CN1917898A - 用于治疗非典型肺部感染的血管活性肠肽的生物活性物质 - Google Patents
用于治疗非典型肺部感染的血管活性肠肽的生物活性物质 Download PDFInfo
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Abstract
一种生物的和药理的高活性肽，用于治疗非典型肺部感染，例如特发性肺纤维变性、过敏性肺炎或者弥漫性泛细支气管炎。本发明用来治疗上述感染的肽包含至少一种非常能保存且特殊的氨基酸序列，这种氨基酸序列明显在同样的肺部感染的发病机理起了重要的作用。可以证明，包含上述这些序列的已知的天然肽“血管活性肠肽(VIP)”和“垂体腺苷酸环化酶激活肽(PACAP)”组成活性剂，它们可以抑制人类树状细胞的成熟并成功运用于治疗上述肺部感染。
Description
技术领域
本发明涉及生物的和药理的高活性肽，用于治疗非典型肺部感染(interstitial lung infection)，例如特发性肺纤维变性(idiopathic pulmonaryfibrosis，IPF)、过敏性肺炎(hypersensitive pneumonia)或者弥漫性泛细支气管炎(diffused panbronchiolitis)。本发明用来治疗上述感染的肽包含至少一种非常能保存且特殊的氨基酸序列，这种氨基酸序列明显在同样的肺部感染的发病机理(pathogenesis)起了重要的作用。可以证明，包含上述这些序列的已知的天然肽“血管活性肠肽(Vasoactive IntestinalPeptide，VIP)”和“垂体腺苷酸环化酶激活肽(Pituitary AdenylateCyclase-Activating Polypeptide，PACAP)”组成活性剂，它们可以成功运用于治疗特发性肺纤维变性和过敏性肺炎。此外本发明公开了对于治疗非典型肺部感染有用的组分。
背景技术
非典型肺部感染
非典型疾病是肺部慢性炎症反应的一种异种组。非典型肺部感染以不同的形式存在，例如特发性肺纤维变性(IPF)、过敏性肺炎，或者弥漫性泛细支气管炎。在疾病过程中出现的病理生理过程通过组织损伤和夸张的组织修复的结合现象而特性化，这些现象是在程序化瘢疤形成中保持正常的细胞生长时发生的。这个反应的典型特征包含重复的组织破坏和剧烈的蛋白水解活性，它改变细胞外基质组分的构成。这些过程导致细胞免疫应答延迟以及强烈地诱导间质组织的生长。
细胞因子，例如肿瘤坏死因子α，以及其它生长因子比如“转化生长因子β(TGFbeta)“已经被长期与这些过程结合起来了。通过它对间质组织生长强烈的刺激作用以及基于它改变细胞免疫过程的能力，TGFbeta可能是最重要的生长因子。
已知如果增加TGFbeta的产生，那么它将在动物模型中引起严重的肺纤维变性。这个生长因子显着提高的过剩表达在人类肺纤维变性中也被观察到。TGFbeta的免疫改变作用也是有名的。它包括阻碍干扰素γ因子的产生，抑制依靠干扰素γ的免疫反应，以及诱导免疫抑制的CD8+淋巴细胞。实际上近年来已经被观察到，在患者中随着程序化纤维变性，细胞免疫也产生了变化，而且它独立于最初的组织损伤。最近的研究显示，在特发性肺纤维变性中的程序化瘢疤形成是与细胞因子平衡变化相结合，细胞因子向产生所谓的“T辅助细胞类型2“反应方向变化。这个反应是通过所谓的Th2细胞因子的增加，例如白细胞介素4(IL-4)、IL-10和IL-13，和通过干扰素γ产生的减少直至完全丧失而特性化的，干扰素γ是所谓的“T辅助细胞类型1“反应主要调节因子。与纤维组织形成中慢性炎症反应相反，肺间质的急性炎症，例如细菌感染产生的后果，是通过T辅助细胞类型1和T辅助细胞类型2细胞因子的同步生产而特性化的，例如干扰素γ、IL-12和IL-4。此外还发生了TGFbeta的生产增加，这也许是激活的伤口愈合的标志。
由于通常特发性肺纤维变性在后期才被识别，因此疾病中的早期细胞内过程是几乎不可观察到的。伤口愈合的强度直接通过炎症机制影响，而炎症机制引起细胞外基质组分和其它细胞内组分转换的提高。慢性炎症通常通过感染产生，并导致病理上过度增加的伤口愈合反应。即使人们知道引起炎症的介质，目前在市场上并不存在药物，借助于它人们可以成功治疗器官纤维变性。通过病理上作用组织的结构重调，百万人口死于这种生命必需的器官***的缓慢损坏。这个过程被描写为纤维变性，并通过纤维增生机制(fibroproliferative mechanism)引发和控制。现今唯一的解决方案是器官移植，但与之相随的是高风险和高成本。
纤维增生反应影响身体的所有器官。在肺的气体交换组织中人们知道它作为肺纤维变性，在肝中作为肝硬化，在肾中作为肾小球硬化症。这些状况被集体称作纤维增生的疾病。在纤维变性中健康的组织会逐步被***和支持组织代替。这个过程以病理上加速的组织细胞生长为基础，而这通常是普通伤口愈合过程负责。因此人们将纤维增生疾病定义为没有控制的加速伤口愈合的疾病。在纤维变性中功能器官组织被替换至完全的器官功能丧失。
现今人们知道多于150种不同的机制，通过它们的影响可能产生肺的损害，它能在自身再引起纤维增生的伤口愈合。
慢性感染、有机或者无机来源的粉末暴露、不同的药物和自身免疫机制属于引起疾病的机制。尽管如此，纤维变性过程是自我独立的过程。轻微的炎症可能导致纤维变性过程惊人的加速。慢性病毒病可能是频率最高的程序性纤维变性的原因，虽然有免疫抑制的治疗。相类似的是慢性细菌和真菌感染，带或者不带胃的打嗝反应，它可能引起支气管末端的慢性炎症，这直接影响邻近肺胞的慢性伤口愈合过程。在细胞水平，代表抗原的细胞，例如树突细胞，在提到的疾病的病理生理中起了重要的作用。通过机能亢进它强大激活比如T淋巴细胞，这导致慢性的免疫激活。因此这些物质对于治疗上述疾病是理想的，它们可以对树突细胞的过度活性进行抑制。
发明内容
本发明第一次说明了VIP、PACAP和某些物质临床前的/细胞的和临床的关系，这些物质具有VIP或者PACAP的生物活性，用于治疗非典型肺部感染，例如发性肺纤维变性(IPF)、过敏性肺炎，或者弥漫性泛细支气管炎。
VIP和PACAP在中心神经***各种不同的区域合成，例如在特殊的脑部地区，比如海马或者脑皮层，以及在外周神经节。VIP还被免疫细胞释放。
血管活性肠肽(VIP)
VIP是由28个氨基酸组成的肽，并且显示以下的氨基酸序列(从N端到C端)：
His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn
(SEQ ID第1号)。
健康的人含有VIP的浓度为大约40pg/ml血清。
VIP是分布广泛的神经激素，它控制非常多的生理效果，例如肠胃分泌、肠胃平滑肌的放松或者脂肪细胞的脂肪分解。在生理条件下VIP是神经内分泌的调节物。科技文献中的报道显示了VIP在健康以及在恶性细胞中涉及生长和繁殖的调节作用(Hultgardh et al.Growth-inhibitory properties of vasoactive intestinal polypeptide.Regul.Pept.22，267-274.1988)。生物效果通过特殊受体调节(VIP-R)，它们位于不同细胞类型的表面(Ishihara et al.，Functional expression and tissue distributionof a novel receptor for vasoactive intestinal polypeptide.Neuron 8，811-819.1992)。通过诱导自身受体，VIP影响在成神经细胞瘤、乳癌、肺癌和肠癌中恶性细胞的生长(Moody et al.，Proc.Natl.Acad.Scid.USA，90，4345，1993)。在某些情况下VIP根据剂量诱导细胞***(Wollmannet al.，Brain Res.，624，339，1993)。VIP以及生物作用相似物和衍生物展示了在平滑肌上的放松作用(Maruno et al.，VIP inhibits basal andhistamine-stimulated proliferation of human airway smooth muscle cells.Am.J.Physiol.268，L1047-L1051，1995)，显示了支气管舒张活性并没有强烈的心血管副作用，在哮喘、在高血压、阳萎、局部缺血和在神经疾病，例如早老性痴呆中有效果(e.g.WO 9106565，EP 0536741，US3,880,826，EP 0204447，EP 0405242，WO 9527496，EP 0463450，EP0613904，EP 0663406，WO 9735561，EP 0620008)。
VIP受体被发现在气管和细支气管的上皮。它们也产生在巨噬细胞、毛细管周围，在气管和细支气管的***，在肺静脉和动脉的泡壁和被覆。神经纤维肽显示在肺中对VIP的合成负责(Dey et al.，Localization of VIP-immunoreactive nerves in airways and pulmonaryvessels of dogs，cat，and human subiects.Cell and Tissue Research 220，231-238.1981；Said，S.I.Vasoactive intestinal polypeptide(VIP)inasthma.Ann.N.Y.Acad.Sci.629，305-318.1991)。VIP减少了肺部组织的抵抗(Hamasaki et al.，Releaxant action of VIP on cat pulmonary artery：comparison with acetylcholine，isoproterenol，and PGE1.J.Appl.Physiol.54，1607-1611.1983；Iwabuchi et al.，Vasoactive intestinal peptide causesnitric oxide-dependent pulmonary vasodilation in isolated rat lung.Respiration 64，54-58.1997；Saga；T.and Said，S.I.Vasoactive intestinalpeptide relaxes isolated strips of human bronchus，pulmonary artery anlung parenchyma.Trans.Assoc.Am.Physicians.97，304-310.1984)。进一步的研究显示肺中VIP-R非常高的表达率，这是通过放射性标记的VIPs的高吸收率标明(Rader et al.，123I-labelled vasoactive intestinal peptidereceptor scintigraphy in patients with colorectal cancer.Br.J.Cancer 78，1-5.1998；Raderer et al.，Iodine-123-vasoactive intestinal peptide receptorscanning in patients with pancreatic cancer.J.Nucl.Med.39，1570.1998；Raderer et al.，Value of peptide receptor scintigraphy using(123)I-vasoactive intestinal peptide and(111)In-DTPA-D-Phel-octreotidein 194 carcinoid patients：Vienna University Experience，1993 to 1998.J.Clin.Oncol.18，1331-1336.2000；Virgolini et al.，Vasoactive intestinalpeptide receptor scintigraphy.J.Nucl.Med.36，1732-1739.1995)。
垂体腺苷酸环化酶激活肽(PACAP)：
PACAP是由38个氨基酸组成的神经肽，并且具有以下的氨基酸序列(从N端到C端)：
His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu-Gly-Lys-Arg-Tyr-Lys-Gln-Arg-Val-Lys-Asn-Lys
(SEQ ID第2号)。
两种形式的肽被鉴定了：PACAP-38和C末端缩短的PACAP-27。PACAP-27显示出与VIP 68％的同源性，它具有以下的氨基酸序列(从N端到C端)：
His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu
(SEQ ID第3号)。
PACAP是腺苷酸环化酶的强大刺激物，并由此诱导不同细胞种类的3，5-环腺苷酸(cAMP)。活性剂作为下丘脑的荷尔蒙、神经传递素、神经调节器、血管扩张剂以及向神经因子。PACAP刺激胰岛素的释放。作为向神经因子，PACAP促成胚胎发生时期大脑的发展。在完全发展好的大脑中，PACAP显示出作为神经保护因子，在多处受伤时阻止神经元降解。PACAP广泛分布于大脑和周边器官，特别是在胰腺、生殖腺以及呼吸道。三个PACAP受体被描述。受体类型I具有对于PACAP很高的亲合力(和对于VIP非常低的亲合力)，然而受体类型II对于PACAP和VIP的亲合力是相似的。另一种PACAP特殊受体PAC1存在。
在本发明中，我们描写已知活性剂的用处，它适合于在药物合成中为了预防和/或治疗非典型肺病(disorder)，例如先天肺纤维变性、过敏性肺炎或者弥漫性泛细支气管炎。
令人惊奇的是，被发现，具有非常能保存的十肽氨基酸序列
Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu(SEQ ID第4号)的肽是树状细胞成熟的高效抑制剂，并且如果给患有先天肺纤维变性、过敏性肺炎或者弥漫性泛细支气管炎的患者它们是高效的。优先使用的物质包含所述氨基酸序列，和包含全部10-60，优先地10-38，最优先地10-28或者10-27个氨基酸，以及拥有相同生物特性的物质例如VIP和PACAP，它们也包含上述氨基酸序列。
在大体上我们发现，类似与VIP和PACAP的肽和多肽具有所述治疗的效果和效率，它们包含以下的氨基酸序列：
(A)n-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-(B)m
其中A，B代表每个天然的氨基酸以及A和B是相互独立的；n，m是从0-25的替换值，n和m是相互独立的。m的值优先为4-18，更优先为5-15，最优先为10-15。
多肽或者肽，其中(A)n(如果n＞2)包含三肽序列His-Ser-Asp(SEQID第14号)和/或Phe-Thr-Asp(SEQ ID第13号)在N末端方向以上特殊的十肽序列，具有提高的活性。
多肽显示特别提高的活性，其中(A)n(如果n＞2)是(X)0-Phe-Thr-Asp-(Y)p并且(X)o(如果o＞2)是(X’)q-His-Ser-Asp-(X”)r，其中X，Y，X’，X”代表天然的氨基酸；和o，p是从0-11的替换值，以及r，q是从0-4的替换值。优先的o和p的值是0-8，更优先的值是1-5。优先的r的值是0-2。
包含所描述通用公式的优先例子拥有以下氨基酸序列
His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn
(VIP，SEQ ID第1号)
His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu-Gly-Lys-Arg-Tyr-Lys-Gln-Arg-Val-Lys-Asn-Lys
(PACAP-38，SEQ ID第2号)
His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu
(PACAP-27，SEQ ID第3号)
综上所述，本发明涉及以下物体：
使用一种物质来制备治疗非典型肺部感染，例如先天肺纤维变性或者过敏性肺炎的药物，以及所述药物在患者中的使用，所述物质拥有VIP或者PACAP的生物活性。
为让本发明之上述和其它目的、特征和优点能更明显易懂，下文特举一较佳实施例，并配合所附图式，作详细说明如下。
附图说明
图1-11显示出VIP在人体树状细胞成熟上的效果。
具体实施方式
根据发明，有治疗效果的适合的物质是具有象VIP或者PACAP同样生物活性的物质，以及比指定的肽和多肽高或者低的生物活性。根据发明，具有同样或者更高生物活性的物质优先。所有归算在这个组中的物质包含氨基酸序列Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu(SEQ ID第4号)。
本发明涉及发表的肽和多肽的衍生物，它们具有相同的生物活性。
此处所用的术语“相同的生物活性”涉及生物的，生理学的或者治疗的活性或者功能性，与所述的肽和多肽的相关特性比较，优先与VIP或者PACAP的相关特性比较。
此处所用的术语“衍生物”涉及肽物质，它或多或少是直接从相应的肽例如VIP或者PACAP衍生而来的，以及例如通过增加、删除、突变或者修饰的改变得到的，但这些并不改变原始肽的生物特性。可使用的VIP的衍生物是例如发表在WO 8905857，WO 9106565，EP0663406和WO 9729126(Fmoc保护的VIP)。根据发明，术语涉及指定的肽和多肽联合物，它由原始肽或者多肽组成，并且连结在亲脂性物质上，例如脂质体。VIP-脂质体发表在例如WO 9527496或者WO9735561，并且在生物可用性和保护防止蛋白质水解方面拥有提高的优势。另外，术语也涉及片段和修饰的片段，例如被削短的片段。
此处所用的术语“相似物”涉及结构和组成不同于发明的肽或者多肽的物质，优先不同于VIP，但是并没有改变生物特性。VIP相似物可以是自然的或者合成的肽，也可以不是肽。根据发明，VIP相似物是肽。发表的VIP相似物的例子可以在EP 0325044(环肽)、EP 0225020(链肽)、EP 0536741(环VIP修饰)、EP 0405242、EP 0184309和EP 0613904中找到。此术语也包括VIP或者PACAP相似物，它们不同于VIP或者PACAP，但是有类似于VIP的结构。根据发明，PACAP本身以及它的削短形式PACAP-27可以是这样的相似物。优先的VIP/PACAP相似物是包含一个或多个普遍氨基酸序列的肽。这里的肽的例子是组氨酸异亮氨酸肽、组氨酸甲硫氨酸肽、“人类生长释放因子”(GRF)、PACAP、分泌素和胰高血糖素。
此处所用的术语“稳定的形态”涉及衍生物或者相似物，但是为了得到在血液和血浆中增强的稳定性和增加的半衰期，原始的肽已经被修饰。在肽通过酶活性被削成片段的情况下，这种的稳定的形态是优先的。可能的稳定的形态是环肽或者多肽，例如环VIP或者环PACAP、融合蛋白，优先Fc-融合蛋白或者嵌钉多肽例如嵌钉VIP或者PACAP。合成此类多肽的方法是在当今技术中已知的。多肽和蛋白质可以通过附加上化学基团而被保护，抵制蛋白质水解。这样的附加可以阻止蛋白水解酶与蛋白质结构进入物理接触，从而防止降解。聚乙二醇就是这样的一种结构，它已经被证明防止蛋白质水解(Sada et al.，J.Fermentation Bioengineering
71：137-139，1991)。除了防止蛋白质水解***外，生物学上活跃蛋白质的化学修饰已经被发现在一定的情况下提供另外的优势，例如稳定性和循环时间的提高或者免疫原性的降低。(US 4,179,337；Abuchowski et al.，Enzymes as drugs.；J.S.Holcerberg andJ.Roberts，eds.pp.367-383，1981；Francis，Focus on Growth Factors 3：4-10；EP 0 401 384)
此处所用的术语“融合蛋白”涉及一种物质，特别是在稳定形态下，它由根据发明的多肽构成，优先VIP或者VIP衍生物或相似物，例如PACAP，并与另外的肽或者蛋白质融合。这样的蛋白质优先是免疫球蛋白分子，更优先它的片段，最优先IgG分子的Fc部分，优先IgG1分子。Fc和VIP融合蛋白质发表在WO 200024278并且提供在血液和血浆中提高的半衰期。Fc-PACAP和Fc-PACAP-27可以引用作为进一步的例子。
根据发明的物质可以在合成药物或者诊断程序中使用，这样可以鉴定个体的病理特性。
此处所用的术语“个体”涉及哺乳动物，特别是人类。物质被使用在药物组分和制备构成，在这之中通常使用在药物接受的载体和溶剂中。在本发明中描写的制备和物质运用的方法都可以在“Remington’sPharmaceutical Sciences”Mack Publishing Co.，Easton PA中找到。
此处所用的术语“药物上接受的支持介质”涉及惰性的，非毒性的固体或者液体填料。
为了吸入，物质应该优先作为气雾剂利用。气雾剂及其合成方法是在当今技术中已知的。如果在直接治疗肺部症状必要的条件下，使用吸入器具的气雾剂和包含本发明中的肽或者多肽的气雾剂，例如VIP或者PACAP是优先的。
根据发明，物质的治疗剂量可以是每天一次或者是很少的剂量通过多次供给应用。
联合治疗
发明的化合物可以用单独物质的形式或者与进一步的活性剂相联合的形式给患者使用，这些活性剂是例如钙水道阻塞活性剂(硫氮草酮)，免疫抑制物质(波尼松龙)，抗菌剂比如抗生素或者抗菌素，它们特定有效抵抗葡萄状球菌、假单胞菌、伯克霍尔德氏菌、血友病细菌、链球菌或者其它肺里的细菌，beta-肾上腺素受体阻止物质以及血管紧缩素受体拮抗物或者血管紧缩素再生酶抑制剂(ramipril，雷米普利)，抗增生物质(atorvastatin，阿托伐他汀)，内皮素受体拮抗物(Bosentan，Altrasentan，Sitaxsentan，Enrasentan，BMS 193884，Darusentan，TBC 3711，BSF 208075，BSF 302146，SPP 301)，或者其它抗增生物质(D-24851，Imatinib mesylate)。本发明也涉及已经发表的肽与至少上述一种药物的联合治疗。
令人惊奇的是，被发现，在上文和权利要求中定义的肽和多肽，特别是VIP和PACAP，是人体树状细胞成熟的抑制剂并且在治疗先天肺纤维变性、过敏性肺炎或者弥漫性泛细支气管炎中显示出有益效果。
实例
图1-11显示出VIP在人体树状细胞成熟上的效果。CD 38是成熟的树状细胞特有的表面蛋白质。如果表面蛋白质出现的非常少，这说明细胞还不成熟并且因此无能力完成它们的生物功能。1μmol VIP(图5)的应用，或者特别是9.1μmol VIP(图9)的应用引起CD 83表面分子的显著下降。这样的下降可以通过值M138.22指出-如果在9.1μmol应用后测量-并与未被处理的细胞(图10)的值M181.26(图1)相比较-用荧光激活分析细胞。这个过程包括通过荧光标记的抗体的帮助寻找细胞表面，这些抗体是针对相应的抗原的(这里是CD 83)。VIP在CD 83分子上的效果是特性的，原因是如果应用相同量的VIP，其它表面分子例如所谓的MHC I(见图2，6和10)或者MHC II(见图3，7和11)是更少的被阻止的。这是可以如下证明的：使用9.1μmolVIP时MHC I的值M170.57与未被处理细胞的MHC I的值M1 85.59相比较，以及使用9.1μmol VIP时MHC II的值M1 77.73与未被处理细胞的MHC II的值M183.94相比较。
表格：
未被处理的细胞：
CD 83 图1
| 标志 | ％选择 | 平均值 |
| 所有 | 100.00 | 202.43 |
| M1 | 81.26 | 238.31 |
MHC I 图2
| 标志 | ％选择 | 平均值 |
| 所有 | 100.00 | 352.27 |
| M1 | 85.59 | 398.25 |
MHC II 图3
| 标志 | ％选择 | 平均值 |
| 所有 | 100.00 | 290.14 |
| M1 | 83.94 | 335.90 |
VIP(1μM)：
CD 83 图6
| 标志 | ％选择 | 平均值 |
| 所有 | 100.00 | 108.13 |
| M1 | 69.70 | 137.30 |
MHC I 图7
| 标志 | ％选择 | 平均值 |
| 所有 | 100.00 | 200.61 |
| M1 | 78.69 | 242.97 |
MHC II 图8
| 标志 | ％选择 | 平均值 |
| 所有 | 100.00 | 170.33 |
| M1 | 77.41 | 207.21 |
VIP(9.1μM)：
CD 83 图10
| 标志 | ％选择 | 平均值 |
| 所有 | 100.00 | 76.48 |
| M1 | 38.22 | 143.06 |
MHC 1 图11
| 标志 | ％选择 | 平均值 |
| 所有 | 100.00 | 136.67 |
| M1 | 70.57 | 174.61 |
MHC II 图12
| 标志 | ％选择 | 平均值 |
| 所有 | 100.00 | 175.73 |
| M1 | 77.73 | 213.25 |
使用的缩写：
VIP ＝血管活性肠肽
PACAP ＝垂体腺苷酸环化酶激活肽
IPF ＝特发性肺纤维变性
TGFbeta ＝转化生长因子betal
cAMP ＝3，5-环腺苷酸
PHI ＝组氨酸异亮氨酸肽
PHM ＝组氨酸甲硫氨酸肽
GRF ＝“人体生长释放因子”肽
CD 83 ＝组分化抗原83
MHC I ＝主组织相容性复合体I型分子
MHC II ＝主组织相容性复合体II型分子
虽然本发明已以较佳实施例揭露如上，然其并非用以限定本发明，任何熟习此技艺者，在不脱离本发明之精神和范围内，当可作些许之更动与润饰，因此本发明之保护范围当视后附之申请专利范围所界定者为准。
序列表
<110>蒙德生技实验研究所(Mondobiotech Laboratories Anstalt)
<120>用于治疗非典型肺部感染的血管活性肠肽的生物活性物质
<130>PMB-0304 INT
<150>CH 01229/03
<151>2003-07-14
<160>14
<170>PatentIn version 3.1
<210>1
<211>28
<212>PRT
<213>Homo sapiens
<400>1
His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln
1 5 10 15
Met Ala Val Lys Lys Tyr Leu Asn Ser Ile Leu Asn
20 25
<210>2
<211>38
<212>PRT
<213>Homo sapiens
<400>2
His Ser Asp Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln
1 5 10 15
Met Ala Val Lys Lys Tyr Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys
20 25 30
Gln Arg Val Lys Asn Lys
35
<210>3
<211>27
<212>PRT
<213>Homo sapiens
<400>3
His Ser Asp Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln
1 5 10 15
Met Ala Val Lys Lys Tyr Leu Ala Ala Val Leu
20 25
<210>4
<211>10
<212>PRT
<213>Homo sapiens
<400>4
Arg Lys Gln Met Ala Val Lys Lys Tyr Leu
1 5 10
<210>5
<211>23
<212>PRT
<213>Homo sapiens
<220>
<221>MISC_FEATURE
<222>(4)..(8)
<223>X is any naturally occuring amino acid residue
<400>5
Phe Thr Asp Xaa Xaa Xaa Xaa Arg Lys Gln Met Ala Val Lys Lys
1 5 10 15
Tyr Leu Asn Ser Ile Leu Asn
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<210>6
<211>23
<212>PRT
<213>Homo sapiens
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Tyr Leu Asn Ser Ile Leu Asn
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<212>PRT
<213>Homo sapiens
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Tyr Leu
<210>8
<211>23
<212>PRT
<213>Homo sapiens
<220>
<221>MISC_FEATURE
<222>(4)..(5)
<223>X is any naturally occuring amino acid residue
<220>
<221>MISC_FEATURE
<222>(9)..(13)
<223>X is any naturally occuring amino acid residue
<400>8
His Ser Asp Xaa Xaa Phe Thr Asp Xaa Xaa Xaa Xaa Xaa Arg Lys Gln
1 5 10 15
Met Ala Val Lys Lys Tyr Leu
20
<210>9
<211>23
<212>PRT
<213>Homo sapiens
<400>9
His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln
1 5 10 15
Met Ala Val Lys Lys Tyr Leu
20
<210>10
<211>23
<212>PRT
<213>Homo sapiens
<400>10
His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln
1 5 10 15
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<210>11
<211>28
<212>PRT
<213>Homo sapiens
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<221>MISC_FEATURE
<222>(4)..(5)
<223>X is any naturally occuring amino acid residue
<220>
<221>MISC_FEATURE
<222>(9)..(13)
<223>X is any naturally occuring amino acid residue
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<223>X at positions 24-27 may be any naturally occuring aminoacid residue；
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<400>11
His Ser Asp Xaa Xaa Phe Thr Asp Xaa Xaa Xaa Xaa Xaa Arg Lys Gln
1 5 10 15
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Claims (12)
1.一种物质的用途，是制备药物，用于治疗患有肺病的患者，所述的肺病是直接或者间接与特发性肺病、过敏性肺炎或者弥漫性泛细支气管炎有关联，其中所述的物质是肽或者多肽，其特征在于它包括以下氨基酸序列：
Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu(SEQ ID第1号)
2.根据权利要求1所述的用途，其特征在于其中所述的肽或者多肽进一步包含以下氨基酸序列：
His-Ser-Asp(SEQ ID第14号)；Phe-Thr-Asp(SEQ ID第13号)。
3.根据权利要求1所述的用途，其特征在于其中所述的肽或者多肽显示以下氨基酸序列：
(A)n-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-(B)m
其中A，B是任意一种天然存在的氨基酸，A和B相互独立；以及n，m是替换值，代表0-25，n和m相互独立。
4.根据权利要求3所述的用途，其特征在于其中，如果n＞2，(A)n表示以下序列：
(X)o-Phe-Thr-Asp-(Y)p
其中X，Y是任意一种天然存在的氨基酸，X和Y相互独立；以及o，p是替换值，代表0-11，o和p相互独立。
5.根据权利要求4所述的用途，其特征在于其中，如果o＞2，(X)n表示以下序列：
(X’)q-His-Ser-Asp-(X”)r
其中X’，X”是任意一种天然存在的氨基酸，X’和X”相互独立；以及r，q是替换值，代表0-4，r和q相互独立。
6.根据权利要求3所述的用途，其特征在于所述的肽或者多肽的序列是从以下组中选出的：
i.Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu(SEQ ID第4号)
ii.he-Thr-Asp-X1-X2-X3-X4-X5-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn(SEQ ID第5号)；
iii.Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn(SEQ ID第6号)；
iv.Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu(SEQ ID第7号)；
v.His-Ser-Asp-X1-X2-Phe-Thr-Asp-X3-X4-X5-X6-X7-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu(SEQ ID第9号)；
vi.His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu(SEQ ID第10号)；
vii.His-Ser-Asp-X1-X2-Phe-Thr-Asp-Asp-X3-X4-X5-X6-X7-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-X8-X9-X10-X11-(X12)(SEQ ID第11号)；
Viii.His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn(VIP，SEQ ID第1号)；
ix.His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu(PACAP-38，SEQ ID第2号)；
x.His-Ser-Asp-X1-X2-Phe-Thr-Asp--X3-X4-X5-X6-X7-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22(SEQ ID第12号)；
xi.His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu-Gly-Lys-Arg-Tyr-Lys-Gln-Arg-Val-Lys-Asn-Lys(PACAP-27，SEQ ID第3号)；
其中X1-X22是任意一种天然存在的氨基酸。
7.根据权利要求1-6所述的用途，其特征在于其中每个所述的肽或者多肽是具有相同生物作用的相似物或者衍生物。
8.根据权利要求7所述的用途，其特征在于其中每个所述的肽或者多肽以稳定的形态存在。
9.根据权利要求1-8所述的用途，其特征在于其中所述的疾病是特发性肺纤维变性。
10.根据权利要求1-8所述的用途，其特征在于其中所述的疾病是过敏性肺炎。
11.根据权利要求1-8所述的用途，其特征在于其中所述的疾病是弥漫性泛细支气管炎。
12.根据权利要求1-8所述的用途，其特征在于其中具有治疗活性的肽以气雾剂的形式使用。
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|---|---|---|---|
| CH12292003 | 2003-07-14 | ||
| CH1229/03 | 2003-07-14 | ||
| PCT/CH2004/000439 WO2005004899A2 (de) | 2003-07-14 | 2004-07-12 | Substanzen mit biologischer aktivität des vasoaktiven intestinalen peptids für die behandlung von interstitiellen lungenerkrankungen |
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| CN1917898A true CN1917898A (zh) | 2007-02-21 |
| CN1917898B CN1917898B (zh) | 2011-08-17 |
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| CN2004800244797A Expired - Fee Related CN1917898B (zh) | 2003-07-14 | 2004-07-12 | 用于治疗间质肺部感染的血管活性肠肽的生物活性物质 |
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| Country | Link |
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| US (1) | US7468353B2 (zh) |
| EP (1) | EP1644028B1 (zh) |
| JP (1) | JP2007513053A (zh) |
| CN (1) | CN1917898B (zh) |
| AT (1) | ATE432079T1 (zh) |
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| CA (1) | CA2532135A1 (zh) |
| DE (1) | DE502004009530D1 (zh) |
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| US8178495B2 (en) | 2008-06-27 | 2012-05-15 | Duke University | Therapeutic agents comprising a GLP-1 receptor agonist and elastin-like peptide |
| US20130172274A1 (en) | 2005-12-20 | 2013-07-04 | Duke University | Methods and compositions for delivering active agents with enhanced pharmacological properties |
| JP2009525946A (ja) | 2005-12-20 | 2009-07-16 | デューク・ユニヴァーシティ | 増強された薬理学的性質を有する活性物質を送達するための方法および組成物 |
| US8841255B2 (en) | 2005-12-20 | 2014-09-23 | Duke University | Therapeutic agents comprising fusions of vasoactive intestinal peptide and elastic peptides |
| KR20100059867A (ko) * | 2007-09-11 | 2010-06-04 | 몬도바이오테크 래보래토리즈 아게 | 치료제로서의 밴드 ３ 단백질 및 ｐａｃａｐ－２７의 용도 |
| KR20100061485A (ko) * | 2007-09-11 | 2010-06-07 | 몬도바이오테크 래보래토리즈 아게 | 치료제로서의 피브로넥틴 단편 （１９６－２０３）의 용도 |
| CA2804755C (en) | 2009-08-14 | 2018-06-05 | Phasebio Pharmaceuticals, Inc. | Modified vasoactive intestinal peptides |
| WO2011066453A2 (en) * | 2009-11-25 | 2011-06-03 | Said Sami I | Pacap and related proteins in the treatment of cancer |
| US9669092B2 (en) * | 2011-02-02 | 2017-06-06 | Emory University | Antagonism of the VIP signaling pathway |
| ES2669190T3 (es) | 2011-06-06 | 2018-05-24 | Phasebio Pharmaceuticals, Inc. | Uso de péptidos intestinales vasoactivos modificados en el tratamiento de la hipertensión |
| EP3139949B1 (en) | 2014-05-08 | 2020-07-29 | Phasebio Pharmaceuticals, Inc. | Compositions comprising a vip-elp fusion protein for use in treating cystic fibrosis |
| AU2016219513B2 (en) | 2015-02-09 | 2021-09-30 | Immunoforge Co., Ltd. | Methods and compositions for treating muscle disease and disorders |
| CA3138891A1 (en) * | 2019-05-07 | 2020-11-12 | Advita Lifescience Gmbh | Vasoactive intestinal peptide (vip) for use in the treatment of drug-induced pneumonitis |
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| US3898329A (en) * | 1971-09-17 | 1975-08-05 | Sami I Said | Vasoactive intestinal peptide, composition and method |
| US4237046A (en) * | 1979-04-27 | 1980-12-02 | Miklos Bodanszky | Polypeptides and methods of preparation |
| US20020115609A1 (en) * | 1997-07-14 | 2002-08-22 | Hayat Onyuksel | Materials and methods for making improved micelle compositions |
| US6322810B1 (en) * | 1997-07-14 | 2001-11-27 | Hayat Alkan-Onyuksel | Materials and methods for making improved micelle compositions |
| US20020114829A1 (en) * | 1998-12-18 | 2002-08-22 | Hayat Onyuksel | Materials and methods for making improved liposome compositions |
| AU4927700A (en) | 1999-06-04 | 2000-12-28 | Universidad Complutense De Madrid | Method for treating endotoxic shock and inflammatory and autoimmune diseases in mammals |
| AU2249701A (en) | 1999-11-12 | 2001-06-06 | David Bernstein | Methods for treating cardiac arrest or pulmonary hypertension and compositions for use therein comprising vasoactive intestinal polypeptide and cardiac device for electrical and chemical regulation and methods of use |
| EP1337557A2 (en) * | 2000-11-28 | 2003-08-27 | Mondobiotech SA | Compounds with the biological activity of vasoactive intestinal peptide for the treatment of pulmonary and arteriolar hypertension |
| WO2003051388A2 (en) | 2001-12-18 | 2003-06-26 | Mondobiotech Laboratories Anstalt | Pharmaceutical composition of interferon gamma or pirfenidone with molecular diagnostics for the improved treatment of interstitial lung diseases |
| CA2472270A1 (en) | 2002-01-26 | 2003-07-31 | Mondobiotech Laboratories Anstalt | Use of compounds having the biological activity of vasoactive intestinal peptide for the treatment of chronic obstructive pulmonary disease |
| EP1515745B1 (en) | 2002-06-10 | 2009-03-18 | MondoBIOTECH Licensing Out AG | Use of compounds having the biological activity of vasoactive intestinal peptide for the treatment of sarcoidosis |
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2004
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- 2004-07-12 WO PCT/CH2004/000439 patent/WO2005004899A2/de active Application Filing
- 2004-07-12 AU AU2004255379A patent/AU2004255379B2/en not_active Ceased
- 2004-07-12 JP JP2006519742A patent/JP2007513053A/ja active Pending
- 2004-07-12 DE DE502004009530T patent/DE502004009530D1/de active Active
- 2004-07-12 ES ES04738079T patent/ES2327640T3/es active Active
- 2004-07-12 CN CN2004800244797A patent/CN1917898B/zh not_active Expired - Fee Related
- 2004-07-12 AT AT04738079T patent/ATE432079T1/de active
- 2004-07-12 CA CA002532135A patent/CA2532135A1/en not_active Abandoned
- 2004-07-12 EP EP04738079A patent/EP1644028B1/de not_active Not-in-force
Also Published As
| Publication number | Publication date |
|---|---|
| AU2004255379A1 (en) | 2005-01-20 |
| CA2532135A1 (en) | 2005-01-20 |
| EP1644028B1 (de) | 2009-05-27 |
| JP2007513053A (ja) | 2007-05-24 |
| US20060223748A1 (en) | 2006-10-05 |
| ATE432079T1 (de) | 2009-06-15 |
| WO2005004899A2 (de) | 2005-01-20 |
| CN1917898B (zh) | 2011-08-17 |
| AU2004255379B2 (en) | 2007-08-16 |
| EP1644028A2 (de) | 2006-04-12 |
| US7468353B2 (en) | 2008-12-23 |
| DE502004009530D1 (de) | 2009-07-09 |
| WO2005004899A3 (de) | 2005-05-26 |
| ES2327640T3 (es) | 2009-11-02 |
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