CN1335853A - 整联蛋白αvβb的抑制剂 - Google Patents
整联蛋白αvβb的抑制剂 Download PDFInfo
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- CN1335853A CN1335853A CN99814760A CN99814760A CN1335853A CN 1335853 A CN1335853 A CN 1335853A CN 99814760 A CN99814760 A CN 99814760A CN 99814760 A CN99814760 A CN 99814760A CN 1335853 A CN1335853 A CN 1335853A
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- leu
- arg
- asp
- thr
- peptide
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Abstract
本发明描述了一些新颖的肽段,它们可作为整联蛋白的配体,具有生物活性。这些肽段具有共同的基序,即-Asp Leu Xaa Xaa Leu,或具一种优选的形式Arg Xaa Asp Leu Xaa Xaa Leu Arg,其中Xaa指任一合适的氨基酸残基。本发明中的肽段可用作整联蛋白αvβ6受体的有效抑制剂,从而可用于治疗各种疾病和病理学上的发现。
Description
本发明描述了一些新颖的肽段，它们可作为整联蛋白的配体，具有生物活性。这些肽段具有共同的结构上的基序，即--Asp Leu Xaa XaaLeu，或具一种优选的形式Arg Xaa Asp Leu Xaa Xaa Leu Arg，其中Xaa指任一合适的氨基酸残基名。本发明中的肽段可用作整联蛋白αvβ6受体的有效抑制剂，从而可用于各种疾病和病理学上状况。
整联蛋白属于异源二聚体家族的I组。异源二聚体一些跨膜受体，它们在细胞---基质和细胞---细胞粘附过程中起一种重要作用(Tuckell et al.，1996，Symp.Soc.Exp.Biol.47)。异源二聚体大致分为三类：β1整联蛋白可作为胞外基质受体；β2整联蛋白对白细胞具可激活性，在炎症过程中可被引发；αv整联蛋白可影响创伤恢复和其他病理过程中的细胞应答(Marshall and Hart，1996，Semin.CancerBiol.7，1991)。
整联蛋白α5β1、αIIbβ3、α8β1、αvβ1、αvβ3和αvβ6都与肽段序Arg-Gly-Asp(RGD)相结合，例如在纤连蛋白天然配体中的RGD序列。含有RGD的可溶性肽段能抑制上述的整联蛋白与纤连蛋白的相互作用。αvβ6是一种相对稀有的整联蛋白(Busk et al.，1992 J.Biol.Chem.267(9)，5790)，在上皮组织修复过程中其数量急剧增加，并优先结合到纤连蛋白和肌腱蛋白的天然基质分子上(wang et al.，1996，Am.J.Respi.CellMol.Biol.15(5)，664)。αvβ6的生理和病理功能目前尚不清楚；然而，人们猜想它在涉及上皮细胞的生理过程和紊乱(如炎症，创伤恢复，肿瘤)中起重要的作用.因而，αvβ6在伤口角质细胞中表达(Haapasalmiet al.，1996，J.Invert.Dermatol.106(1)，42)。由此，人们认为除创伤修复和炎症以外的病理性皮肤疾病，如牛皮癣，也受该整联蛋白的促进/拮抗剂的影响。此外，αvβ6在呼吸道上皮细胞中起一重要作用(Weinacker et al.，1995，Am.J.Respir.Cell.Mol.Biol.12(5)，547)，因而αvβ6合适的促进/拮抗剂能成功用于呼吸道紊乱，如支气管炎、哮喘、肺纤维样变性和呼吸道肿瘤。最后，我们已经知道αvβ6在肠上皮细胞中也起重要作用，因而，该整联蛋白的合适的促进/拮抗剂能用于治疗胃/肠道的炎症、肿瘤和创伤。
到目前为止，尚未发现能选择性结合到αvβ6整联蛋白上的低分子量抑制剂。迄今已知的天然高分子量配体和抗体较难用于治疗和诊断。而本发明的目的便是去发现αvβ6除此之外的、有效的、特异性的和有选择性的配体，其中肽段优选，因它们不仅能用于前述的治疗领域，而且可用作诊断剂和试剂。
已经发现，下式所示的肽化合物及其可溶性盐分子对携带上文提及的受体的细胞产生作用，或者，当他们结合到这些细胞表面时，就可作为αvβ6介导的细胞粘连的人工配体。它们尤其可作为αvβ6整联蛋白抑制剂，特异的抑制αvβ6整联蛋白受体与其它受体的作用，如与纤连蛋白的结合。这种作用能用J.W.Smith等在1990年第265期J.Biol.chem.12267-12271页所述的方法来证实。血管发生起源对血管整联蛋白与胞外基质蛋白间相互作用的依赖性在1994年264期Science 569-571页的文章有描述，此文作者是P.C.Brooks、R.A.Clark和D.A.Cheresh.
进一步发现，这些新物质具有极有价值的药理学性质和良好的耐受性，可用作药物。这一点在较后部分有较详细的叙述。
在前述领域中，如带有合适的标记(如生物素基团)，本发明中的肽化合物可进一步用作体内发现和定位上皮系统的病理环境的诊断剂。本发明还包括了上述肽化合物与其它活性化合物的缀合物，如其与细胞毒素活性物质的缀合物及其与放疗标记物和PET诊断剂的缀合物，也包括了上述肽化合物与标记蛋白如GFP和抗体，或与蛋白质药物如IL-2的融合蛋白。
因此，本发明涉及式I中的肽化合物：
W1-X1nArg X2 Asp Leu X3X4Leu X5X6m-W2 I
其中：X1、X2、X3、X4、X5、X6各独立选自下列氨基酸之一：Ala、Asn、Asp、Arg、Cys、Gln、Glu、Gly、Phe、His、Ile、Leu、Lys、Met、Nle、高-Phe、Phg、Pro、Ser、Thr、Trp、Tyr、Val及他们可能的衍生物。
W2是OH、OR、NHR、NR2、NH2之一。
W1是H或酰基。
R是含1-6个碳原子的烷基；n、m各代表0-15中的一个数字，当其假定值大于1时，X1和X6基团可相同或不同。
根据本发明，这些氨基酸或氨基酸残基还包括其天然氨基酸的衍生物，或其同系物，或其异构体。这些氨基酸残基通常是通过α-氨基和α-羧基(肽键)相互连接。
此外，本发明优选涉及一些肽化合物，这些化合物中X2是Thr、Ser、Asp、Gly之一；更优选的X3是Asp、Glu、Arg、Lys、His、Tyr之一的化合物；最优选的是那些X4是Ser、Tyr、Thr、Gly、val之一的化合物。
因此，优选的肽化合物(含义和简写见上下文)包括式II：
W1-X1 nArg Thr Asp Leu X3X4Leu Arg X6 m-W2 IIa，
W1-X1 nArg Ser Asp Leu X3X4Leu Arg X6 m-W2 IIb，
W1-X1 nArg Asp Asp Leu X3X4Leu Arg X6 m-W2 IIc，
W1-X1 nArg Ser Asp Leu X3X4Leu Arg X6 m-W2 IId，
W1-X1 nArg Gly Asp Leu X3X4Leu Arg X6 m-W2 IIe，
及符合通式III的：
W1-X1 nArg X2Asp Leu Asp X4Leu Arg X6 m-W2 IIIa，
W1-X1 nArg X2Asp Leu Glu X4Leu Arg X6 m-W2 IIIb，
W1-X1 nArg X2Asp Leu Arg X4Leu Arg X6 m-W2 IIIc，
W1-X1 nArg X2Asp Leu Lys X4Leu Arg X6 m-W2 IIId，
W1-X1 nArg X2Asp Leu His X4Leu Arg X6 m-W2 IIIe，
W1-X1 nArg X2Asp Leu Tyr X4Leu Arg X6 m-W2 IIIf，
和符合通式IV的：
W1-X1 nArg X2Asp Leu X3Ser Leu Arg X6 m-W2 IVa，
W1-X1 nArg X2Asp Leu X3Tyr Leu Arg X6 m-W2 IVb，
W1-X1 nArg X2Asp Leu X3Thr Leu Arg X6 m-W2 IVc，
W1-X1 nArg X2Asp Leu X3Gly Leu Arg X6 m-W2 IVd，
W1-X1 nArg X2Asp Leu X3Val Leu Arg X6 m-W2 IVe.
根据本发明，尤其优选的肽化合物是符合式V的：
W1-X1 nArg Thr Asp Leu Asp Ser Leu Arg X6 m-W2 V
在此式中更为优选符合式VI的：
W1-X1 nArg Thr Asp Leu Asp Ser Leu Arg Thr X6 m-1-W2 VI
最后，下列的个体化合物更为优选，这些化合物也包括它们的N-和C-末端修饰物：
(a)H-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Arg-Thr-Tyr-Thr-Leu-
OH
(b)H-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Arg-OH
(c)Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Arg-Thr-OH
(d)Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Arg-Thr-NH2
(e)H-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Arg-Thr-OH
(f)H-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Arg-Thr-NH2
(g)H-Arg-Thr-Asp-Leu-Tyr-Tyr-Leu-Arg-Thr-Tyr-OH
(h)Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Arg-NH2
文中缩写代表下列氨基酸的基团：
Ala A 丙氨酸
Asn N 天冬酰氨
Asp D 天冬氨酸
Arg R 精氨酸
Cys C 半胱氨酸
Glu Q 谷氨酰氨
Glu E 谷氨酸
Gly G 甘氨酸
His H 组氨酸
Ile I 异亮氨酸
Leu L 亮氨酸
Lys K 赖氨酸
Met M 蛋氨酸
Nle 正亮氨酸
Orn 鸟氨酸
Phe F 苯丙氨酸
Phg 苯基甘氨酸
Pro P 脯氨酸
Ser S 丝氨酸
Thr T 苏氨酸
Trp W 色氨酸
Tyr Y 酪氨酸
Val V 缬氨酸
如果上文提及的氨基酸有许多异构体形式，则它们的这些存在形式及其混合物都包括在上下文中，例如它们可作为式I-VI中化合物的成分。此外，所有提到的氨基酸，例如作为式I-VI中化合物成分的氨基酸本身就可为自己提供合适的保护基团。
式I-VI中的化合物可含有1或多个手性中心，因此有多种立体异构形式。上述各式包含所有形式，尤指D-和L-形式，尤其是对于对映体和外消旋化合物而言。最后，本发明上下文中式I-VI的化合物还包括其相应的盐，尤其是那些生理学上可接受的盐。
所谓的前体药物衍生物也包括在本发明中的化合物中，也即式I中的化合物经过修饰后的化合物，例如经过烷基、酰基、糖或寡肽修饰后的化合物，这些化合物在体内可被迅速的切割为本发明中的活性化合物。此外，本发明中的化合物还包括本发明中的肽化合物的衍生物及已知的标记化合物，这些标记化合物可使我们易于探测到这些肽段的存在。生物素酰化的肽段和荧光标记的肽段便是两个具体例子。
一般情况下，本发明中的肽段是线形的，但他们也能够环化。本发明中不仅包括式I-VI中提到的肽段，也包括这些化合物的混合物和制剂，另外，还包括那些以一种适当方式影响本发明中的肽段基本药理学作用的、具药理学活性的化合物和佐剂。
另外，本发明中的化合物及其制剂的出发物质是由目前已知且常用的方法制备的，这些方法在文献中都有描述(例如标准著作如Houben-Weyl，methoden der organischen Chemie[Methods ofOrganic Chemistry]，Georg-Thieme_Verlag，stuttgart)，也即在已知的且适合于前述反应的反应条件下去制备。另外也可用已知的各种变式去制备。
本发明中的肽段优选的利用固相合成及随后的分离和纯化方法，如Jonczyk和Meienhofer已描述过的(Peptides，Proc，8thAm.Pept.Symp.，Eds.V.Hurby and D.H.Rich，Pierce Comp.III，p.73-77，1983，or Angew.Chem.104，1992，375)，或据合成法来制备(J.Am.Chem.Soc.94，1972，3102)。此外，可利用常用的氨基酸及肽的合成法来制备，例如Novabiochem-1999 Catalog and PeptideSynthesis Handbook of Calbiochem-novabiochem GmbH，D-65796 BadSoden中的方法，及许多标准著作和已出版的专利申请中的方法。另外，生物素酰化的和荧光标记的肽/蛋白质能从标准方法(例如，E.A.Bager和M.WIlcheck在Biochemical Analysis第26卷上有文章：抗生物素蛋白-生物素复合体用于分子生物学；Handbook offluorescent Probes and Research Chemicals，6th edtion，1996，by R.P.Haugland，Molecular Probes，inc.；或专利WO97/14716)来制备。
当然式I-VI中的肽段可通过溶剂分解，尤其是水解来释放，或通过氢解来释放其功能性衍生物。溶剂分解或氢解的优选出发物是那些含有相应的氨基和/或羟基保护基，而不是自由的氨基和/或羟基的物质。其中，优选那些携带氨基保护基而不是含有与N相连的H原子的物质，或携带羟基保护基而不是羟基H原子的物质。这种优选原则适用于羧酸，它们可通过保护基如酯替代-CO-OH中的羟基的功能基团来得到保护。
氨基保护基这个词普遍为人所知，它涉及那些适于保护(用于阻断)氨基不发生化学反应、但在分子的另一部位发生了合适的反应后又易于去除的基团。羟基保护基这个词也同样为人所知，它涉及那些适于保护羟基不发生化学反应、但在分子的另一部位发生了合适的反应后又易于去除的基团。化合物从他们的功能基团中的释放依赖于保护基团的使用，例如，使用强酸，TFA或高氯酸尤为便利，还可利用其他强无机酸如盐酸和硫酸；强有机羧酸如三氯乙酸，或者磺酸如苯磺酸或对甲苯磺酸。氢解中可去除的保护基(如苄氧羰基和苄基)可在催化剂(如金属催化剂钯，在一支持物如碳上更有利)去除掉。所有的程序都是众所周知的，这里不再进行更详细的描述。
前面已经提及，本发明的肽包含其生理活性的盐，他们同样也可由标准方法来制备。因此，利用一种酸，可将符合式I的碱转化为由相关的酸加成产生的盐，例如在惰性溶剂如乙醇或其蒸汽中，等量的酸碱发生反应。对于此反应，需要有合适的酸尤其是可产生生理可接受的盐的酸。因此，可用无机酸，如硫酸、硝酸、氢卤酸如盐酸或氢溴酸、磷酸如正磷酸、氨基磺酸；此外，有机酸，尤其是脂肪酸、脂环酸、芳脂族酸、芳香酸或杂环单或多元羧酸、磺酸或硫酸，例如甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、pimelic acid、延胡索酸、马来酸、乳酸、酒石酸、苹果酸、柠檬酸、葡萄糖酸、抗坏血酸、烟酸、异烟酸、甲基或乙基磺酸、乙基二磺酸、2-羟基乙基磺酸、苯磺酸、对甲苯磺酸、萘单和二磺酸、月桂醇磺酸。生理不能接受的酸的盐，如苦味酸盐，可用于分离和/或纯化本发明中的化合物。另一方面，通过与碱反应，式I中的酸能转化为生理可接受的金属或铵盐。在这种情况下，可能产生多种盐，尤其是钠盐、钾盐、镁盐、钙盐和铵盐，此外是替代的铵盐，例如二甲基---、二已基---、二异丙基铵盐，单乙醇-，二乙醇-或二异丙醇铵盐环己基、二环己基铵盐，二苯乙烯基二铵盐。此外也可产生诸如含有精氨酸或赖氨酸的盐。
前面已提及，本发明中的化合物可作为人和畜药物中的活性物质，尤其是预防和/或治疗与上皮细胞相关的紊乱。此处特别强调皮肤、呼吸器官、胃肠区的紊乱、炎症及创伤修复过程，例如中风、咽喉痛、pectoris、肿瘤病、骨软化疾病如骨质疏松、病理性血液疾病如炎症、肺纤维样变性、眼科疾病、糖尿病型视网膜疾病、斑疹退化、近视眼、眼的网状内皮细胞真菌病、风湿性关节炎、骨关节炎、发红性的青光眼、溃疡性结肠炎、Crohn’s病、动脉硬化、牛皮癣、血管形成手术后的血管再狭窄、以及急性肾功能衰竭或肾炎。
本发明涉及上下文定义的结构式中的肽化合物。并且，在专利要求中包括他们的那些可作为药剂、诊断剂或试剂的生理状态下可接受的盐。
本发明尤其涉及那些合适的药剂，他们可作为抑制剂用于防治直接或间接基于αvβ6整联蛋白受体之上的紊乱，尤其是病理性的生血管紊乱、血栓、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松、炎症、传染病。另外也可用于影响创伤修复过程。
本发明也涉及合适的药物制剂，这些药物至少包括式I-VI中的一种药物，也包括合适的载体和/或赋形剂。
此外，按照权利要求和药物生产说明书，本发明涉及肽化合物和/或他们的生理可接受盐，这些药物可用于防治直接或间接基于αvβ6整联蛋白受体之上的紊乱，尤其是病理性的生血管紊乱、血栓、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松、炎症、传染病。另外也可用于影响创伤修复过程。本发明中的药物或组成他们的药剂可用于人或畜药。可能的赋形剂是无机物或有机物，它们适于肠道给药(如口服)或非经肠给药，或局部给药，或喷雾吸入的形式，并且它们不与新化合物如水、植物油、苄甲醇、烷烯基乙二醇、聚乙二醇、三乙酸甘油、明胶、碳水化合物如乳糖或淀粉、硬脂酸镁、滑石、石油凝胶等反应。片剂、丸剂、有被片剂、胶囊、粉剂、颗粒、浆、汁或滴尤其适用于口服；栓剂适用于直肠给药；溶液尤其是油溶液或水溶液，以及悬浮液、乳剂和植入物适于非经肠给药；油膏、乳脂制剂和粉剂用于局部给药。这些新化合物可冷冻干燥，冻干物用做如注射用药剂。注射用药剂可灭菌，也可和/或含有载体，如润滑剂、防腐剂、稳定剂和/或吸湿因子、盐用于影响渗透压、缓冲物质、颜料、调味剂和/或一或多种活性化合物如一或多种维生素。如以喷雾吸入的方式给药，则含有溶解或悬浮在一种推进剂或推进剂混合物中的活性化合物的喷雾可被利用。此处的活性化合物以微小粒子形式存在较为便利，因为可能有一种或多种额外的生理可接受的溶剂如乙醇存在。吸入液可借助常用的吸入器来给药。
本发明中的物质给药规则与其他已知的、商业用肽(如US-A-4472305中描述的)相似。优选剂量大约为0.05-500mg/单位剂量，尤其是0.5-100mg/单位剂量。日服量最好在大约0.01-20mg/kg体重。然而，具体剂量要依赖于各种因素，例如特定化合物的利用效率、年龄、体重、健康状况和性别、饮食、给药时间及给药途径、排泄率、药物的结合及用于治疗的特定紊乱的严重程度。体表接种是优选的方式。
最后，本发明还包括重组DNA序列，这些序列中的部分编码一些蛋白质区域，而这些蛋白质区域含有式I-VI的肽结构基序。
正如在1994年91期Ch.Andree et al.Proc.Natl.Acad.Sci.z.第12188-12192中所描述，这些DNA可利用微粒将其转入细胞中；若利用其他载体如脂质体，这种向细胞内的转移将增加(A.I.Aronsohnand J.A.Hughes J.Drug Targeting，5，163-169(1997))。
相应的，利用杆状病毒可将这些DNA用于酵母；也可用于哺乳动物以生产本发明中的肽。
如果动物感染了这种重组DNA，感染细胞自身最终能产生本发明中的肽，并且它们能直接结合到αvβ6整联蛋白受体如肿瘤细胞上，以阻遏其生长。
利用已知的常用技术能制备出合适的重组DNA，例如，它们能以含有编码病毒外壳蛋白的DNA片段的病毒DNA形式存在。通过利用重组体，尤其是利用这类非病原性病毒感染宿主，表达整联蛋白αvβ6的宿主细胞能够优先被攻击(导向)
各种腺病毒是较合适的病毒。它们已多次用做哺乳动物细胞内外源基因的载体。它们许多特性使得它们可作为良好的基因治疗工具，从1997年第四期Gene therapy 第1004-1012页S.J.Watkins的文章中可见一斑(也可见1993年Hum.Gene therapy759-769页J.Engelhardt等的文章).从1998年102期J.Clin.Invert 184-193页A.Fasbender等的文章中能发现，借助病毒载体和非病毒载体进行的基因治疗有一共同的问题，即基因转移的效率有限。利用上述的腺病毒外壳蛋白中αvβ6整联蛋白额外的配体序列，在DNA转移如囊性纤维化跨膜转导调节蛋白(CFTR)cDNA中可取得进步。
只需将血管紧张肽DNA替换为本发明中的DNA序列，其余与T.Tanaka等在1998年58期Cancer Research第3362-3369页的工作相似。本发明中的DNA序列还可用于借助逆转录病毒或腺病毒载体进行的细胞转染。
将本发明中的肽置于脂/肽/DNA脂质复合体中----这个复合体连同含有脂/DNA(不含肽)的脂质复合体是用于转染细胞培养物的---则本发明中的肽可用于基因的治疗。例如，1998年Human Gene Therapy第9期575-585页，Hart S.L等的文章---利用非病毒整联蛋白寻靶载体提高脂质介导的转染---有对脂/肽/DNA脂质复合体制备的描述。
例如，脂/肽/DNA可用下述方法来制备：1μg/ml脂质转染液(等摩尔DOTMA(N-[1-(2，3-二油氧基)丙基]-N，N，N-三甲基氯化铵)与DOPE(二油基磷脂酰乙醇胺)的混合物)、10g/ml的质粒DNA和100μg/ml肽。这种情况下，DNA和肽都溶解在细胞培养基中。脂质复合体可由三种成分以特定重量比(如脂∶DNA∶肽＝0.75∶1∶4)混合来制备.人类基因治疗用的脂质体DNA复合体已有描述(Caplen N.J etal.，1995：Liposome-mediated CFTR gene transfer to the nasalepithelium of patients with cystic fibrosis，Nature Medicine 1，39-66)。
因此，本发明也涉及基因释放系统中适当的修饰重组DNA的应用，尤其是病毒DNA，它们可用于防治直接或间接基于αvβ6整联蛋白受体之上的紊乱，尤其是病理性的血管生成紊乱、血栓、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松、炎症、传染病。另外也可用于影响创伤修复过程。
本发明中的新化合物也可用作整联蛋白的配体，以制备亲和层析柱，进而制备纯态的整联蛋白。抗生物素蛋白衍生的支持物体系如琼脂糖及式I中的新化合物的络合物可由已知方来合成(如E.A.Bayer和M.Wilchek在第26卷Methods of Biological Analysis上的文章：抗生物素蛋白——生物素复合体作为分子生物学工具的应用)。这种情况下，合适的多元支持物是肽化学中熟知的多元固相，它们具有优先亲水特性。例如交联多糖如纤维素、琼脂糖和葡聚糖，酰胺，基于聚乙二醇的多聚形式或Tentakel多聚物。
例1
制备和纯化本发明中的肽段
原则上，制备和纯化是按Fmoc策略进行的，这个策略是利用商业用的连续的流动肽合成仪将酸不稳定树脂上的酸不稳定侧链保护起来，具体参见Haubner等的详述(J.Am.Chem.Soc.118，1996，17703).下文中，肽的合成与纯化是举肽酰胺Ac-RTDLDSLR-NH2为例来描述的。对于合成肽酸，按用户使用说明，对三氯苯甲基氯化物树脂就要用适当的C-末端Fmoc氨基酸包被，进而按用户使用说明在合成仪中使用。主要的步骤是冲洗---去除Fmoc保护基团---冲洗---偶联下一个Fmoc氨基酸---加帽(乙酰化)---冲洗。在最后一个氨基酸偶联上之后，如果此时的N-末端酰化作用是所要的，就可在利用适当的已激活的酰基基团如乙酸酐去除最后一个Fmoc保护基团后得到。使用商业合成仪，按照经典程序(apparatus and milligen 9050 PepSynthesizerTMHandbook，1987)，每一步偶联使用2克9-Fmoc-aminoxanthenyloxy树脂(Novabiochem，0.37mmol/g)，偶联60分钟，随后使用0.45克羟基苯并三唑水合物(HoBt)、0.5ml乙基二异丙胺，4当量的二异丙基碳的亚胺(DIC)和4当量的溶于二甲基甲酰胺的Fmoc氨基酸。冲洗步骤在DMF中，历时10分钟，去除步骤在哌啶/DMF(体积比1∶4)中，历时5分钟；N-末端乙酰化(加帽)则用乙酸酐/吡啶/DMF(体积比2∶3∶15)，历时15分钟。先偶联Fmoc-Arg(Pmc)，然后Fmoc-Leu，然后Fmoc-Ser(But)，然后fmoc-Asp(OBut)，然后，然后Fmoc-Leu，然后Fmoc-Asp(OBut)，然后Fmoc-Thr(But)，最后是Fmoc-Arg(Pmc)。经过DMF和异丙醇冲洗和随后在VACUO中的干燥，得到了3.48克N-末端酰化的肽酰树脂：Ac-Arg(Pmc)-Thr(But)-Asp(OBut)-Leu-Asp(OBut)-Ser(But)-Leu-Arg(Pmc)-aminoxanthenyloxy树脂。
对这个肽酰树脂作如下处理：在室温下用三氟乙酸/茴香醚/三氯甲烷(74ml/3.7ml/74ml)处理4小时，过滤，在抽真空浓缩和用二乙基醚研磨，得到0.6克肽的沉淀物：Ac-Arg-Thr-Asp-leu-Asp-Ser-Leu-Arg-NH2。利用固定相为0.3％TFA中Lichrosorb RP-18(250-25，7um，Merck KgaA)的RP-HPLC，在8ml/min流速下，用4-24％2-丙醇梯度淋洗2小时，以纯化该肽段，在215nm下用紫外流通光度计进行检测。
含产品的馏分进行冷冻干燥。按照FAB-MS(快速原子轰击质谱)，得到的产品与预期相同：C41H73N15O15M 1015.5g/mol；(M+H)+是1016。
在Super RP18e(250-4，Merck KgaA)分析HPLC中，流速1ml/min，以A(PH3.5 0.08M磷酸盐，15％乙腈)与B(PH3.5 0.03M磷酸盐，75％乙腈)之比为0-99％的混合液梯度洗脱50分钟，在215nm处检测，纯化的产品Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Arg-NH2的保留时间为7.22分钟。
进一步的HPLC分析是在下面两个系统中进行的：
系统A：Lichrosorb 60 RP-select B(250-4，Merck KgaA，Darmstadt，德国)，流速1ml/min，以0.3％三氟乙酸中0-80％的2-丙醇梯度洗脱50分钟，在215nm处检测。
系统B：Superspher 100 RP18e(250-4，Merck KgaA，Darmstadt，德国)，流速10ml/min，0.1％三氟乙酸中30-70％的乙腈梯度洗脱50分钟，在215nm处检测。
例2
表1中肽的制备和纯化与例1相似
表1
| 结构 | MW(g/mol) | FAB-MS[M+H]实测 | Rt(HPLC)/min(系统A) | Rt(HPLC)/min(系统A) |
| RTDLDSLRTYTL | 1453.6 | 1456 | 21.9 | |
| DSLRTYTL | 968.1 | 969 | 18.6 | |
| RTDLDSL | 818.9 | 820 | 18.6 | 23.6 |
| DLDSLRTY | 982.1 | 983 | 16.6 | |
| RTDLDSLR | 975.1 | 975 | 13.5 | |
| RTDLDSLRTY | 1239.3 | 1239 | 16.6 | |
| Ac-RTDLDSLRT | 1118.2 | 1119 | 16.2 | 15.6 |
| RTDLDSLRT | 1076.2 | 1076 | 13.9 | |
| RTDLPSLRTY | 1221.4 | 1221 | 19.2 | |
| RTDLDLRT-NH2 | 988.1 | 989 | 13.4 | |
| Ac-RTDLDLRT-NH2 | 1030.2 | 1031 | 15.3 | |
| RTDLYYLMDL | 1302.5 | 1302 | 28.2 | |
| RTDLDSLRT-NH2 | 1075.2 | 1076 | 11.1 | 13.8 |
| RTDLDPLRTY | 1249.4 | 1250 | 16.3 | |
| RTDLYYLRTY | 1363.5 | 1363 | 11.5 | |
| Ac-RTDLDSLRT-NH2 | 1117.2 | 1118 | 13.2 | 15.0 |
| Ac-RTDLDSLR-NH2 | 1015.5 | 1016 | See Example1 | |
| TDLDSLRT | 920.0 | 920 | 14.8 | |
| PVDLYYLMDL | 1241.5 | 1241 | 36.1 |
所用的对比化合物为已知的RGD肽段，如GRGDSPK，环状-RGDfV，及线形肽段DLYYLMDL。
例3
αvβ6整联蛋白制剂的制备：
应用14D9.F8抗体亲和层析(Mitjan et al.，1995，J CellSci.108，2825)，按照现有的αvβ3的重组技术，可从杆状病毒表达系统中得到和纯化以可溶性的截短的跨膜形式存在的αvβ6(Weinacker etal.，1994，J.Biol.Chem.269，6940)。人类αv和β6cDNA克隆已普遍为人所知，一般也都能接触到。应用允许同时表达两种不同靶cDNAs的转移载体PAcUW31(Clontech Lab.Inc.，USA)，以便使截短的跨膜αvβ6从重组杆状病毒中表达出来。为此，制备了一种αv转移载体，利用限制性酶EcoRI和XbaI(Mehta et al.，见上述文献)将跨膜截短的(ΔTM)αv从质粒αvΔTM(pBAc9)处切断。然后，通过平头连接将其克隆到多角体蛋白启动子的PAcUW31下游BamHI切割位点处。利用限制性酶EcoRI和XbaI将跨膜截短的β6cDNA从质粒pcDNAneoβ6上切下(Weinacker et al.，见上述文献)，然后，同样的通过平头连接将其克隆到多角体蛋白启动子的PACUW31下游BamHI切割位点处。串联的载体包括截短的αv和β6，这些载体用于获得重组杆状病毒(Mehta etal.，见上述文献)。用重组杆状病毒感染HIGH FIVE昆虫细胞，培养48-72小时后，将细胞培养物上清液流过上面提及的亲和柱，在PH3.1下洗脱，得到可溶的受体。所有的步骤都是在室温、无去污剂的条件下进行的。洗脱峰收集液经在40度中和、浓缩及透析，最终产物保存在零下80度。因而，得到的可溶性的人受体重组体具有生物活性，且保留其配体特异性。用于可溶性αvβ3的相似制备方法在EP 0846 702中有描述。
例4
αvβ6/纤连蛋白受体结合试验
本发明中的成品肽和竞争性的纤连蛋白都结合到溶液中固定化的αvβ6受体上，Q值可作为被检肽与αvβ6选择性结合的一个量度。在此处，Q值是被检肽IC50值与标准肽IC50值的商，所用的标准肽是线性的7-RGD肽：GRGDSPK(ref./Patent cf.Pytela et al.Sciencce 231，1559，(1986))。
细节上讲，结合试验是按下述进行的：
可溶性αvβ6受体在微量滴定板上的固定化是通过先将蛋白溶液在TBS++中将其稀释后，在4℃培养过夜(100μl/孔)，使可溶性αvβ6受体在微量滴定板上固定化。用3％(W/V)BSA在TBS++(200μl/孔)中培育(2h，37℃)可阻断非特异性结合位点。用TBS++冲洗3次，将多余的BSA去掉。肽段在TBS++中进行系列稀释(1∶10)，然后在固定化的整联蛋白(50μl肽+50μL配体/孔；2h；37℃)和生物素化的纤连蛋白(2μg/ml)中培育。用TBS++冲洗3次将未结合的纤连蛋白和肽除掉。通过与碱性磷酸酶偶联的抗生物素抗体(Biorad)(在TBSA++中1∶20,000，100μl/孔)共培育来检测已结合的纤连蛋白。用TBSA++冲洗3次后，与基质溶液(5mg对硝基苯磷酸，1ml乙醇胺，4ml H2O，100μl/孔)共培育(10-15分钟，25℃，避光)，然后进行比色法检测。加入0.4M NaOH(100μl/孔)终止酶反应。色强度在405nm下利用ELISA检测器确定，并调零。那些没有受体包被的孔作为零值。本实验所用标准肽是GRGDSPK。待检测的IC50值可从图中读出，本发明中肽的Q值需结合标准肽的IC50值才能得到。本实验的结果已总结到下表中。
表2
| 结构 | Q值＝IC50 测试肽/IC50 标准肽 |
| GRGDSPK | 1.0(IC50＝400nM) |
| cyclo-(RGDfV) | 0.6 |
| DLYYLMDL | 无活性 (IC50＞50μM) |
| RTDLDSLRTYTLDSLRTYTLRRDLDSLDLDSLRTYRTDLDSLRRTDLDSLRTYAc-RTDLDSLRTRTDLDSLRTRTDLDLRT-NH2Ac-RTDLDLRT-NH2RTDLYYLMDLRTDLDSLRT-NH2RTDLDPLRTYRTDLYYLRTYAc-RTDLDSLRT-NH2TDLDSLRTPVDLYYLMDL | 0.27无活性 (IC50＞50μM)2.5无活性 (IC50＞50μM)0.170.100.0290.111.10.50.330.0560.500.0420.01366无活性 (IC50＞50μM) |
Q值小于1表明它们表现出相对于标准蛋白较好的与受体结合的能力，而与天然纤连蛋白相比，标准肽已具有较好的结合能力。
例5
与前例相似，出于对比的目的，用不同的整联蛋白(如αvβ3、αvβ5)与它们相应的配体(如玻连蛋白、血纤蛋白原)进行了整联蛋白配体结合试验。
例6
DNA脂质复合体的一般制备及其在基因治疗中的应用：
脂与DNA以重量比5∶1(脂∶DNA)混合于Krebs-Hepes溶液(140mmNaCl，1mmMgCl2，2mmCaCl2，6mmKCl，10mmHEPES，10mmD-葡萄糖；PH9.0)中。此处单独剂量是30μgDNA/200μl.利用一个泵式喷雾器，将200μl的脂-DNA复合体喷于鼻上皮细胞，这样重复10次，每次间隔15分钟，DNA总剂量是300μg。
下面的例子涉及到药剂制备：
例A 注射小瓶
在3升蒸馏水中，100g式I的活性化合物和5g Na2HPO4的溶液，用2N HCl调PH6.5，无菌过滤，装入注射瓶中，在无菌环境下冷冻干燥，然后无菌密封。每一注射小瓶含5g活性化合物。
例B 栓剂
20g式I中某一活性化合物与100g大豆卵磷脂、1400g可可黄油融合，倾入模子中，让其冷却。每一栓剂含20mg活性化合物。
例C 溶液
1g式I中某一活性化合物、9.38gNaH2PO4、28.48gNa2HPO4·12H2O和苯札氯胺溶于940ml双蒸水中制成溶液，调PH6.8，定容至1升，然后辐射灭菌。这种溶液可用作眼用滴剂。
例D 油膏
500mg式I中某一活性化合物在无菌条件下与99.5g石油凝胶混合。
例E 片剂
1Kg式I中某一活性化合物与4kg乳糖、1.2kg大豆淀粉、0.2kg滑石、0.1kg硬脂酸镁混合，以常用方法制成片剂，每片含10mg活性物质。
例F 糖衣片剂
与例E相似，片剂压制成后，用常用方法包被一层由蔗糖、大豆淀粉、黄蓍胶和染料组成的外壳。
例G 胶囊
2Kg式I中某一活性化合物以常用方法注入硬明胶囊中，每个胶囊含20mg活性化合物。
例H 安瓿在60升双蒸水中加入1Kg式I中某一活性化合物制成溶液，无菌过滤，注入安瓿瓶中，无菌条件下冷冻干燥和密封。每瓿瓶含10mg活性化合物。
例I 吸入式喷雾剂
14g式I中某一活性化合物溶于10升等渗溶液中，将其注入泵式喷雾器中，则此溶液可喷于鼻或嘴上。每一喷雾涨泡(大约0.1ml)相应于大约0.14mg剂量。
序列表<110>Merck Patent GmbH<120>整联蛋白avB6的抑制剂<130>P9858857-bzrs<140>PCT/EP99/09842<141>1999-12-11<160>21<170>PatentIn ver.2.1<210>1<211>12<212>PRT<213>人工序列<220><223>人工序列描述：avβ6
抑制性肽 1<400>1Arg Thr Asp Leu Asp Ser Leu Arg Thr Tyr Thr Leu1 5 10<210>2<211>8<212>PRT<213>人工序列<220><223>人工序列描述：avβ6
抑制性肽 2<400>2Asp Ser Leu Arg Fhr Tyr Thr Leu1 5<210>3<211>7<212>PRT<213>人工序列<220><223>人工序列描述：avβ6
抑制性肽 3<400>3Arg Thr Asp Leu Asp Ser Leu1 5<210>4<211>8<212>PRT<213>人工序列<220><223>人工序列描述：avβ6
抑制性肽 4<400>4Asp Leu Asp Ser Leu Arg Thr Tyr1 5<210>5<211>8<212>PRT<213>人工序列<220><223>人工序列描述：avβ6
抑制性肽 5<400>5Arg Thr Asp Leu Asp Ser Leu Arg1 5<210>6<211>10<212>PRT<213>人工序列<220><223>人工序列描述：avb6
抑制性肽 6<400>6Arg Thr Asp Leu Asp Ser Leu Arg Thr Tyr
1 5 10<210>7<211>9<212>PRT<213>人工序列<220><221>SITE<222>(1)<223>Xaa＝Acety1-Arg<220><223>人工序列描述：avb6
抑制性肽 7<400>7Xaa Thr Asp Leu Asp Ser Leu Arg Thr1 5<210>8<211>9<212>PRT<213>人工序列<220><223>人工序列描述：avb6
抑制性肽 8<400>8Arg Thr Asp Leu Asp Ser Leu Arg Thr1 5<210>9<211>10<212>PRF<213>人工序列<220><223>人工序列描述：avb6
抑制性肽 9<400>9Arg Thr Asp Leu Pro Ser Leu Arg Thr Tyr1 5 10<210>10<211>8<212>PRF<213>人工序列<220><221>SIFE<222>(8)<223>Xaa＝Thr-NH2<220><223>人工序列描述：avb6
抑制性肽 10<400>10Arg Thr Asp Leu Asp Leu Arg Xaa1 5<210>11<211>8<212>PRT<213>人工序列<220><221>SITE<222>(1)<223>Xaa＝Acetyl-Arg<220><221>SITE<222>(8)<223>Xaa＝Thr-NH2<220><223>人工序列描述：avb6
抑制性肽 11<400>11Xaa Thr Asp Leu Asp Leu Arg Xaa1 5<210>12<211>10<212>PRT<220><221>SITE<222>(9)<223>Xaa-Thr-NH2<220><223>人工序列描述：avβ6
抑制性肽 16<400>16Xaa Thr Asp Leu Asp Ser Leu Arg Xaa1 5<210>17<211>8<212>PRT<213>人工序列<220><221>SITE<222>(1)<223>Xaa＝Acetyl-Arg<220><221>SITE<222>(8)<223>Xaa＝Arg-NH2<220><223>人工序列描述：avβ6
抑制性肽 17<400>17Xaa Thr Asp Leu Asp Ser Leu Xaa1 5<210>18<211>8<212>PRT<213>人工序列<220><223>人工序列描述：avβ6
抑制性肽 18<400>18Thr Asp Leu Asp Ser Leu Arg Thr1 5<210>19<211>20<212>PRT<213>人工序列<220><223>人工序列描述：avβ6
抑制性肽 19<400>19Pro Val Asp Leu Tyr Tyr Leu Met Asp Leu1 5 10<220><223>人工序列描述：avb6
抑制性肽 15<400>15Arg Thr Asp Leu Tyr Tyr Leu Arg Thr Tyr1 5 10<210>16<211>9<212>PRT<213>人工序列<220><221>SITE<222>(1)<223>Xaa＝Acetyl-Arg<220><221>SITE<222>(9)<223>Xaa＝Thr-NH2<220><223>人工序列描述：vb6
抑制性肽 16<400>16Xaa Thr Asp Leu Asp Ser Leu Arg Xaa1 5<210>17<211>8<212>PRT<213>人工序列<220><221>SITE<222>(1)<223>Xaa＝Acetyl-Arg<220><221>SITE<222>(8)<223>Xaa＝Arg-NH2<220><223>人工序列描述：avb6
抑制性肽 17<400>17Xaa Thr Asp Leu Asp Ser Leu Xaa1 5<210>18<211>8<212>PRF<213>人工序列<220><223>人工序列描述：avb6
抑制性肽 18<400>18Thr Asp Leu Asp Ser Leu Arg Thr1 5<210>19<211>10<212>PRF<213>人工序列<220><223>人工序列描述：avb6
抑制性肽 19<400>19Pro Val Asp Leu Tyr Tyr Leu Met Asp Leu1 5 10<210>20<211>7<212>PRT<213>人工序列<220><223>人工序列描述：avb6
抑制性肽 20<400>20Arg Arg Asp Leu Asp Ser Leu1 5<210>21<211>10<212>PRT<220><221>SITE<222>(1)<223>Xaa＝任何天然AS，以及Nle，homo-Phe，
Phg或H，N-terminal：H或Acetyl<220><221>SITE<222>(3)<223>Xaa＝任何天然AS，以及hom-Phe，Phg，
Nle<220><221>SITE<222>(6)..(7)<223>Xaa＝任何天然AS，以及Nle，homo-Phe，Phg<220><221>SITE<222>(9)..(10)<223>Xaa＝任何天然A5，以及Nle，Phg，
homo-Phe；an Position 9 auch H；C-端：OH，
NH2，OR，NH-Alkyl，N-Alkyl<400>21Xaa Arg Xaa Asp Leu Xaa Xaa Leu Xaa Xaa1 5 10
Claims (16)
1.式I中的肽化合物：
W1-X1nArg X2 Asp Leu X3X4Leu X5X6m-W2 I
其中：
X1、X2、X3、X4、X5、X6各代表下列氨基酸之一：Ala、Asn、Asp、Arg、Cys、Gln、Glu、
Gly、Phe、His、Ile、Leu、Lys、Met、Nle、高-Phe、Phg、Pro、Ser、THr、Trp、Tyr、Val及他们可能的衍生形式，
W1是H或酰基，
W2是OH、OR、NHR、NR2、NH2之一，
R是含1-6个碳原子的烷基；n、m各代表0-15中的一个数字。
2.权利要求1的肽化合物，其中的X2是选自Thr、Ser、Asp、Gly之一的氨基酸。
3.权利要求1的肽化合物，其中的X3是选自Asp、Glu、Arg、Lys、His、Tyr之一的氨基酸。
4.权利要求1的肽化合物，其中的X4是Ser、Tyr、Thr、Gly、val之一的氨基酸。
5.权利要求1的肽化合物，其在式V：
W1-X1n Arg Thr Asp Leu Asp Ser Leu Arg X6m-W2 V中具有式I中的含义。
6.权利要求5中的合式VI的肽化合物：
W1-X1 nArg Thr Asp Leu Asp Ser Leu Arg Thr X6 m-1-W2 VI。
7.权利要求1-6之一中式I或II的肽化合物及它们的可用作药物的生理可接受的盐。
8.权利要求7中药物，它可用作抑制剂来防治基于αvβ6整联蛋白受体的表达和病理功能上的紊乱。
9.权利要求8中的药物，用于防治血栓、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松、纤维样变性炎症、传染病，牛皮癣，也可用于影响创伤修复过程。
10.由权利要求7-9之任一的至少一种药物组成的药物制剂，及视需而定的载体和/或赋形剂，以及其他视需而定的活性化合物。
11.权利要求1-6的肽化合物和/或其可药用盐在生产防治基于αvβ6整联蛋白的表达和病理功能的紊乱的药物中的应用。
12.权利要求11中的应用：用于防治血栓、心肌梗塞、冠心病、动脉硬化、肿瘤、骨质疏松、纤维样变性、牛皮癣、炎症、传染病，以及影响创伤修复过程的药物的生产。
13.重组DNA，包括编码与权利要求1-6之一的肽化合物相对应的肽段的DNA序列。
14.权利要求13的重组体病毒DNA。
15.病毒，其特征在于它有一外壳蛋白，此蛋白的序列与权利要求1-6的肽化合物的序列相对应。
16.权利要求15的病毒的用途，用于生产可防治基于αvβ6整联蛋白受体的表达和病理功能的紊乱的药物。
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| DE19929410A1 (de) * | 1999-06-26 | 2000-12-28 | Merck Patent Gmbh | Inhibitoren des Integrins avß6 |
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| EP2287199B1 (en) | 2002-03-13 | 2017-08-02 | Biogen MA Inc. | Anti-alpha V beta 6 antibodies |
| KR20050102634A (ko) | 2003-02-06 | 2005-10-26 | 메르크 파텐트 게엠베하 | 펩티드성 설폰아미드 |
| CN104072614B (zh) | 2005-07-08 | 2017-04-26 | 生物基因Ma公司 | 抗-αvβ6 抗体及其用途 |
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| WO2008112004A2 (en) | 2006-08-03 | 2008-09-18 | Astrazeneca Ab | ANTIBODIES DIRECTED TO αVβ6 AND USES THEREOF |
| AU2007354317A1 (en) * | 2006-10-19 | 2008-12-04 | Biogen Idec Ma Inc. | Treatment and prevention of chronic asthma using antagonists of integrin alphaVbeta6 |
| WO2009093251A2 (en) * | 2008-01-24 | 2009-07-30 | Gavish-Galilee Bio Applications Ltd | Reovirus vaccine based on sigma c protein sequence |
| WO2014007547A1 (en) * | 2012-07-03 | 2014-01-09 | Il Yang Pharm. Co.,Ltd. | Novel peptides and use thereof |
| US10035860B2 (en) | 2013-03-15 | 2018-07-31 | Biogen Ma Inc. | Anti-alpha V beta 6 antibodies and uses thereof |
| WO2014144466A1 (en) | 2013-03-15 | 2014-09-18 | Biogen Idec Ma Inc. | Anti-alpha v beta 6 antibodies and uses thereof |
| RU2769702C2 (ru) | 2017-02-28 | 2022-04-05 | Морфик Терапьютик, Инк. | Ингибиторы интегрина avb6 |
| EP3589285A4 (en) | 2017-02-28 | 2020-08-12 | Morphic Therapeutic, Inc. | INHIBITORS OF INTEGRIN (ALPHA-V) (BETA-6) |
| EP3617206A1 (en) | 2018-08-29 | 2020-03-04 | Morphic Therapeutic, Inc. | Integrin inhibitors |
Family Cites Families (1)
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|---|---|---|---|---|
| NZ219515A (en) * | 1987-02-10 | 1989-09-27 | Wellcome Found | Fusion proteins comprising influenza virus ha and a nonnatural antigenic epitope |
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1999
- 1999-12-11 CA CA002355874A patent/CA2355874A1/en not_active Abandoned
- 1999-12-11 EP EP99963507A patent/EP1140989A1/de not_active Withdrawn
- 1999-12-11 JP JP2000589556A patent/JP2002533064A/ja active Pending
- 1999-12-11 CZ CZ20012212A patent/CZ20012212A3/cs unknown
- 1999-12-11 BR BR9916323-3A patent/BR9916323A/pt not_active IP Right Cessation
- 1999-12-11 CN CN99814760A patent/CN1335853A/zh active Pending
- 1999-12-11 WO PCT/EP1999/009842 patent/WO2000037487A1/de not_active Application Discontinuation
- 1999-12-17 AR ARP990106525A patent/AR022395A1/es not_active Application Discontinuation
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- 2001-06-18 NO NO20013013A patent/NO20013013L/no not_active Application Discontinuation
- 2001-07-18 ZA ZA200105929A patent/ZA200105929B/en unknown
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| CZ20012212A3 (cs) | 2001-09-12 |
| WO2000037487A1 (de) | 2000-06-29 |
| CA2355874A1 (en) | 2000-06-29 |
| ZA200105929B (en) | 2003-03-18 |
| AR022395A1 (es) | 2002-09-04 |
| NO20013013D0 (no) | 2001-06-18 |
| BR9916323A (pt) | 2001-10-30 |
| WO2000037487A8 (de) | 2001-03-29 |
| NO20013013L (no) | 2001-06-18 |
| JP2002533064A (ja) | 2002-10-08 |
| EP1140989A1 (de) | 2001-10-10 |
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