的细胞类型很接近的细胞系进行实验可能会有优势。然而,另一些例子里,在一些根据方便选用的非相关细胞或细胞系中进行候选P′1类似物的初步筛选和测试,在更特异的细胞系和必要时动物模型里进行后期的安全性和有效性实验可能更适用。
除了无细胞检测和细胞检测外,P′1类似物的蛋白酶抗性可以在许多动物模型中任何一种的体内进行。初步测试P′1类似物的蛋白水解反应可在野生型动物体内进行,在这样的初步测试中,P′1类似物的潜在阳性或阴性作用并不重要,重要的是P′1类似物是否能够抗蛋白水解。一旦一个特殊的P′1类似物在任何以上描述的无细胞试验、细胞试验、或体内试验中显示出蛋白酶抗性,可进行进一步的体外和体内试验以确定P′1类似物的治疗效果。
其他试验可用于评估蛋白酶抗性P′1类似物的特异功能活性,这些试验可根据特殊的P′1类似物来选择。例如,当多肽是一种生长因子,该生长因子类似物的功能活性可通过无细胞试验或细胞试验测定其与生长因子受体的结合能力并与天然多肽进行比较来检测。当多肽是一种肽类激素,该肽类激素的功能活性可通过无细胞试验或细胞试验测定其与受体的结合能力并与天然多肽进行比较来检测。当多肽是一种转录因子,该转录因子类似物的功能活性可通过测定其与合适DNA契合序列的结合能力或是否激活含有契合序列的报告重组子,并天然多肽进行比较来检测。在任何这些例子中,功能检测也可在动物模型中进行。
以下说明性例子提供了测定特殊多肽的P′1类似物的潜在方法。
1.促胰岛素活性试验
在某种方案中,本发明的P′1类似物是肽类激素类似物。活性GLP-1肽,7-34、7-35、7-36、7-37有促胰岛素活性,本发明提供了制备这些活性GLP-1肽的肽类似物的方法,GLP-1肽类似物的蛋白水解抗性能够很容易地被测定。另外,GLP-1肽类似物的功能活性可以通过检测该肽类激素类似物的促胰岛素特征来展示。促胰岛素活性能够通过,例如,将该已知多肽类似物加入到动物细胞中,或注射于动物体内,然后分别监测释放到培养基或动物循环系统中的免疫反应性胰岛素(IRI)。IRI的存在可通过一个特异性检测胰岛素的放射免疫试验来检测。
db/db小鼠是一种肥胖和糖尿病基因工程鼠品系,该db/db鼠在有高血糖和高胰岛素血症同时伴有肥胖,因此可作为肥胖2型糖尿病(NIDDM)的动物模型。可以从,例如Jackson实验室,购买到db/db小鼠。在一个示例性实施方案中,用一个包含有肽类激素类似物或对照的方案对db/db小鼠进行治疗,给药前和给药后的一定时间(如60分钟)从个小鼠的下眼眶采血。血糖测定可以用数种常规方法进行,如用血糖测定仪。然后对比对照组和肽类激素类似物组的血糖水平。
外源性GLP-1类似物的代谢途径的跟踪也可用非糖尿病小鼠和2型糖尿病小鼠模型的任一种来进行,候选类似物的效果的确定也一样。例如,高效液相(HPLC)、特异性放射免疫(RIAs)和酶联免疫吸附试验(ELISA)的联合使用,可检测GLP-1类似物的完整生物学活性和其代谢。参见,实例Deacon等(1995)Diabetes 44:1126-1131。在给予GLP-1后,可用NH2端导向的RIA和ELISA来测定完整的肽,以检测其在各试验之间的浓度差异,CO2H端特异性RIA可用来检测NH2端被截断的代谢产物。如果是非类似物,皮下注射后,GLP-1呈时间依赖性地迅速降解,形成一个在HPLC与GLP-1(9-36)同洗脱的代谢产物,并与GLP-1有同样的免疫反应谱。例如,给糖尿病病人皮下注射GLP-1后30分钟(n为8),代谢产物占用CO2H端RIA测得的血浆免疫反应增高的88.5+1.9%,其水平较健康受试者高(78.4+3.2%;n=8;P<0.05)。参见Deacon等,supra。静脉滴注后,GLP-1也大量降解。
测定GLP-1的促胰岛素释放活性的其他方法在U.S.Patent5,545,618上有公开。
(d)药物制剂
作为治疗用药,选定的P′1类似物与药学上可接受的载体一起制成制剂,以一个治疗有效量给予受试者,该有效治疗量根据不同的给药途径而定,如口服、静脉、或胃肠外给药,以将肽运达理想组织。在某些实施方案中,类似物是无热原的,即不会导致病人体温上升到临床上不能接受的水平。合适的药学上可接受的载体为那些常规用于肽类药物的物质,如稀释剂、赋形剂或相似物,参考可见″Remington′s Pharmaceutical Sciences″,17th Ed.,Mack PublishingCompany,Easton,Pa.,1985中药物制剂的一般指导原则。在本发明的一个实施方案中,该化合物被制成滴注制剂,如用作完全胃肠外液体营养补充治疗,或注射制剂,如皮下、肌肉或静脉注射,并且相应地制成无菌和无热原的水溶液,选择性地调节pH到人体可接受的范围,如微酸性或生理pH。所以,该化合物可以与载体,如蒸馏水,生理盐水、磷酸盐缓冲液或5%的葡萄糖溶液一同给药。如果愿意,P′1类似物水溶液可以结合一种可溶性增强剂,如乙酸和氢氧化钠,来加强其效果。
本发明中的类似物可以以药学上可接受的盐的形式给药。这些盐的例子包括,但不限于,那些与有机酸(如乙酸、乳酸、马来酸、柠檬酸、苹果酸、抗坏血酸、琥珀酸、苯甲酸、甲磺酸、或甲苯磺酸)形成的盐,与无机酸(如盐酸、硫酸或磷酸)形成的盐,与高分子酸(如鞣酸、羧甲基纤维素、多聚乳酸(polylactic)、多聚甘油酸(polyglycolic)或多聚乳酸甘油酸共聚物)形成的盐。
本发明中的P′1类似物的有效治疗剂量及其药学上可接受的载体物质(如碳酸镁、乳糖、或治疗性类似物可与其形成微球的磷脂)一起形成治疗性组合物(如丸剂、片剂、胶囊或液体剂),通过口服、静脉、透皮、肺部、阴道、皮下、鼻腔、离子渗透、气管内、颅内、心内、心包内、肌肉内给药给受试者。通过口服给药的丸剂、片剂或胶囊可以用保护性物质包裹,以保护活性组合物在胃内停留的时间内不受胃酸和肠酶的消化而顺利到达小肠。该治疗性组合物也可以生物降解或非生物降解持续释放制剂的形式皮下或肌肉给药。参见,例如美国专利序号3,773,919和4,767,628PCT申请号WO 94/15587。持续给药也可以植入或体外泵入(如INFUSAIDTM泵)的方法来完成。给药方式可以试间歇性的,如每日注射,或连续低剂量,如持续释放制剂。
本发明的治疗或诊断组合物以足以治疗或诊断疾病的量给予机体。本发明中的肽治疗以上提到的疾病或紊乱的有效剂量取决于给药的方式、受试者的年龄、体重和治疗情况,最终由参与治疗的医生或兽医决定。
以上提到的肽制剂用于治疗糖代谢、脂肪代谢和进食紊乱有关疾病也在本发明关注的范围内。
本发明的其他特征和优点显见于详述和权利要求中。
(v)使用方法
(1)诊断用途
本发明的肽类激素类似物可以以放射性标记或非标记的形式用于诊断或治疗疾病,这些疾病包括但不限于与糖代谢、脂肪代谢、进食和高血压有关的疾病。
优选用本发明的化合物的放射性标记复合体诊断和治疗疾病。在放射性标记方案中,本发明中的化合物可用于放射性同位素指引的外科手术,如WO 93/18797 and in Woltering,等(1994)Surgery116,1139-1147中所描述的。在一个优选实施方案中,发射γ射线的放射性核素,如99Tc,与本发明中的化合物形成的复合物被用于诊断SSTR-表达性肿瘤,继之,发射β射线的放射性核素,如188Re或186Re,与本发明中的化合物形成的复合物被用于治疗该肿瘤。
为了进行诊断,有效诊断剂量的本发明中的诊断或放射性诊断剂被使用,优选静脉给药。诊断有效剂量被定义为用常规的方法,如磁源、计算机化的断层摄影、γ闪烁成像、SPECT、PET和类似技术能够在体内有效定位或测到该诊断或放射性诊断剂的量。
闪烁成像用于诊断为优选,99Tc标记的本发明中的化合物以单一单位注射剂量用于机体,本发明提供的99Tc标记化合物可以与任何常规用于静脉注射的介质,如生理盐水介质或血浆介质一起给药。一般来讲,使用的单位剂量的放射性强度约为0.01mCi到100mCi,优选1mCi到50mCi。注射液单位剂量的体积约为0.01mL到10mL。注射用药后数分钟内体内显象即发生。然而,如果需要,显象也可在该放射性标记的化合物注射病人体内后数小时或更长的时间发生。在大多数例子中,约在0.1小时的时间内,给药剂量中的足够量将聚集于成象部位以便进行闪烁摄影。依据本发明,任何闪烁摄影成像技术均可使用。
(2)治疗方法
多肽在体内通常被蛋白酶水解,对于能够被已知治疗性多肽组合物治疗的疾病和状况,P′1类似物提供了一个改良的治疗方法。由于治疗性多肽因水解而降低或清除,及在一些情况下水解导致功能性拮抗物的产生,致使许多多肽药物在治疗某些特殊疾病或状况时的安全性和有效性大打折扣。因此,抗蛋白酶的P′1类似物的方法和组合物为各种疾病和病况的治疗提供了改良的方法。
为更清楚地阐明P′1类似物适用于治疗各种疾病和状况。我们提供了下述无限性例子,在某些实施方案中,本发明中的P′1类似物是肽类激素类似物。在某些实施方案中,这些肽类激素具有降低血糖水平、减肥、缓解受损的血糖耐受、抑制肝糖再生、抑制血脂水平和抑制醛糖还原酶的功能。它们因此可用于预防和/或治疗充血性心衰、高血糖症、肥胖、高脂血症、糖尿病并发症(包括糖尿病视网膜病、肾病、神经病变、白内障、冠心病和动脉粥样硬化),进而治疗肥胖有关的高血压和骨质疏松。所以,本发明的一个方面是治疗疾病的方法,该方法给予病人或受试者含有效治疗剂量的一个或多个肽类激素类似物,如这里公开的肽类激素类似物。
在某些实施方案中,用于治疗的抗蛋白水解类似物包括活性GLP-1肽的P′1类似物,具有生物学活性的各种长度的GLP-1肽包括:GLP-1(7-34)、GLP-1(7-35)、GLP-1(7-36)和GLP-1(7-37),以下是其序列:
GLP-1(7-37):HAE GTFTSDVSSY LEGQAAKEFI AWLVKGRG;
GLP-1(7-36):HAE GTFTSDVSSY LEGQAAKEFI AWLVKGR(-NH2);
GLP-1(7-35):HAE GTFTSDVSSY LEGQAAKEFI AWLVK;and
GLP-1(7-34):HAE GTFTSDVSSY LEGQAAKEFI AWLV.
在某些实施方案中,本发明涉及到改良血糖代谢的方法。GLP-1肽的P′1类似物可用于糖尿病病人,糖尿病是一种以胰岛素分泌的相对或绝对降低、胰岛素敏感性降低或胰岛素抵抗引起的高血糖症为特征的疾病,该疾病的发病和死亡主要由血管、肾、神经系统并发症引起。口服葡萄糖耐受试验在临床用于诊断糖尿病,在口服葡萄糖耐受试验中,病人对葡萄糖装载或攻击的生理反应被评估。在进食葡萄糖后,评估病人对葡萄糖攻击的生理反应,一般来讲,在几个预先设定的时间点测定病人的血糖水平(病人血浆、血清或全血中的葡萄糖浓度)。
这样,一方面,本发明涉及到治疗,涉及到蛋白酶抗性P′1类似物用于治疗心脏疾病、高血糖症、肥胖、高脂血症、糖尿病病发症(包括糖尿病视网膜病、肾病、神经病变、白内障、冠心病和动脉粥样硬化),进而治疗肥胖有关的高血压和骨质疏松。
在某些实施方案中,该受试P′1类似物可用作治疗各种心脏有关疾病的治疗方案的一部分,示例性的心脏相关疾病包括心肌梗、缺血-再灌注损伤、充血性心衰、和心脏停博。该受试P′1类似物也可用于心脏疾病的预防。
在某些实施方案中,该受试类似物可用于诱导对抑郁、睡眠窒息症、情感性分裂症、伴有精力不集中注意力缺陷综合症、记忆力丧失、健忘和发作性睡病的治疗和改善的唤醒。
在某些实施方案中,治疗有效剂量的蛋白酶抗性GLP-2类似物可以用于患有胃肠道疾病的病人。已经确定GLP-2可以用作营养剂,促进胃肠道组织的生长。GLP-2的效果尤其明显地表现在促进小肠生长的方面,这里称其为“肠道营养”效果。
这样,一方面,本发明涉及到治疗并涉及到使用GLP-2来促进胃肠道组织的生长和增殖,特别是小肠组织。例如,该方法可被用作创伤、炎症或肠道组织切除后的治疗方案的一部分,如需要强化肠道粘膜上皮的生长和修复时。
关于小肠组织,这样的生长可以很方便地通过与未治疗的对照组比较其小肠组织重量和长度的增加来测定。受试GLP-2类似物对小肠的作用也表现在增加隐窝加绒毛轴的高度方面。这里称这种活性为“肠营养”活性。受试方法的效果也可以用增加隐窝细胞的增殖和/或降低小肠细胞的程序性死亡来检测。这些细胞效果在空肠最为明显,包括空肠后段,特别是空肠前段。当实验动物用化合物治疗(或通过基因工程操作后自身表达该化合物)后出现小肠重量明显增加、隐窝加绒毛轴高度增加、或增加隐窝细胞的增殖增强、或小肠细胞的程序性死亡降低,该化合物被认为具有“肠营养作用”。一个可用于确定这种胃肠道生长的模型在US Patent 5,834,428中有公开。
通常,能够从增加小肠组织和继而增加小肠粘膜功能中的任一种受益的病人是该受试方法的候选者。可被治疗的特殊情况包括各种形式的腹泻,包括由小麦中的α-谷胶毒性反应引起的、以大量肠绒毛丧失为特征的乳糜性腹泻;低γ球蛋白血症性腹泻,这种腹泻常见于伴有各种常见的免疫缺陷或低γ球蛋白血症的病人,特征是绒毛高度降低。治疗效果可以通过肠道活检检查绒毛性状、通过生化试验检测营养吸收、通过病人体重的增加与病情有关的症状的减轻来监测。其他可以用本方法治疗的情况,或可用本方法进行预防的情况包括放射性肠炎、感染或感染后肠炎、节段性回肠炎、毒素和其他化学治疗剂引起的肠道损伤及短肠综合征。
更普遍的,本发明提供了一个治疗消化道疾病的治疗方法。用于此处的术语“消化道”指食物通过的管道,包括胃和肠。这里所用的术语“消化道疾病”指伴有消化道粘膜的质量或数量异常的疾病,包括溃疡或炎症性肠道疾病;先天的或后天获得的消化和吸收紊乱,包括吸收不良综合征、肠粘膜屏障功能丧失引起的疾病、蛋白丧失胃肠综合征;溃疡性疾病,包括胃溃疡、十二指肠溃疡、小肠溃疡、结肠溃疡和直肠溃疡;炎症性肠道疾病,包括食道炎、胃炎、十二指肠炎、肠炎、结肠炎、节段性回肠炎、直肠炎、胃肠的Behcet病、放射性肠炎、放射性结肠炎、放射性直肠炎、肠炎和药物性肠炎;吸收不良综合征,包括基础性吸收不良综合征,如二糖-分解酶缺乏、葡萄糖-半乳糖吸收不良、果糖吸收不良,继发性吸收不良综合征,如由静脉或胃肠道外营养或成份进食引起的消化道粘膜萎缩,小肠截断和分流引起的疾病,如短肠综合征,结膜穹隆(cul-de-sac)综合征;不消化性吸收不良综合征,如胃切除引起的疾病,如倾倒综合征。
这里所用的术语“消化道疾病药物”指用于消化道疾病的预防和治疗的药剂,包括如消化道溃疡药物、消化道炎症治疗药物、消化道粘膜萎缩治疗药物和消化道损伤治疗药物,消化道功能改善药物,包括胃肠道粘膜屏障功能的恢复和消化吸收功能改善药物。溃疡包括消化性溃疡和腐蚀性急性溃疡,又名急性粘膜损伤。
该方法因为促进肠粘膜增生,可用于消化和吸收不良的病理状况的预防和治疗,即粘膜萎缩的治疗和预防或消化道组织发育不全和外科切除导致的组织减少的治疗,同时改善消化和吸收。进一步,该方法可用于由于炎性疾病如肠炎、节段性回肠炎和溃疡性结肠炎引起的粘膜病理状态的治疗,还可用于消化道手术后引起的功能减低的治疗,例如,倾倒综合征,另可与抑制胃蠕动及食物从胃到空肠的快速移动一道用于十二指肠溃疡的治疗。进一步,胰高血糖素样肽可被有效地用于促进外科侵入的愈合并改善消化道功能。所以,本发明也提供了消化道粘膜萎缩的治疗药物、消化道损伤的治疗药物和含有胰高血糖素样肽作为活性成份的改善消化道功能的药物。
另外,本发明的方法能用于转变胰腺肽、肽YY和神经肽Y的药代动力学,它们都是胰腺多肽家族的成员。特别是已证明DPP IV以改变其受体选择性的方式涉及到这些肽的加工过程,可很容易地设计出这些具有DPP IV抗性的类似物。
神经肽(NPY)被认为作用于血管平滑肌紧张度以及血压的调节。NPY也降低心脏收缩力。NPY也是已知的最强的食欲刺激剂(Wilding等,(1992)J Endocrinology 132:299-302)。该中枢性激活进食(刺激食欲)效应主要由NYP Y1受体介导,并引起体内脂肪聚集(Stanley等,(1989)Physiology and Behavior 46:173-177)。例如,一个NPY类似物的可能用途就是生产刺激食欲的药物。虽然大半个世界都在努力减肥,但也有以增肥为目的情况发生。进食障碍的病例在世界范围内有增高趋势。随时间推移,患进食障碍的个体出现病理性食欲丧失,这种食欲丧失使再进食变得极端困难,这种进食困难常常在患者的体重低至甚至威胁生命的水平时仍然持续。因此,食欲刺激剂的使用将极大地加强健康护理者鼓励和支持严重营养不良的进食障碍病人再进食的能力。
试图在长时间营养不良后再进食遭遇困难的个体不只限于进食障碍者。任何原因引起的营养不良都可导致严重的食欲压抑,这给快速和容易地补充适当的营养给这些患者设置了障碍。刺激食欲的药物在治疗营养不良的患者方面将会有很多用途。
食欲丧失和消耗综合征常与其他疾病和状况有关,例如,各种癌症患者和AIDS患者常伴有消耗。这种严重的体重减轻和肌肉组织丧失可导致各种其他的并发症,包括能量丧失和免疫系统的进一步抑制。因此,有助于克服伴随其他疾病的食欲丧失和消耗的疗法和治疗将极大地改善那些正在与各种疾病搏斗的病人的生活质量。
最后的关于使用药物来刺激食欲和增加体重的例子涉及到农业领域,这些药物将有助于饲养动物,如商用牲畜,使它们有较高的平均重量和平均脂肪含量。例如,这样的治疗剂可通过喂食和喂水的方式给予牛、猪、鸡、羊、火鸡、山羊、水牛、鸵鸟等,以生产出较大的动物在食品工业中销售。
肽YY(PYY)和胰腺肽(PP)涉及到进食障碍、胃肠道紊乱和胰腺肿瘤(参见U.S.Patent 5,574,010)。
DPP IV已证明与生长激素释放激因子(GHRF)有关联,GHRF是一类同源肽包括胰高血糖素、肠泌素、血管活性肠肽(VIP)、组氨酸异亮氨酸肽(PHI)、垂体腺苷酸环化酶激活多肽(PACAP)、抑胃肽(GIP)和毒蜥皮肽(Kubiak等(1994)Peptide Res 7:153)家族中的成员。GHRF由下丘脑分泌,刺激垂体前叶释放生长激素(GH)。因此,该方法可用于改善对某些生长激素缺陷的儿童的临床治疗,在成人的临床治疗方面可改善营养和改变身体组成(肌肉对脂肪)。该方法也可用于动物方面,如提高奶产量和生产产量更高、瘦肉更多的牲畜。
本发明着重于在治疗方法中使用P′1类似物,方法中P′1类似物可单独构成治疗方案,也可是一个或多个P′1类似物作为一个更复杂的多因子治疗方案的一部分。例如,在治疗糖尿病和/或糖尿病并发症的方法中,本发明着重于给予病人P′1类似物,如GLP-1类似物。本发明进一步考虑在某些情况下,可能优选地给予病人一个以上的P′1类似物。如治疗方法可含有给予两个或两个以上的P′1类似物。这些类似物可以是同一多肽类似物(如GLP-1的两个不同类似物),或不同多肽的类似物。进一步,本发明认为可将一个或多个P′1类似物用作一个复杂治疗方案的一部分。在治疗糖尿病和糖尿病并发症时,示例性的治疗方案可以包括给予一个或多个P′1类似物、给予胰岛素并调节饮食和锻炼。
在进一步的多方面治疗方案中,本发明着重于给予一个或多个P′1类似物和一个或多个抑制内源性切割天然蛋白的特殊酶活性的抑制剂。在GLP-1的例子中,示例性的方法将含给予一个或多个肽类似物及一个或多个DPP IV抑制剂。一种特定酶的抑制剂可以是特异性的(如只调节DPP IV活性的抑制剂)或非特异性的(如调节多种丝氨酸蛋白酶的抑制剂)。另外,本发明还着重于给予一个或多个肽类似物及一个或多个降解内源性切割天然蛋白的特定酶的酶。在使用GLP-1的例子中,示例性的方法将含给予一个或多个肽类似物及一个或多个降解DPP IV的酶。这样的酶可以是特异性的(如一种只降解DPP IV的酶)或该酶可以降解多种其它蛋白(如可以降解多种丝氨酸蛋白的酶)。
(f)商业方法
本发明的其它方面提供了某种进行商业运作的方法。特别是实践本发明的方法可鉴别某些肽酶抗性的P′1类似物,如肽类激素类似物。该技术步骤与其他步骤之一的结合,提供了进行制药、农用化学品、生物技术、或优选生命科学商业活动的新方法。例如本发明中的P′1类似物可在多种疾病模型中测试其作为药物的有效性,在所得制剂配制、包装并随后上市用于疾病治疗之前,需对潜在的治疗组合物进行毒性和其他安全性方面的试验。换言之,这种制剂的开发和上市权或这些步骤的实施权可以授权给第三方考虑。在本发明的某些其他方面,这样鉴别的P′1类似物可用于提供给第三方考虑的信息中,以使其获得对该P′1类似物在生物或治疗方面的功效和负作用的更好了解。
在某些实施方案中,初步鉴别的P′1类似物可用于进一步优化,如进一步改良前导类似物的结构。这种优化可引致发展出具有最大蛋白水解抗性,并结合有药学上的其他如溶解、渗透、生物利用、毒性、致突变和药代方面所需的特性的类似物。
对前导类似物的结构修饰主要针对以上列举的参数进行。然而这种修饰必须考虑到对类似物的效能和活性的可能影响。例如当一个前导类似物在动物实验中显示毒性较大,可在保留所需的抗蛋白酶特性的前提下对该类似物进行降低毒性的修饰。
候选类似物(无论是否进行了修饰以改良体内性状的类似物)或类似物的联合必须进行药效和毒性试验。这样的治疗概况研究在制药领域被广泛应用。在进行人体试验之前,大量深入的治疗概况研究(临床前研究)需要完成,以确立初步的安全和效果参数。临床前研究建立该药物的作用机理,通过体外(如试管、烧杯、培养皿等)和动物试验研究其生物利用度、吸收、分布、代谢和消除。动物试验用于测试该药物能否提供所需的结果。使用不同剂量的药物来检测其效果、确认其可能发生的有害负作用并评估毒性。
简短地说,本领域技术人员应该知道,候选蛋白酶抗性类似物的鉴别是研发一个用于治疗的药物制剂的第一步。一定量的含有已知P′1类似物的药物制剂用于某种状况和疾病的治疗必须既安全又有效。常规用于本领域的早期药物试验,帮助回答潜在药物的安全和有效性方面的问题。在P′1类似物特别案例中,其药物制剂的有效性可很容易地在细胞培养物中进行初步评价,然后在小鼠和大鼠模型中进行。本领域技术人员可以很容易地选择出P′1类似物将要针对的特殊疾病的合适细胞和动物模型。简短地说,不同剂量的所述药物制剂可以以不同的时间表给予小鼠或大鼠。给药途径应该根据类似物的特殊性质和P′1类似物将要导入的细胞类型来进行选择。对照小鼠可给予安慰剂(如载体或赋形剂)。
在一个实施方案中,治疗概况研究包括类似物在细胞和动物体的毒性试验;对候选类似物进行药代动力学和代谢分析;在动物疾病模型中确定其有效性。在某些例子中,方法包括分析结构与活性的关系,根据有效性、安全性和药代动力学优化前导类似物。这些步骤的目标是选出一个候选类似物进行临床前研究,进而在人体试验前向FDA提出新药研究申请(“IND”)。
对前导类似物进行优化和进行治疗概况研究,一个目的就是要开发对某种蛋白酶有抗性且用药后负作用最小的P′1类似物。类似物在体外使用时,示例性类似物不应该对细胞培养物有额外毒性、不应该致细胞培养物突变、不应该对细胞培养物有致突变作用。在体内使用时,示例性类似物不应该有额外毒性(当用于人体是应该只有能够耐受的毒性)、不应该有致突变作用及不应该有致癌性。
毒性研究指对有效治疗剂量的药物制剂用于机体后可能发生的有害负作用进行评估。负作用可能有害也可能无害,一个与药物制剂有关的负作用可否接受由食品和药物监督管理局在正常审批过程中决定。该决定不是一成不变的(hard and fast),被认为可接受的负作用因影响因素而变化,这些因素包括:(a)被治疗的病情的严重程度,(b)其他可用的治疗和与这些治疗有关的负作用。例如,术语癌症包含一组复杂的涉及到异常调节的细胞生长、增殖和分化的疾病状态。作用仍被认为是可以接受的。在本发明中,一个负作用的严重与否取决于被治疗的状况和其他可用的治疗该状况的方法。
毒性试验可与有效性试验串连进行,给予有效治疗剂量的小鼠同时可用来监测制剂的负作用。
一个或多个在动物体内证明安全和有效的蛋白酶抗性P′1类似物能被制成药物制剂,然后这样的制剂可上市、流通和销售。示例性的P′1类似物和这些类似物的药物制剂可以单独销售,或制成药包/或药盒销售。进一步,在上述提到的任一方面,对一个或多个P′1类似物设计的商业运作方法可任选地包括编制病人和/或病人的医疗保险公司帐单的体系,和从病人和/或病人的保险公司收取适当的偿付体系。
实施例
以下实施例用于说明而非限制。
实施例1:蛋白酶抗性GLP-1类似物
给予GLP-1治疗是糖尿病的候选治疗方法。然而,阻碍给予GLP-1治疗的一个障碍是GLP-1在体内被DPP IV迅速降解。DPP IV的切割位点在GLP-1N端的丙氨酸和谷氨酸之间,先前的研究表明这种切割给予外源性GLP-1后极短的时间内就可发生(图1)。
为得到抵抗蛋白水解作用的肽类似物,我们构建了一个在GLP-1的P′1位点含四取代的类似物。在以下实施例中用到GLP1(7-37)。简短地讲,我们在GLP-1的P′1位的谷氨酸上进行了取代。两种所做和所试验过的取代是3-二甲基-天冬氨酸和3-丁基-甲基-甘氨酸。所得的类似物被命名为GLP-1(3DMA)(其中P′1位取代是3-二甲基-天冬氨酸)和GLP-1(BM)(其中P′1位取代是3-丁基-甲基-甘氨酸)。
图2是证实GLP-1(3DMA)和GLP-1(BM)与天然GLP-1相比具有抗DPP IV切割抗性的实验的概括。然而,最希望得到的肽类似物不仅要抗蛋白水解,而且还保留了天然肽的所有或大部分生物学活性。于是,我们进行了一系列实验来确定这些具有很强抗DPP IV降解能力的GLP-1类似物是否也保留了天然GLP-1的生物学活性。
实施例2:蛋白酶抗性GLP-1类似物保留了天然GLP-1的功能活性。
我们进行了一系列实验来测试GLP-1(3DMA)和GLP-1(BM)与天然GLP-1比较的功能活性。图3-4概括了这些实验的结果。简短地讲,我们检测了GLP-1的两个功能性质:GLP-1与其受体的结合和通过cAMP的产生来测定的信号传导。图3概括了测试GLP-1(3DMA)活性的试验。左边的图比较了受体结合动力学。我们注意到,GLP-1(3DMA)保留了与GLP-1受体结合的能力。另外我们注意到,与天然多肽相比,虽然结合力不完全相同,但相似。
右边的图是进一步的分析,它概括了确定GLP-1(3DMA)是否能够激起与天然GLP-1相似的信号的实验。用编码人GLP-1受体的cDNA瞬时转染COS-7细胞(接近106/10cm板),转染后一天,用胰酶将细胞消化,接种24孔板(密度接近105/孔)。转染后两天,分别用天然GLP-1(0.3μM)和GLP-1(3DMA)(10μM)与细胞在室温下孵育1小时,并设无二者的对照孔。用闪烁放射免疫亲近法检测细胞裂解物中与受体介导的信号相关的cAMP含量。如图3所示,GLP-1(3DMA)通过GLP-1受体使信号增强到与天然GLP-1无差别的程度。图4概括了对GLP-1(BM)活性进行检测的类似实验。简短地讲,用编码人GLP-1受体的cDNA瞬时转染COS-7细胞(接近106/10cm板),转染后一天,用胰酶将细胞消化,接种24孔板(密度接近105/孔)。转染后两天,分别用天然GLP-1(0.3μM)和GLP-1(BM)(10μM)与细胞在室温下孵育1小时,并设无二者的对照孔。用闪烁放射免疫亲近法检测细胞裂解物中与受体介导的信号有相关关系的cAMP含量。如图4所示,GLP-1(BM)通过GLP-1受体使信号增强到与天然GLP-1无差别的程度
实施例3:叔-亮氨酸取代的GLP-1类似物抵抗DPP IV的降解作用
实验1和实验2提供的数据证明在GLP-1的P′1位点上的两种不同取代生成了蛋白酶抗性肽类似物。我们还另外证明P′1位点上的第三种取代也能产生蛋白酶抗性肽类似物。简短地讲,用叔-亮氨酸取代(TLE)了GLP-1(7-37)的P′1位上的谷氨酸,并对DPP IV切割这种肽类似物的能力进行了测试。
图5显示了用DPP IV处理GLP-1(7-37)两小时(下色谱图)后与未用蛋白酶处理的GLP-1(7-37)(上色谱图)的HPLC/MS分析结果。正如所预期的那样,DPP IV处理导致GLP-1出现时间依赖性降解。
图6显示的是TLE修饰的GLP-1(7-37)类似物的HPLC/MS分析。用人DPP IV处理TLE修饰的GLP-1类似物两小时,对比该类似物与未用DPP IV处理的类似物在时间过程中的降解。层析结果的比较(注:上图为未被处理的肽类似物,下图为被处理的类似物)证明TLE修饰的GLP-1类似物可抵抗DPP IV的降解。
实施例4:P′1位上的各种取代可产生对其它蛋白酶的抗性
上述实施例提供了大量证据证明P′1位上的各种取代可产生对丝氨酸蛋白酶DPP IV的抗性。但是,这种P′1位的四取代方法产生的蛋白酶抗性不是DPP IV底物特异的。我们也已证明在模型底物的P′1位进行四取代获得了对凝血酶切割的抗性。虽然凝血酶同为丝氨酸蛋白酶,但其识别的切点与DPP IV不同,此处概括的结果提示,本发明中构建P′1类似物以获得抗任何各种蛋白酶的降解的方法有着广泛的应用范围。
图7概括了在凝血酶的模型底物的P′1位进行叔-亮氨酸取代从而获得抗蛋白水解抗性的证明实验。简短地讲,WALAPRSFA肽是凝血酶的模型底物。凝血酶的切点在精氨酸残基后。因此,该模型肽的丝氨酸残基是P′1位的。
WALAPR↓SFA
上述示例中,P′1位的丝氨酸用黑体字标明,箭头代表凝血酶在精氨酸后的切割位点。
为测试P′1位四取代引起抗凝血酶水解的能力,我们制备了在P′1位含叔-亮氨酸(TLE)的模型肽。该模型肽类似物序列如下,其中X代表TLE取代。
WALAPRXFA
为对比模型肽类似物与天然模型肽被凝血酶消化的情况,这些肽被10nM凝血酶在0.1M HEPES pH 8,0.14M NaCl,5mM CaCl2,0.5%PEG6000中消化4小时,消化完毕,比较消化和未消化的肽的C18反相HPLC结果,各个层析主峰的质谱结果见图7。如图7所示,未经修饰的肽被凝血酶有效切割,生成切割产物WALAPR。相反,TLE取代的肽类似物在此种条件下不能被凝血酶切割。
实施例5:稳定二甲基天冬氨酸GLP-1类似物的体内结果
图8显示使用三个不同剂量(40μg,4μg,0.4μg)的毒蜥外泌肽-4的糖尿病小鼠与生理盐水对照溶液的糖尿病小鼠相比体内不同时间血糖变化的百分比。
图9显示使用40μg剂量的GLP-1(TPA1B4)类似物的糖尿病小鼠与生理盐水对照或GLP-1对照的糖尿病小鼠相比体内不同时间血糖变化的百分比。
图10显示使用三个不同剂量(800μg,80μg,8μg)的GLP-1(TPA1B4)的糖尿病小鼠与生理盐水对照的糖尿病小鼠相比体内不同时间血糖变化的百分比。
GLP-1(TPA1B4)类似物是带有C末端酰胺和第9位β-二甲基天冬氨酸残基的GLP-1残基7-36片段类似物,TPA1B4的序列是:
HAXGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2
体内实验用雌性5-7周龄的BKS.Cg-m+/-LePr(db)/J鼠进行,实验开始前用两周时间将小鼠调节到自然生长(vivarium)状态,小鼠在加压、单独通气的笼子中饲养,用标准的啮齿类动物食物喂养,随意进食和饮水。血糖用ThereaSense Freestyle监测仪测定。每次测定时用针将小鼠尾静脉划破,采血一小滴(约10μL)。各指示剂量的GLP-1类似物(TPA1B)和毒蜥外泌肽-4用0.2ml磷酸盐缓冲液(PBS)溶解后腹腔内注射。本实验的盐水对照组注射0.2mlPBS。血糖浓度分别在t=0、30分、1小时、2小时、3小时、4小时、5小时(和6小时)。图8和图9的为5只小鼠的平均值。
图11显示使用20mg/kg剂量的GLP-1类似物(TPA1B4)的糖尿病小鼠与生理盐水对照或GLP-1对照的糖尿病小鼠相比体内不同时间血糖变化的百分比。
图12显示使用20mg/kg剂量的GLP-1类似物(TPA1B4)的糖尿病小鼠与生理盐水对照或GLP-1对照的糖尿病小鼠体内不同时间血糖水平的比较。
雌性5-7周龄的BKS.Cg-m+_LePr(db)/J鼠进行,实验开始前用两周时间将小鼠调节到自然生长(vivarium)状态,小鼠在加压、单独通气的笼子中饲养,用标准的啮齿类动物食物喂养,随意进食和饮水。血糖用ThereaSense Freestyle监测仪测定。每次测定时用针将小鼠尾静脉划破,采血一小滴(约10μL)。小鼠从给药前两小时开始禁食直至实验结束。GLP-1类似物(TPA1B)和GLP-1用磷酸盐缓冲液(PBS)溶解后,腹腔内注射0.4ml指示剂量给药。本实验的盐水对照组注射0.4ml PBS。血糖浓度分别在t=0、30分、1小时、4小时测定。给出的值为10只小鼠的平均值。
图13显示使用三个不同剂量(8μg,0.8μg,0.08μg)的毒蜥外泌肽-4的糖尿病小鼠与生理盐水对照的糖尿病小鼠体内不同时间血糖变化的百分比。
图14显示使用800μg剂量的GLP-1的糖尿病小鼠与生理盐水对照的糖尿病小鼠体内不同时间血糖变化的百分比。
图15显示使用8μg和0.8μg两个剂量的GLP-1类似物(P1732)的糖尿病小鼠与生理盐水对照的糖尿病小鼠体内不同时间血糖变化的百分比。
GLP-1类似物P1732是GLP-1残基7-36的类似物,该类似物结合了尾部带有C末端酰胺的毒蜥外泌肽-4的一部分、且第9位上有一个β-二甲基天冬氨酸残基。P1732序列如下:
HAXGTFTSDVSSYLEGQAAKEFIAWLVKGRPSSGAPPPS-NH2
体内实验用雌性5-7周龄的BKS.Cg-m+/_LePr(db)/J鼠进行,实验开始前用两周时间将小鼠调节到自然生长状态,小鼠在加压、单独通气的笼子中饲养,用标准的啮齿类动物食物喂养,随意进食和饮水。血糖用ThereaSense Freestyle监测仪测定。每次测定时用针将小鼠尾静脉划破,采血一小滴(约10μL)。小鼠从给药前两小时开始禁食直至实验结束。GLP-1类似物(P1732)用磷酸盐缓冲液(PBS)溶解后,腹腔内注射0.4ml指示剂量给药,本实验的盐水对照组注射0.4ml PBS。分别在用药前和用药后的30、60和240分钟测定血糖。给出的P1732数据为5只小鼠的平均值、盐水对照为10只小鼠平均值。
图16显示的是式(II)的示例性实施方案,其中天然存在的氨基酸在β位(3-位)被R1和R2修饰,这里R1和R2为独立的低级烷基或卤素。在优选实施方案中,R1和R2二者皆为低级烷基。在更优选的实施方案中,R1和R2独立为甲基、乙基或丙基。在最优选的实施方案中,R1和R2二者都是甲基。
所有出版物、专利或专利申请通过整体引用结合到本文中,其程度与每个出版物、专利或专利申请通过整体引用具体而单独指明地结合到本文中相同。
等价物或等同方法
本领域技术人员用常规的实验就能识别或确定无数的这里描述的化合物的等价物及其使用方法的方法。这样的等价物或等同方法被认为在本发明的范围内并被下述权利要求所保护。
序列表
<110>塔夫茨大学信托人(Trustees of Tufts College)
W.W.巴乔夫钦(Bachovchin,William W.)
H.-S.赖(Lai,Hung-sen)
D.G.桑福德
<120>肽和多肽药物的稳定类似物
<130>TUU-PWO-011
<140>PCT/US04/15488
<141>2004-05-17
<150>US 60/471,411
<151>2003-05-15
<160>36
<170>FastSEQ for Windows Version 4.0
<210>1
<211>30
<212>PRT
<213>人(Homo Sapiens)
<400>1
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg
20 25 30
<210>2
<211>30
<212>PRT
<213>人(Homo Sapiens)
<400>2
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg
20 25 30
<210>3
<211>33
<212>PRT
<213>人(Homo Sapiens)
<400>3
His Ala Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp
<210>4
<211>42
<212>PRT
<213>人(Homo Sapiens)
<400>4
Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210>5
<211>36
<212>PRT
<213>人(Homo Sapiens)
<400>5
Tyr Pro Ser Lys Pro Asp Asn Pro Gly Glu Asp Ala Pro Ala Glu Asp
1 5 10 15
Met Ala Arg Tyr Tyr Ser Ala Leu Arg His Tyr Ile Asn Leu Ile Thr
20 25 30
Arg Gln Arg Tyr
35
<210>6
<211>27
<212>PRT
<213>人(Homo Sapiens)
<400>6
Ala Pro Leu Glu Pro Val Tyr Pro Gly Asp Asn Ala Thr Pro Glu Gln
1 5 10 15
MetAla Gln Tyr Ala Ala Asp Leu Arg Arg Tyr
20 25
<210>7
<211>36
<212>PRT
<213>人(Homo Sapiens)
<400>7
Tyr Pro Ile Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu
1 5 10 15
Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr
20 25 30
Arg Gln Arg Tyr
35
<210>8
<211>39
<212>PRT
<213>人(Homo Sapiens)
<400>8
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Glu Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210>9
<211>39
<212>PRT
<213>人(Homo Sapiens)
<400>9
His Ser Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210>10
<211>31
<212>PRT
<213>人(Homo Sapiens)
<220>
<221>ACT_SITE
<222>3
<223>Xaa=任何氨基酸
<400>10
His Ala Xaa Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly
20 25 30
<210>11
<211>30
<212>PRT
<213>人(Homo Sapiens)
<220>
<221>ACT_SITE
<222>3
<223>Xaa=任何氨基酸
<400>11
His Ala Xaa Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg
20 25 30
<210>12
<211>33
<212>PRT
<213>人(Homo Sapiens)
<220>
<221>ACT_SITE
<222>3
<223>Xaa=任何氨基酸
<400>12
His Ala Xaa Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn
1 5 10 15
Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr
20 25 30
Asp
<210>13
<211>42
<212>PRT
<213>人(Homo Sapiens)
<220>
<221>ACT_SITE
<222>3
<223>Xaa=任何氨基酸
<400>13
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210>14
<211>36
<212>PRT
<213>人(Homo Sapiens)
<220>
<221>ACT_SITE
<222>3
<223>Xaa=任何氨基酸
<400>14
Tyr Pro Xaa Lys Pro Asp Asn Pro Gly Glu Asp Ala Pro Ala Glu Asp
1 5 10 15
Met Ala Arg Tyr Tyr Ser Ala Leu Arg His Tyr Ile Asn Leu Ile Thr
20 25 30
Arg Gln Arg Tyr
35
<210>15
<211>27
<212>PRT
<213>人(Homo Sapiens)
<220>
<221>ACT_SITE
<222>3
<223>Xaa=任何氨基酸
<400>15
Ala Pro Xaa Glu Pro Val Tyr Pro Gly Asp Asn Ala Thr Pro Glu Gln
1 5 10 15
Met Ala Gln Tyr Ala Ala Asp Leu Arg Arg Tyr
20 25
<210>16
<211>36
<212>PRT
<213>人(Homo Sapiens)
<220>
<221>ACT_SITE
<222>3
<223>Xaa=任何氨基酸
<400>16
Tyr Pro Xaa Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu
1 5 10 15
Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr
20 25 30
Arg Gln Arg Tyr
35
<210>17
<211>39
<212>PRT
<213>人(Homo Sapiens)
<220>
<221>ACT_SITE
<222>3
<223>Xaa=任何氨基酸
<400>17
His Gly Xaa Gly Thr Phe Thr Ser Asp Leu Ser Lys Glu Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210>18
<211>39
<212>PRT
<213>人(Homo Sapiens)
<220>
<221>ACT_SITE
<222>3
<223>Xaa=任何氨基酸
<400>18
His Ser Xaa Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210>19
<211>27
<212>PRT
<213>人(Homo Sapiens)
<400>19
Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala
1 5 10 15
Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg
20 25
<210>20
<211>36
<212>PRT
<213>人(Homo Sapiens)
<400>20
Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala
1 5 10 15
Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Pro Ser Ser Gly Ala
20 25 30
Pro Pro Pro Ser
35
<210>21
<211>27
<212>PRT
<213>人(Homo Sapiens)
<400>21
Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala
1 5 10 15
Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg
20 25
<210>22
<211>30
<212>PRT
<213>人(Homo Sapiens)
<400>22
Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn Leu Ala Ala
1 5 10 15
Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr Asp
20 25 30
<210>23
<211>39
<212>PRT
<213>人(Homo Sapiens)
<400>23
Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys Ile His Gln
1 5 10 15
Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys Lys Asn Asp
20 25 30
Trp Lys His Asn Ile Thr Gln
35
<210>24
<211>33
<212>PRT
<213>人(Homo Sapiens)
<400>24
Lys Pro Asp Asn Pro Gly Glu Asp Ala Pro Ala Glu Asp Met Ala Arg
1 5 10 15
Tyr Tyr Ser Ala Leu Arg His Tyr Ile Asn Leu Ile Thr Arg Gln Arg
20 25 30
Tyr
<210>25
<211>24
<212>PRT
<213>人(Homo Sapiens)
<400>25
Glu Pro Val Tyr Pro Gly Asp Asn Ala Thr Pro Glu Gln Met Ala Gln
1 5 10 15
Tyr Ala Ala Asp Leu Arg Arg Tyr
20
<210>26
<211>33
<212>PRT
<213>人(Homo Sapiens)
<400>26
Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg
1 5 10 15
Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg
20 25 30
Tyr
<210>27
<211>44
<212>PRT
<213>人(Homo Sapiens)
<400>27
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210>28
<211>41
<212>PRT
<213>人(Homo Sapiens)
<400>28
Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln Leu Ser Ala
1 5 10 15
Arg LysLeu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly Glu Ser Asn
20 25 30
Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210>29
<211>31
<212>PRT
<213>人(Homo Sapiens)
<400>29
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly
20 25 30
<210>30
<211>30
<212>PRT
<213>人(Homo Sapiens)
<400>30
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg
20 25 30
<210>31
<211>28
<212>PRT
<213>人(Homo Sapiens)
<400>31
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys
20 25
<210>32
<211>27
<212>PRT
<213>人(Homo Sapiens)
<400>32
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val
20 25
<210>33
<211>9
<212>PRT
<213>人(Homo Sapiens)
<400>33
Trp Ala Leu Ala Pro Arg Ser Phe Ala
1 5
<210>34
<211>9
<212>PRT
<213>人(Homo Sapiens)
<220>
<221>ACT_SITE
<222>7
<223>Xaa=任何氨基酸
<400>34
Trp Ala Leu Ala Pro Arg Xaa Phe Ala
1 5
<210>35
<211>30
<212>PRT
<213>人(Homo Sapiens)
<220>
<221>ACT_SITE
<222>3
<223>Xaa=任何氨基酸
<400>35
His Ala Xaa Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg
20 25 30
<210>36
<211>39
<212>PRT
<213>人(Homo Sapiens)
<220>
<221>ACT_SITE
<222>3
<223>Xaa=任何氨基酸
<400>36
His Ala Xaa Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
Claims (25)
1.一种生物活性肽或多肽因子的蛋白酶抗性类似物,该肽或多肽因子的氨基酸序列包括在生理条件下被靶蛋白酶切割的蛋白酶底物序列,其中所述类似物的氨基酸序列与所述肽或多肽因子相对应,但所述蛋白酶底物序列的P′1残基被具有四取代的Cβ碳的氨基酸类似物所替代,相对所述肽或多肽因子来说,该P′1残基替代降低了该类似物对所述靶蛋白酶切割的敏感性。
3.权利要求2的蛋白酶抗性类似物,其中R1和R2独立选自甲基、乙基或丙基。
4.权利要求2的蛋白酶抗性类似物,其中R1和R2均为甲基。
5.权利要求2的蛋白酶抗性类似物,其中R3选自低级烷基、苯基、羟苯基、吲哚、咪唑、羟基、-COOH、-CH2COOH、-CH2CH2-NC(=NH)NH2、-CH2C(=O)NH2、-CH2CH2C(=O)NH2、-SH或-CH2SCH3。
6.权利要求2的蛋白酶抗性类似物,所述蛋白酶抗性类似物保留了至少50%的所述活性肽或多肽因子的生物学活性。
7.权利要求2的蛋白酶抗性类似物,其中靶蛋白酶为丝氨酸蛋白酶、金属蛋白酶、天冬氨酸蛋白酶或半胱氨酸蛋白酶。
8.权利要求2的蛋白酶抗性类似物,其中所述生物学活性多肽因子选自GLP-1、GLP-2、GIP、NPY、PP和PYY。
9.权利要求2的蛋白酶抗性类似物,其中所述生物学活性多肽因子选自脑啡肽、Leu-脑啡肽、Met-脑啡肽、血管紧张素I、血管紧张素II、血管加压素、内皮素、血管活性肠肽、神经降压素、内啡肽、胰岛素、grarnicidin、paracelsin、δ-睡眠诱导肽、促性腺激素释放激素、人甲状旁腺激素(1-34)、Wrighton等描述的截断的红细胞生成素类似物(Wrighton等,1996,Science 273:458-463)、特殊的EMP-1、心钠肽(ANP、ANF)、人脑钠肽(hBNP)、抗菌肽、运动升压素、neurophysins、弹力素、guamerin、心房肽I、心房肽II、心房肽III、δ啡肽I、δ啡肽II、血管升压素、缓激肽、强啡肽、强啡肽A、强啡肽B、生长激素释放因子、生长激素、生长激素释放肽、缩宫素、降钙素、降钙素基因相关肽、降钙素基因相关肽II、生长激素释放肽、速激肽、促肾上腺皮质激素(ACTH)、脑钠多肽、胆囊收缩素、促肾上腺皮质激素释放因子、diazeparn结合抑制剂片段、FMRF-酰胺、甘丙肽、胃肠释放多肽、胃肠抑制多肽、胃泌素、胃泌素释放肽、胰高血糖素、胰高血糖素样肽-1、胰高血糖素样肽-2、LHRH、黑色素聚集激素、促黑素(MSH)、α-MSH、吗啡调节肽、促胃动素、神经激肽-A、神经激肽-B、神经介素13、神经介素C、神经介素K、神经介素N、神经介素U、神经肽K、神经肽Y、垂体腺苷酸环化酶激活多肽(PACAP)、胰多肽、肽YY、肽组氨酸-甲硫氨酸酰胺(PHM)、肠泌素、生长抑素、底物K、促甲状腺激素释放激素(TRH)、京都啡肽、促黑素抑制素(MIF-1)、血小板生成素类似物、特别是AF 12505、胰岛素样生长因子I(57-70)、胰岛素样生长因子I(30-41)、胰岛素样生长因子I(24-41)、胰岛素样生长因子II(33-40)、胰岛素样生长因子II(33-40)、胰岛素样生长因子II(69-84)、生长激素(GH)-释放肽-6(GHRP-6)、β-白介素1(163-171)、β-白介素II(44-56)、白介素II(60-70)、表皮生长因子、双价水蛭素(水蛭肽)、水蛭肽-I、C-型利尿钠肽、鸟氨酸加压素(也称8-鸟氨酸-加压素)、奥曲肽、eptifibatide、降钙素基因相关肽(CGRP)、内吗啡肽-1;内吗啡肽-2、伤害感受肽、血管紧张素原、肾上腺髓质素、抗心律失常肽(AA-P)、拮抗剂G、indolicidin、骨钙蛋白、cortistatin 29、cortistatin 14、PD-145065、PD-142893、纤维蛋白原结合抑制肽、瘦体素、GR 83074、副甲状腺激素相关多肽、血管紧张素原、亮抑酶肽,及其任何修饰的或截断的类似物。
10.一种生物活性肽或多肽因子的蛋白酶抗性类似物,该肽或多肽因子的氨基酸序列包括在生理条件下被靶脯氨酸后切割蛋白酶切割的蛋白酶底物序列,其中所述类似物的氨基酸序列与所述肽或多肽因子序列相对应,但所述蛋白酶底物序列的P′1残基被式I的氨基酸类似物替代:
其中,
R1和R2独立选自低级烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基、烷氧基、羧基、氨基甲酰基、羰基、卤素、羟基、胺或氰基,或R1和R2一起形成4-7个原子的环;R3选自低级烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基、氨基、烷氧基、卤素、羧基、氨基甲酰基、羰基、氰基、硫代烷基、酰基氨基、酰氨基、氰基、硝基、叠氮基、硫酸酯基、磺酸酯基、亚磺酰氨基、-(CH2)mR4、-(CH2)mOH、-(CH2)mCOOH、-(CH2)mO-低级烷基、-(CH2)mO-低级烯基、-(CH2)nO(CH2)mR4、-(CH2)mSH、-(CH2)mS-低级烷基、-(CH2)mS-低级烯基、-(CH2)nS(CH2)m-R4、(CH2)mNH2、(CH2)mN-C(=NH)NH2、-(CH2)mC(=O)NH2或-(CH2)mNH2;
R4每次出现独立代表芳基、芳烷基、环烷基、环烯基或杂环;
m为0、1或2;且
n为0、1或2。
11.一种药物制剂,所述药物制剂包含权利要求1-10中任一项的蛋白酶抗性类似物。
12.一种封装的药物制剂,所述药物制剂包含权利要求1-10中任一项的蛋白酶抗性类似物与药学上可接受的赋形剂、标签和/或病人用药说明书。
13.一种封装的兽用药物制剂,所述兽用药物制剂包含权利要求1-10中任一项的蛋白酶抗性类似物与可接受的赋形剂、标签和/或动物用药说明书。
14.一种治疗或预防给予蛋白酶抗性类似物将会有益的疾病的方法,所述方法包括给予权利要求1-10中任一项的生物活性肽或多肽因子。
15.权利要求14的方法,其中蛋白酶抗性类似物为GLP-1、GIP或PYY类似物,所述疾病选自一种或多种胰岛素抗性、葡萄糖不耐受、心脏相关疾病、高血糖症、高胰岛素血症、肥胖、高脂血症、高脂蛋白血症、消化道粘膜异常、进食紊乱和胃肠道紊乱。
16.权利要求14的方法,其中蛋白酶抗性类似物为GLP-2类似物,所述疾病选自一种或多种节段性回肠炎和炎症性肠道疾病。
17.权利要求1-10中任一项的蛋白酶抗性类似物,进一步含有毒蜥外泌肽-4的C末端氨基酸序列。
18.权利要求17的蛋白酶抗性类似物,其中毒蜥外泌肽-4的C末端氨基酸序列为PSSGAPPPS。
21.权利要求20的方法,其中所述疾病或病症选自心脏相关疾病、高血糖症、肥胖、高脂血症、糖尿病并发症、肥胖相关高血压、骨质疏松、抑郁、情感性分裂症、睡眠窒息症、伴有精力不集中的注意力缺陷综合征、记忆力丧失、健忘、发作性睡病和胃肠道疾病。
22.权利要求21的方法,其中所述疾病或病症为选自心肌梗塞、缺血再灌注损伤、充血性心衰和心脏停博的心脏相关疾病。
23.权利要求21的方法,其中所述疾病或病症选自抑郁情感性分裂症、睡眠窒息症、注意力缺陷综合征、记忆力丧失、健忘和发作性睡病。
24.权利要求21的方法,其中所述疾病或病症为选自局限性肠炎(节段性回肠炎)和炎性肠道疾病的胃肠疾病。
25.一种调节血糖代谢的方法,所述方法包括给予生物活性肽或多肽因子的蛋白酶抗性类似物,所述肽或多肽因子有以下氨基酸序列:
HAXGTFTSDVSSYLEGQAAKEFIAWLVKGRPSSGAPPPS-NH2
其中X为式II的氨基酸类似物:
其中
R1和R2独立选自低级烷基或卤素;
R3选自低级烷基、芳基、羟基基团、-(CH2)m-COOH、-(CH2)m-NH2、-(CH2)m-N-C(=NH)NH2、-(CH2)m-C(=O)NH2、-SH或-(CH2)m-S-CH3;
m为0、1或2。
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EP2275117B1 (en) * | 2001-07-31 | 2016-10-26 | The Government of the United States of America, as represented by the Secretary of the Department of Health and Human Services | GLP-1, exendin-4, peptide analogs and uses thereof |
IL160493A0 (en) | 2001-08-23 | 2004-07-25 | Lilly Co Eli | Glucagon-like peptide-1 analogs |
US7020706B2 (en) | 2002-06-17 | 2006-03-28 | Bmc Software, Inc. | Method and system for automatically updating multiple servers |
US20040024285A1 (en) | 2002-06-21 | 2004-02-05 | Helmut Muckter | Blood pump with impeller |
EP1633384B1 (en) * | 2003-05-15 | 2012-03-14 | Trustees Of Tufts College | Stable analogs of glp-1 |
BRPI0615573A2 (pt) * | 2005-09-08 | 2011-05-24 | Tufts College | análogos de glp-1 estabilizados |
-
2004
- 2004-05-17 EP EP20040752496 patent/EP1633384B1/en not_active Expired - Lifetime
- 2004-05-17 CN CN2004800198500A patent/CN1822851B/zh not_active Expired - Fee Related
- 2004-05-17 CA CA2525574A patent/CA2525574C/en not_active Expired - Fee Related
- 2004-05-17 US US10/847,220 patent/US7259234B2/en not_active Expired - Fee Related
- 2004-05-17 ES ES04752496T patent/ES2383752T3/es not_active Expired - Lifetime
- 2004-05-17 AT AT04752496T patent/ATE549028T1/de active
- 2004-05-17 AU AU2004240630A patent/AU2004240630B2/en not_active Ceased
- 2004-05-17 JP JP2006533167A patent/JP4699374B2/ja not_active Expired - Fee Related
- 2004-05-17 WO PCT/US2004/015488 patent/WO2004103390A2/en active Application Filing
- 2004-05-17 CN CN2011100388475A patent/CN102174102A/zh active Pending
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- 2011-01-07 AU AU2011200062A patent/AU2011200062B2/en not_active Ceased
- 2011-08-09 US US13/205,844 patent/US9102756B2/en not_active Expired - Fee Related
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Cited By (12)
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CN102675453A (zh) * | 2011-03-09 | 2012-09-19 | 杭州中肽生化有限公司 | 一种促肾上腺皮质激素的类似物及其制备方法和用途 |
CN102675453B (zh) * | 2011-03-09 | 2016-04-20 | 中肽生化有限公司 | 一种促肾上腺皮质激素的类似物及其制备方法和用途 |
CN106232623A (zh) * | 2014-04-22 | 2016-12-14 | Txp制药股份有限公司 | 具有支链氨基酸探针的肽类似物 |
CN104004061A (zh) * | 2014-06-23 | 2014-08-27 | 苏州普罗达生物科技有限公司 | 白介素-33抑制剂多肽及其应用 |
CN104004059A (zh) * | 2014-06-23 | 2014-08-27 | 苏州普罗达生物科技有限公司 | 一种关于白介素-33抑制剂多肽及其应用 |
CN104004061B (zh) * | 2014-06-23 | 2016-03-02 | 南通普悦生物医药有限公司 | 白介素-33抑制剂多肽及其应用 |
CN104004059B (zh) * | 2014-06-23 | 2016-03-30 | 周越 | 一种关于白介素-33抑制剂多肽及其应用 |
CN108853147A (zh) * | 2018-07-24 | 2018-11-23 | 苏州大学 | 一种缓释外泌体的多肽纳米纤维水凝胶及其制备方法与应用 |
CN108853147B (zh) * | 2018-07-24 | 2021-12-24 | 苏州大学 | 一种缓释外泌体的多肽纳米纤维水凝胶及其制备方法与应用 |
CN109232747A (zh) * | 2018-09-26 | 2019-01-18 | 哈尔滨工业大学 | 强啡肽a(1-8)与神经降压素(8-13)相偶联的环化杂合肽及其合成方法和应用 |
CN111265653A (zh) * | 2020-02-09 | 2020-06-12 | 华中科技大学同济医学院附属协和医院 | 心房利钠肽在制备炎症性肠病治疗药物中的应用 |
CN111265653B (zh) * | 2020-02-09 | 2023-05-09 | 华中科技大学同济医学院附属协和医院 | 心房利钠肽在制备炎症性肠病治疗药物中的应用 |
Also Published As
Publication number | Publication date |
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JP2007530442A (ja) | 2007-11-01 |
US9102756B2 (en) | 2015-08-11 |
WO2004103390A3 (en) | 2005-06-30 |
WO2004103390A2 (en) | 2004-12-02 |
IL232501A (en) | 2016-11-30 |
US20120130044A1 (en) | 2012-05-24 |
CA2525574A1 (en) | 2004-12-02 |
HK1088840A1 (en) | 2006-11-17 |
US7994121B2 (en) | 2011-08-09 |
ATE549028T1 (de) | 2012-03-15 |
US7259234B2 (en) | 2007-08-21 |
US20050049177A1 (en) | 2005-03-03 |
US20080051557A1 (en) | 2008-02-28 |
IL171854A (en) | 2014-05-28 |
EP1633384B1 (en) | 2012-03-14 |
CN1822851B (zh) | 2011-04-13 |
CA2525574C (en) | 2015-06-30 |
AU2011200062A1 (en) | 2011-01-27 |
AU2011200062B2 (en) | 2013-01-10 |
CN102174102A (zh) | 2011-09-07 |
US20170246255A1 (en) | 2017-08-31 |
EP1633384A2 (en) | 2006-03-15 |
AU2004240630A1 (en) | 2004-12-02 |
AU2004240630B2 (en) | 2010-10-07 |
IL232501A0 (en) | 2014-06-30 |
JP4699374B2 (ja) | 2011-06-08 |
ES2383752T3 (es) | 2012-06-26 |
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