CN117940145A - 具有抗血管生成活性的肽 - Google Patents
具有抗血管生成活性的肽 Download PDFInfo
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- CN117940145A CN117940145A CN202280060775.0A CN202280060775A CN117940145A CN 117940145 A CN117940145 A CN 117940145A CN 202280060775 A CN202280060775 A CN 202280060775A CN 117940145 A CN117940145 A CN 117940145A
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Abstract
本发明涉及长度等于或小于5个氨基酸的肽或其衍生物,所述肽或其衍生物包含:序列DKY,优选XDKY(SEQ ID No.7)或DKYX(SEQ IDNo.8),或者序列DRY,优选XDRY(SEQ ID No.9)或DRYX(SEQ IDNo.10),其中X是任意氨基酸,所述肽或其衍生物用作药物,特别地用于治疗由病理性血管生成引起的病症;以及药物组合物,所述药物组合物包含所述肽或其衍生物及至少一种可药用赋形剂。
Description
技术领域
本发明涉及具有抗血管生成活性的肽以及包含所述肽的药物组合物,所述肽可用于治疗血管生成相关的病症,例如如癌症、慢性炎症和新血管形成病症。
背景技术
血管生成是血管形成的复杂过程。该过程涉及生物化学事件和细胞事件二者,包括(i)通过血管生成刺激来活化内皮细胞(endothelial cell,EC);(ii)胞外基质降解,活化的EC侵入到周围组织中,并迁移至血管生成刺激的源头;以及(iii)EC增殖并分化以形成新的血管。
血管生成的控制是涉及血管生成刺激物和抑制物的高度调节过程。在人和健康动物中,血管生成发生在特定和有限的情况中。例如,血管生成通常在以下观察到:胎儿和胚胎发育中,正常组织和器官的发育和生长中,伤口愈合中,以及黄体、子宫内膜和胎盘的形成中。
在某些疾病中,血管生成的控制受到损害,并因此发生所谓的病理性血管生成,即,形成支持病理状态的过量或不需要的血管,并且在许多情况下导致与这些疾病相关的细胞和/或组织损伤。
病理性血管生成在肿瘤形成中发挥重要作用,因为肿瘤需要血管来提供营养和氧并除去细胞废物。同时,肿瘤中血管的形成使癌细胞进入血流并在全身循环,从而产生转移。
肿瘤(其中血管生成是重要的)包括实体瘤以及良性肿瘤例如听神经瘤、神经纤维瘤、沙眼和化脓性肉芽肿。病理性血管生成还与某些血癌(例如白血病)以及骨髓的多种急性或慢性肿瘤性疾病相关。
病理性血管生成在多种慢性炎性疾病(例如炎性肠病、银屑病、结节病和类风湿性关节炎)中也发挥重要作用。在这样的疾病中发生的慢性炎症依赖于患病组织中毛细管芽(sprout)的持续形成以维持炎性细胞的流入。炎性细胞的流入和存在产生了肉芽肿,并因此维持慢性炎性状态。
正常和病理性二者的血管生成需要一种或更多种血管生成因子的作用。这样的因子包括例如血管生成蛋白(angiogenin,ANG)、血管内皮生长因子(vascular endothelialgrowth factor,VEGF-血管内皮生长因子)、碱性成纤维细胞生长因子(basic fibroblastgrowth factor,bFGF)、酸性成纤维细胞生长因子(acidic fibroblast growth factor,aFGF)、表皮生长因子(epidermal growth factor,EGF)、肿瘤坏死因子-α(tumor necrosisfactor-alpha,TNF-α)、肿瘤生长因子-α(tumor growth factor-alpha,TGF-α)和肿瘤生长因子-β(tumor growth factor-beta,TGF-β)。
血管生成在大量血管生成相关疾病中的中心性促使寻找抗血管生成剂(即阻遏或抑制病理性血管生成的药剂)。
已分离或开发了许多抗血管生成剂。其包括软骨衍生因子、血管抑制性类固醇、维生素D的血管抑制性类似物、血管抑素、内皮抑素和verostatin。
存在许多不同类别的抗血管生成剂,其通过示例的方式包括抑制生长因子作用的药剂、抗侵袭剂和血管破坏剂。
抑制生长因子的作用的药剂包括:
(i)受体拮抗剂,例如,抗VEGF受体抗体,如CA 2213833中所述的);
(ii)蛋白激酶C抑制剂;
(iii)酪氨酸激酶抑制剂,例如,VEGF受体酪氨酸激酶抑制剂,如WO 96/40116中所述的);
(iv)Tie-1和/或Tie 2受体信号传导的调节剂;以及
(v)蛋白质表达的抑制剂,例如,VEGF表达的抑制剂,如US4987071中所述的)。
抗侵袭剂包括:
(i)基质金属蛋白酶抑制剂,例如,普啉司他(prinomastat)(US5753653)、伊洛马司他(ilomastat)(WO 92/9556)、马立马司他(marimastat)(WO 94/2447)和巴马司他(batimastat)(WO 90/5719),
(ii)尿激酶纤溶酶原激活物受体拮抗剂,例如,WO96/40747和WO 2000/001802中所述的化合物,以及
(iii)尿激酶纤溶酶原激活物抑制剂,例如,WO 2000/005245中所述的化合物。
血管破坏剂包括康普瑞汀(combretastatin)(US4996237)以及WO 99/02166和WO00/40529中所述的化合物。
已知的抗血管生成剂包括抗血管生成肽,例如EP1640382A1,EP1668129A1,EP1786451A2,EP1799716A1,EP1812030A2,EP1951750A2,EP3209683A1,EP3621597A1中所述的那些。
WO2004/031220公开了具有序列DRYYNLRSK(SEQ ID NO.6)的肿瘤靶向肽,其直接或间接与至少一种效应单元偶联以用于治疗癌症或癌症相关疾病,例如选自上皮癌、肉瘤、黑素瘤或转移瘤的实体瘤。
WO2008/085828公开了具有携带“CXC”基序的序列GDRYCL的肽,其为G-X(3)-CL,可用于调节细胞、组织或器官中的血管形成。
WO00/63236公开了具有序列DRYLKFRPV的肽,其能够通过在黑素瘤周围形成肽相关底物的物理屏障来调节靶细胞对底物的黏附,特别是抑制黑素瘤细胞附着,从而阻止其转移。
发明内容
本申请人面临的问题是寻找用于治疗与病理性血管生成相关的疾病的新的肽。
人疱疹病毒6(human herpesvirus 6,HHV-6)是在人群体中高度流行的β-疱疹病毒。HHV-6包含两个公认的种类(HHV-6A和HHV-6B)。HHV-6A/B显示出高基因组同源性并具有U94基因。U94在病毒生命周期和相关疾病方面具有关键功能,在病毒复制、整合和再激活方面具有已证实或推定的作用。在自然感染期间,U94引发免疫应答,并且抗U94应答的普遍性和程度与特定疾病相关。特别地,U94可在细胞水平上完全模拟病毒的一些作用,包括抑制细胞迁移、诱导细胞因子和HLA-G表达以及抑制血管生成,从而支持U94在HHV-6相关疾病的发生方面的直接作用(Caselli E.,et al.,“The U94 Gene of Human Herpesvirus 6:ANarrative Review of Its Role and Potential Functions,”Cells.2020 Dec;9(12):2608)。
基于这些观察,本申请人假设由U94基因表达的病毒蛋白质中一定有一部分具有抗血管生成活性,并启动了深入的研究和开发以鉴定该部分。
由U94基因表达的病毒蛋白质是如在图6中所示的490个氨基酸的序列(SEQ IDNo.1)。
在大量实验之后,本申请人出乎意料地发现抗血管生成作用来自所述病毒蛋白质的第14至17位的四个氨基酸序列,即KDKY序列(SEQ ID No.2)。
继续实验,本申请人进一步发现抗血管生成作用出乎意料地来源于所述病毒蛋白质的第15至17位的仅三个氨基酸的序列,即DKY序列,并且这种作用在DRY序列的情况下被维持。
因此,在第一方面中,本发明涉及长度等于或小于5个氨基酸的肽或其衍生物,所述肽或其衍生物包含:序列DKY,优选XDKY(SEQ ID No.7)或DKYX(SEQ ID No.8),或者序列DRY,优选XDRY(SEQ ID No.9)或DRYX(SEQ ID No.10),其中X是任意氨基酸,所述肽或其衍生物用作药物。
有利地,本发明涉及根据本发明的第一方面的肽,其用于治疗由病理性血管生成引起的病症,例如如肿瘤和/或慢性炎症和/或新血管病症。
在第二方面中,本发明涉及药物组合物,所述药物组合物包含(a)长度等于或小于5个氨基酸的肽或其衍生物以及(b)至少一种可药用赋形剂,所述肽或其衍生物包含:序列DKY,优选XDKY(SEQ ID No.7)或DKYX(SEQ ID No.8),或者序列DRY,优选XDRY(SEQ IDNo.9)或DRYX(SEQ ID No.10),其中X是任意氨基酸。
在第三方面中,本发明涉及用于在有此需要的对象中治疗由病理性血管生成引起的病症(例如如肿瘤和/或慢性炎症和/或新血管形成病症)的方法,所述方法包括施用有效量的长度等于或小于5个氨基酸的肽或其衍生物,所述肽或其衍生物包含:序列DKY,优选XDKY(SEQ ID No.7)或DKYX(SEQ ID No.8),或者序列DRY,优选XDRY(SEQ ID No.9)或DRYX(SEQ ID No.10),其中X是任意氨基酸。
在第四方面中,本发明涉及长度等于或小于5个氨基酸的肽或其衍生物,所述肽或其衍生物包含:序列DKY,优选XDKY(SEQ ID No.7)或DKYX(SEQ ID No.8),或者序列DRY,优选XDRY(SEQ ID No.9)或DRYX(SEQ ID No.10),其中X是任意氨基酸。
附图说明
图1示出了本说明书的实验部分的实施例1的结果。
图2示出了本说明书的实验部分的实施例2的结果。
图3示出了本说明书的实验部分的实施例3的结果。
图4示出了本说明书的实验部分的实施例4的结果。
图5示出了本说明书的实验部分的实施例5的结果。
图6示出了由人疱疹病毒6(HHV-6)的U94基因所表达的蛋白质的490个氨基酸的序列(SEQ ID No.1)。
具体实施方式
在第一方面中,本发明涉及长度等于或小于5个氨基酸的肽或其衍生物,所述肽或其衍生物包含:序列DKY,优选XDKY(SEQ ID No.7)或DKYX(SEQ ID No.8),或者序列DRY,优选XDRY(SEQ ID No.9)或DRYX(SEQ ID No.10),其中X是任意氨基酸,所述肽或其衍生物用作药物。
根据本发明的肽可包含最少3个氨基酸最多5个氨基酸,并因此由3、4或5个氨基酸的肽组成。有利地,根据本发明的肽由3、4或5个氨基酸的肽组成。
根据本发明的肽可包含下表A中列出的任意天然氨基酸。
表A
根据本发明的肽还可包含本领域已知的任何经修饰或非常规的氨基酸,例如如2-氨基己二酸、3-氨基己二酸、β-丙氨酸、β-氨基丙酸、2-氨基丁酸、4-氨基丁酸、哌啶酸、6-氨基己酸、2-氨基庚酸、2-氨基异丁酸、3-氨基异丁酸、2-氨基庚二酸、2,4-二氨基丁酸、锁链素、2,2’-二氨基庚二酸、2,3-二氨基丙酸、N-乙基甘氨酸、N-乙基天冬酰胺、羟赖氨酸、别羟赖氨酸、3-羟脯氨酸、4-羟脯氨酸、异锁链素、别异亮氨酸、N-甲基甘氨酸、肌氨酸、N-甲基异亮氨酸、6-N-甲基赖氨酸、N-甲基缬氨酸、正缬氨酸、正亮氨酸和鸟氨酸。
根据本发明多个方面的肽可以是经修饰肽的形式,其中N端和/或C端被有机化合物化学修饰或保护。
如本说明书和所附权利要求书中使用的与根据本发明多个方面的肽相关的术语“衍生物”或“的衍生物”意指其中N端和/或C端被有机化合物化学修饰或保护的肽,所述有机化合物例如如磷酰基(-PO3 2-)、糖基、酰基、烷基、羧基、胺、生物素、泛素。
修饰的一些实例包括磷酸化、糖基化、酰化(包括乙酰化、月桂酰化(lauroylation)、豆蔻酰化、棕榈酰化)、烷基化、羧基化、羟基化、糖化、生物素化、泛素化和酰胺化。
优选地,根据本发明多个方面的肽可在其N端,最优选通过酰化进行修饰,所述酰化包括例如乙酰化、月桂酰化、豆蔻酰化、棕榈酰化。
根据其长度,根据本发明多个方面的肽可通过本领域公知的方法例如通过自动化肽合成仪来合成或通过遗传改造技术产生。例如,通过遗传改造来制备编码包含融合配偶体和肽的融合蛋白的融合基因,并随后将其转化到宿主细胞中以表达融合蛋白。然后,使用蛋白酶或化合物将肽切割并从融合蛋白中分离,以产生期望的肽。出于该目的,可将编码氨基酸残基的DNA序列插入到编码融合配偶体和肽的多核苷酸之间,所述氨基酸残基可被以下切割:蛋白酶例如因子Xa或肠激酶,或者化合物例如CNBr或羟胺。
根据本发明多个方面的肽可以以立体异构体或立体异构体的混合物存在;例如,构成所述肽的氨基酸可具有L构型、D构型或彼此独立的外消旋。因此,可获得异构体混合物以及外消旋物或非对映体混合物或者纯的非对异构体或对映体,这取决于不对称碳的数目以及存在哪种异构体或异构体混合物。肽的优选结构是纯的异构体,即对映体或非对映体。肽的优选结构包括具有L构型的氨基酸。除非另有说明,否则应当理解,当指出氨基酸可以是Ala时,其选自L-Ala-、D-Ala-或者二者的外消旋或非外消旋混合物。
在第二方面中,本发明涉及药物组合物,所述药物组合物包含(a)长度等于或小于5个氨基酸的肽或其衍生物以及(b)至少一种可药用赋形剂,所述肽或其衍生物包含:序列DKY,优选XDKY(SEQ ID No.7)或DKYX(SEQ ID No.8),或者序列DRY,优选XDRY(SEQ IDNo.9)或DRYX(SEQ ID No.10),其中X是任意氨基酸。
本发明的药物组合物可包含相对于组合物的总重量的按重量计0.0001%至20%、优选地按重量计0.0001%至15%、更优选地按重量计0.001%至10%、并且甚至更优选地按重量计0.01%至5%的量的肽或其衍生物。
优选地,本发明的药物组合物以合适的剂型进行制备,该剂型包含有效量的至少一种上述肽以及至少一种可药用赋形剂。
合适的剂型的一些实例是用于经口施用的片剂、胶囊剂、包衣片剂、颗粒剂、溶液剂和糖浆剂;用于表面施用的溶液剂、软膏剂和油膏剂;用于经皮施用的医用贴剂;用于经直肠施用的栓剂;以及无菌可注射溶液剂。另一些合适的剂型包括用于经口、可注射或经皮施用的持续释放和基于脂质体的剂型。
如本文中所述的,本发明的药物组合物包含至少一种上述肽以及可药用赋形剂,如本文中使用的,所述可药用赋形剂包括如适合于所期望的特定剂型的任意和全部溶剂、稀释剂、或另一些载剂、分散剂或悬浮助剂、表面活性剂、等张剂、增稠剂或乳化剂、防腐剂、固体黏合剂、润滑剂等。
可用作可药用赋形剂的物质的一些实例包括但不限于以下:糖类,例如乳糖、葡萄糖和蔗糖;淀粉,例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;adragosta粉末;麦芽;明胶;滑石;赋形剂,例如可可脂和栓剂蜡;油类,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和豆油;二醇类,例如丙二醇;酯类,例如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,例如氢氧化镁和氢氧化铝;海藻酸;无热原水;等张盐溶液;林格液(Ringer’s solution);乙醇和磷酸盐缓冲溶液;其他无毒相容性润滑剂,例如月桂基硫酸钠和硬脂酸镁;着色剂;释放剂;包衣剂;甜味剂;矫味剂和芳香剂;防腐剂;以及抗氧化剂。
术语“可药用”和“生理学上可接受的”旨在没有任何特定限制地限定适合于制备待向生物体施用的药物组合物的任何物质。
剂型还可包含另一些传统成分,例如:防腐剂、稳定剂、表面活性剂、缓冲剂、渗透压调节盐、乳化剂、甜味剂、染料、香料等。
本发明的药物组合物可经口、肠胃外、通过吸入喷雾剂、表面、经直肠、经鼻、经颊、经阴道或通过植入的储库来施用。如本发明和所附权利要求书中使用的术语肠胃外包括皮下、皮内、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、病灶内以及颅内注射或输注技术。
本发明的药物组合物还可通过吸入(喷雾剂、散剂或气雾剂)施用或者通过植入(例如外科手术)例如通过可植入装置(例如支架)来施用。
本发明的药物组合物剂型可通过药物化学家熟悉的技术来制备,并且所述技术包括混合、制粒、压缩、溶解、灭菌等。
有利地,本发明涉及长度等于或小于5个氨基酸的肽或其衍生物在治疗由病理性血管生成引起的病症中的用途,所述肽或其衍生物包含:序列DKY,优选XDKY(SEQ ID No.7)或DKYX(SEQ ID No.8),或者序列DRY,优选XDRY(SEQ ID No.9)或DRYX(SEQ ID No.10),其中X是任意氨基酸。
优选地,上述肽和包含其的药物组合物用于治疗由病理性血管生成引起的疾病,例如如癌症和/或慢性炎症和/或新生血管病症。
可用本发明的肽和药物组合物有效治疗的肿瘤的一些实例是实体瘤和血癌。
可用本发明的肽和药物组合物治疗的实体瘤包括肉瘤和上皮癌,例如纤维性星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突胶质细胞瘤、脑膜瘤、黑素瘤、成神经细胞瘤、视网膜母细胞瘤,以及良性实体瘤例如听神经瘤、神经纤维瘤、沙眼和化脓性肉芽肿。
易于用本发明的肽和药物组合物治疗的血癌(例如白血病)包括例如急性淋巴细胞白血病和急性髓细胞白血病(成髓细胞白血病、早幼粒细胞白血病、粒-单核细胞白血病、单核细胞白血病和红白血病);慢性白血病(慢性髓细胞[粒细胞]白血病和慢性淋巴细胞白血病);以及真性红细胞增多症、淋巴瘤(霍奇金病(Hodgkin’s disease)和非霍奇金病)、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症(macroglobulinemia)。
具体而言,本发明的肽和药物组合物可用于治疗纤维肉瘤、黏液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因肿瘤(Ewing’s tumor)、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管源性癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、维尔姆斯瘤(Wilms’tumor)、宫颈癌、睾丸癌、肺癌、小细胞肺癌、膀胱癌、上皮癌、胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突胶质细胞瘤、脑膜瘤、黑素瘤、成神经细胞瘤、视网膜母细胞瘤、听神经瘤、神经纤维瘤、沙眼和化脓性肉芽肿。
用于治疗癌症的本发明的药物组合物可任选地包含一种或更多种抗肿瘤剂,例如,(i)生物碱,例如多西他赛(docetaxel)、依托泊苷(etoposide)、trontecan、紫杉醇、替尼泊苷(teniposide)、拓扑替康(topotecan)、长春碱、长春新碱和长春地辛;(ii)烷化剂,例如白消安(busulfan)、英丙舒凡(improsulfan)、哌泊舒凡(piposulfan)、氮丙啶(aziridine)、苯佐替派(benzodepa)、卡波醌(carboquone)、美妥替哌(meturedepa)、乌瑞替派(uredepa)、六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(triethylenephosphoramide)、三乙撑硫代磷酰胺(triethylenethiophosphoramide)、苯丁酸氮芥(chlorambucil)、chloraphazine、环磷酰胺、雌莫司汀(estramustine)、异环磷酰胺、氮芥、盐酸甲氧氮芥、美法仑(melphalan)、新氮芥、培磷酰胺、苯芥胆甾醇、泼尼莫司汀(prednimustine)、曲磷胺、卡莫司汀(carmustine)、氯脲菌素、福莫司汀(photemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine)、达卡巴嗪(dacarbazine)、甘露莫司汀(mannomustine)、二溴甘露醇、二溴卫矛醇、哌泊溴烷(pipobroman)、替莫唑胺(temozolomide);(iii)抗生素及类似物,例如阿克拉霉素(aclacinomycin)、放线菌素、安曲霉素(anthramycin)、氮杂丝氨酸、博来霉素(bleomycin)、放线菌素C、卡柔比星(carubicin)、嗜癌菌素、色霉素、放线菌素D、柔红霉素(daunorubicin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、伊达比星(idarubicin)、美诺立尔(menogaril)、丝裂霉素、霉酚酸、诺加霉素(nogalamycin)、橄榄霉素、培来霉素(peplomycin)、pyarubicin、普卡霉素(plicamycin)、紫菜霉素(porphyromycin)、嘌呤霉素(puromycin)、链黑霉素、链脲霉素、杀结核菌素、净司他丁(zinostatin)、佐柔比星(zorubicin);(iv)抗代谢剂,例如二甲叶酸、依达曲沙(edatrexate)、甲氨蝶呤(methotrexate)、pyritrexim、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate)、克拉屈滨(cladribine)、氟达拉滨(fludarabine)、6-巯基嘌呤、硫咪嘌呤、硫代鸟嘌呤、安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮杂尿苷、阿糖胞苷、去氧氟尿苷、乙嘧替氟(emitefur)、依诺他滨(enocitabune)、氮尿苷、氟尿嘧啶、吉西他滨(gemcitabine)、替加氟;L-天冬酰胺酶;(v)免疫调节剂,例如干扰素-α、干扰素-β、干扰素-γ、白介素-2、香菇多糖、丙帕锗(propagermanium)、PSK、罗喹美克(roquinimex)、sizofican、乌苯美司(ubenimex);(vi)铂复合物,例如卡铂、顺铂、米铂(miboplatin)、奥沙利铂(oxaliplatin);(vii)抗肿瘤激素或类似物,例如卡鲁睾酮(calusterone)、屈他雄酮(dromostanolone)、环硫雄醇(epithiostanol)、美雄烷(mepitiostane)、睾内酯(testolacone)、氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane)、比卡鲁胺(bicalutamide)、氟他胺(flutamide)、尼鲁米特(nilutamide)、屈洛昔芬(droloxifene)、他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、氨鲁米特(aminoglutethimide)、阿那曲唑(anastrozole)、法倔唑(fadrozole)、福美司坦(formestane)、来曲唑(letrozole)、磷雌酚(phosphestrol)、己烷雌酚(hexestrol)、聚雌二醇磷酸酯、布舍瑞林(buserelin)、戈舍瑞林(goserelin)、亮丙瑞林(leuprolide)、曲普瑞林(triptorelin)、乙酸氯地孕酮(chlormadinone acetate)、甲羟孕酮、乙酸甲地孕酮(megestrol acetate)、美仑孕酮(melengestrol);卟吩姆钠(porfimer sodium);batimastar;以及亚叶酸。
可用本发明的肽和药物组合物有效治疗的慢性炎性疾病的一些实例为炎性肠病(例如克罗恩病(Crohn’s disease)和溃疡性结肠炎)、银屑病、结节病和类风湿性关节炎。
可用本发明的肽和药物组合物有效治疗的新生血管病症的一些实例是(i)角膜病症,例如如眼部玫瑰痤疮(acne rosacea)、特应性角膜炎、细菌性溃疡、化学烧伤、接触镜片的过度使用、角膜移植排斥、流行性角膜结膜炎、真菌性溃疡、单纯疱疹感染、带状疱疹感染、卡波西肉瘤(Kaposi’s sarcoma)、脂质变性、边缘性角质松解症、分枝杆菌感染、蚕蚀性角膜溃疡(Mooren’s ulcer)、新生血管性青光眼和晶体后纤维增生症、pemfigoid放射状角膜切开术、filectenulosis、多动脉炎、原生动物感染、早产儿视网膜病变、类风湿性关节炎、史蒂文-约翰逊病(Steven Johnson’s disease)、上缘角膜炎、梅毒、系统性狼疮、Terrien边缘变性、维生素A缺乏和韦格纳结节病(Wegener’s sarcoidosis),以及(ii)视网膜病症,例如如动脉闭塞、白塞病(Behcet’s disease)、卵黄状黄斑变性(Best disease)、慢性视网膜脱离、葡萄膜炎/慢性神经炎、阻塞性颈动脉疾病、糖尿病性视网膜病变、视网膜静脉周围炎(Eales disease)、高黏滞综合征、感染引起的视网膜炎或脉络膜炎、莱姆病(Lyme disease)、黄斑变性、分枝杆菌感染、视窝、佩吉特病(Paget’s disease)、激光术后并发症、推定的眼部组织胞浆菌病、弹性纤维假黄瘤、早产儿视网膜病变、镰状细胞贫血、类肉瘤、眼底黄色斑点症(Stargardt disease)、弓形虫病、与红变(rubeosis)相关的疾病、以及由纤维血管或纤维组织异常增生引起的疾病,其包括无论是否与糖尿病相关的所有形式的增生性玻璃体视网膜病变。
以下实施例旨在进一步举例说明本发明,但不限制本发明。
实施例
材料和方法
细胞培养
将人脐静脉内皮细胞(human umbilical vein endothelial cell,HUVEC)进行分离和表征,如Caruso A.et al.,“HHV-6 infects human aortic and heartmicrovascular endothelial cells,increasing their ability to secreteproinflammatory chemokines,”J Med Virol.2002;67:528-533中所述的。
将细胞在补充有10%(体积/体积)胎牛血清(fetal bovine serum,FBS)的内皮细胞生长培养基(EGM MV;Promo cell,Heidelberg,Germany)中在37℃下于包含5%CO2的湿润气氛中培养。
人肺微血管内皮细胞(human lung microvascular endothelial cell,HL-mEC)购自Lonza Clonetics(Walkersville,MD,USA)并在包含10%FBS的EGM-2MV生长培养基(Lonza,Basel,Switzerland)中培养。使贴壁细胞生长直至80%至90%汇合。
所有实验均用第2至6代的细胞进行。
表达U94基因的质粒的克隆、产生和核转染
使用质粒U94 pSR2PH作为模板来扩增U94来源的基因。将PCR产物插入到pVAX1表达载体中。使用Amaxa核转染技术(Lonza)按照制造商的方案进行细胞的核穿孔。将表达U94或U94来源的基因的无内毒素质粒添加至重悬于100μl的核转染缓冲液中的细胞(1×106)。实验在核转染之后24小时时进行。
管形成测定
管形成测定如Caccuri F.et al.,“Evolution toward beta common chainreceptor usage links the matrix proteins of HIV-1 and its ancestors to humanerythropoietin,”Proc Natl Acad Sci USA.2021;11810中所述的进行。
简言之,将150μl的Cultrex基底膜提取物(基质胶;10mg/ml)(Trevigen Inc.,Gaithersburg,MD,USA)或降低生长因子的基质胶(Trevigen Inc.)转移至预冷的48孔培养板。然后将板在37℃下孵育1小时。
将细胞重悬于包含10%FBS的EGM生长培养基中并接种(5×104个/孔)。在接种细胞之后的不同时间时观察血管形成。将毛细管结构用Hitachi KP-D50相机进行拍照,并随后定量为管的数目/孔。
在一些实验中,将HUVEC用最佳浓度的人促血管生成分子进行刺激,所述人促血管生成分子例如血管内皮生长因子A(vascular endothelial growth factor-A,VEGF-A)、成纤维细胞生长因子2(fibroblast growth factor-2,FGF-2)或白介素-8(interleukin-8,IL-8)。使用经核转染的细胞或用U94来源的肽刺激的细胞进行实验。
球体测定
使用经核转染的细胞或用U94来源的肽刺激的细胞进行测定。通过将HUVEC(1.5×105个细胞/ml)与5mg/ml甲基纤维素(Sigma-Aldrich)在包含10%FBS的EGM生长培养基中混合来产生球体,使最终体积达到10ml。
然后将细胞(100μl/孔)添加至96孔板(Greiner Bio-one,Kremsmünster,Austria),并在37℃下在5%CO2气氛中孵育24小时。
单独地,将胶原蛋白I凝胶溶液(大鼠尾,Corning)维持在冰上,并通过添加NaOH0.1M和PBS10×中和至最终pH为7.4。
然后,将24孔板用中和的胶原蛋白(200μl/孔)进行包被,并在37℃下在湿润的5%CO2培养箱中孵育1小时。
将来自96孔板的球体收集在Eppendorf管中,并在4000×rpm下离心5至10秒。当区分出清晰的沉淀时,将上清液除去并将沉淀保持在约100μl的胶原蛋白I中和溶液中。
将每种胶原蛋白-球体混合物以100μl/孔快速添加至预包被的24孔板,并孵育1小时。在1小时之后,将500μl的不同刺激物添加或不添加至孔以完全覆盖表面,并将板进一步孵育24小时。
将从球体核中出现的萌芽用Hitachi KP-D50相机进行拍照,并用来自板的三个不同孔的类似尺寸的球体对芽数目进行计数。
HL-mEC的SARS-CoV-2感染
使用临床SARS-CoV-2分离株AP66进行感染实验,如先前在Caccuri F.et al.,“Apersistently replicating SARS-CoV-2 variant derived from an asymptomaticindividual,”J Transl Med.2020;18:362中所述的。
所有实验均是在生物安全等级3(biosafety level 3,BLS-3)实验室中用单一病毒接种体以MOI(感染复数)为1来进行的。
统计学分析
将获自多个独立实验的数据表示为平均值±标准偏差(standard deviation,SD)。使用单因素ANOVA来分析数据的统计学显著性,并且使用Bonferroni事后检验来比较数据。对于P<0.05,认为差异是显著性的。使用GraphPad Prism 8软件进行统计学测试。
实施例1
为了评价序列SEQ ID No.2的肽影响HUVEC响应于由不同血管生成介导物发挥的刺激的能力的能力,在不存在(NT)或存在单独的最佳浓度的不同促血管生成刺激物(VEGF-A,FGF-2或IL-8)的情况下或者在存在对照肽(CTRL)或序列SEQ ID No.2(KDKY)的肽的情况下,将HUVEC接种在生长降低的基质胶上。
如在图1中示出的,未经处理的HUVEC(NT)在接种于基质胶上之后8小时时形成单层。同时,用每种促血管生成分子(VEGF-A、FGF-2或IL-8)处理的HUVEC迁移并排列以形成在毛细管网络中组织的管。这种血管生成活性没有被对照肽(CTRL)改变,并且在用序列SEQID No.2的肽处理的细胞中显著受损。
图1中的图示出了每个孔中所形成的管的数目。该值代表一式三份进行的具有类似结果的三个中的一个代表性实验的平均值。使用单因素ANOVA检验进行统计学分析,并使用Bonferroni事后检验来比较数据(****p<0.0001)。
实施例2
在用血管生成因子刺激之后,可诱导包埋在生物聚合物凝胶中的HUVEC球体以形成内皮芽,从而代表模拟体内血管生成的3D细胞模型,如在Laib AM,Bartol A,Alajati A,Korff T,Weber H,Augustin HG.Spheroid-based human endothelial cell microvesselformation in vivo.Nat Protoc.2009;4:1202-1215中所述的。
在此基础上,在不存在(NT)或存在单独的不同促血管生成刺激物(VEGF-A,FGF-2或IL-8)或者不同促血管生成刺激物(VEGF-A,FGF-2或IL-8)与对照肽(CTRL)或与序列SEQID No.2(KDKY)的肽组合的情况下,将HUVEC来源的球体并入到I型胶原蛋白凝胶中。
如在图2中示出的,任何促血管生成刺激物(VEGF-A、FGF-2或IL-8)均强烈地促进微血管外生长(outgrowth),而序列SEQ ID No.2的肽诱导萌芽响应的急剧降低。
图2中的图示出了每个球体所形成的芽的数目。该值代表一式三份进行的具有类似结果的三个中的一个代表性实验的平均值。使用单因素ANOVA检验进行统计学分析,并使用Bonferroni事后检验来比较数据(****p<0.0001)。
这些数据强烈表明,序列SEQ ID No.2的肽可通过干扰自发性血管生成的潜在机制并阻碍内皮细胞响应于数种有效的促血管生成分子的刺激来充当血管抑制子。
实施例3
经SARS-CoV-2感染的HL-mEC分泌大量的促血管生成分子,其维持HL-mEC在生长因子降低的基质胶中促进血管生成的能力。
实际上,经SARS-CoV-2感染的HL-mEC的分泌瘤(secretoma)不仅能够表达VEGF-A和FGF-2,而且表达血管生成的数种诱导物例如金属蛋白酶(metalloproteinase,MMP)、胰岛素样生长因子结合蛋白-1(insulin-like growth factor binding protein-1,IGFBP-1,胰岛素生长因子结合蛋白-1(insulin growth factor binding protein-1))、与肝素结合的EGF样生长因子(HB-EGF,肝素结合的表皮生长因子(heparin binding--epidermalgrowth factor))、粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophage colony-stimulating factor,GM-CSF)、内皮联蛋白、血管生成蛋白和神经鞘胚素(artemin)。
为了理解序列SEQ ID No.2的肽是否可抵抗通过由经SARS-CoV-2感染的HL-mEC所分泌的大量促血管生成分子而诱导的血管生成,在不存在或者存在对照肽(CTRL)或序列SEQ ID No.2(KDKY)的肽的情况下,通过将经感染的细胞接种在生长因子降低的基质胶上来进行实验。
如在图3中示出的,在存在序列SEQ ID No.2的肽的情况下,经SARS-CoV-2感染的HL-mEC未表现出任何血管生成活性。另一方面,对照肽CTRL未干扰由SARS-CoV-2感染所诱导的促血管生成活性。
图3中的图示出了每个孔中所形成的管的数目。该值代表一式三份进行的具有类似结果的三个中一个代表性实验的平均值。使用单因素ANOVA检验进行统计学分析,并使用Bonferroni事后检验来比较数据(****p<0.0001)。NT指示未经感染的HL-mEC。
实施例4
在球体测定中还观察到了序列SEQ ID No.2的肽的抗血管生成作用。
实际上,如在图4中示出的,在用对照肽CTRL处理或未经处理的经SARS-CoV-2感染的球体中观察到芽的急剧外生长,而序列SEQ ID No.2(KDKY)的肽有效地抑制了SARS-CoV-2诱导的血管生成。
图4中的图示出了每个球体所形成的芽的数目。该值代表一式三份进行的具有类似结果的三个中的一个代表性实验的平均值。使用单因素ANOVA检验进行统计学分析,并使用Bonferroni事后检验来比较数据(****p<0.0001)。NT指示未经感染的HL-mEC。
这些数据确定了序列SEQ ID No.2的肽的强烈且广泛的抗血管生成活性。
实施例5
为了准确理解哪些氨基酸是实现抗血管生成活性所需要的,以D构型合成了四种四肽,其中原始的肽KDKY(SEQ ID No.2)的每个单个氨基酸被丙氨酸(A)替换,即ADKY(SEQID No.3)、KAKY(SEQ ID No.4)、KDAY(SEQ ID No.5)和KDKA(SEQ ID No.6)。
在包含单独的或者与10ng/ml对照肽(CTRL)或KDKY、AKDY、KAKY、KDAY或KDKA组合的50ng/ml VEGF-A或FGF-2的完全培养基中,将HUVEC接种在经生长因子降低的基质胶包被的孔上。
如在图5A至B中示出的,只有序列ADKY(SEQ ID No.3)的肽在用VEGF-A或FGF-2处理的HUVEC上维持了有效的抗血管生成活性。
然后,合成了DKY序列肽和DRY序列肽,并且如上所述验证了其抗血管生成活性。
在包含单独的或者与10ng/ml CTRL、KDKY、DKY或DRY组合的50ng/ml VEGF-A或FGF-2的完全培养基中,将HUVEC接种在经生长因子降低的基质胶包被的孔上。
如在图5C至D中示出的,DKY序列肽和DRY序列肽二者能够阻断由VEGF-A或FGF-2促进的血管生成活性,如同序列KDKY(SEQ ID No.2)的肽一样。
该结果确定了DKY序列对于抗血管生成活性的重要性,并且确定了在生物活性表位中Lys(K)替换为Arg(R)的常规容差(tolerance)。
图5中的图示出了每个孔中所形成的管的数目。该值代表一式三份进行的具有类似结果的三个中的一个代表性实验的平均值。使用单因素ANOVA检验进行统计学分析,并使用Bonferroni事后检验来比较数据(****p<0.0001)。NT指示未经处理的细胞。
序列表
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Claims (10)
1.长度等于或小于5个氨基酸的肽或其衍生物,所述肽或其衍生物包含:序列DKY,优选XDKY(SEQ ID No.7)或DKYX(SEQ ID No.8),或者序列DRY,优选XDRY(SEQ ID No.9)或DRYX(SEQ ID No.10),其中X是任意氨基酸,所述肽或其衍生物用作药物。
2.根据权利要求1所述的肽,其用于治疗由病理性血管生成引起的病症。
3.根据权利要求2所述应用的肽,其中所述由病理性血管生成引起的病症选自肿瘤、慢性炎症和新血管形成病症。
4.根据权利要求1至3中任一项所述应用的肽,其中所述肽的长度等于3或4个氨基酸。
5.根据权利要求1至3中任一项所述应用的肽,其中所述衍生物是其中N端和/或C端被有机化合物化学修饰或保护的肽,所述有机化合物选自磷酰基(PO3 2-)、糖基、酰基、烷基、羧基、胺、生物素、泛素。
6.药物组合物,所述药物组合物包含(a)长度等于或小于5个氨基酸的肽或其衍生物以及(b)至少一种可药用赋形剂,所述肽或其衍生物包含:序列DKY,优选XDKY(SEQ ID No.7)或DKYX(SEQ ID No.8),或者序列DRY,优选XDRY(SEQ ID No.9)或DRYX(SEQ ID No.10),其中X是任意氨基酸。
7.根据权利要求6所述的药物组合物,其中所述药物组合物包含按重量计0.0001%至20%的量的所述肽或其衍生物,优选按重量计0.0001%至15%的量的所述肽或其衍生物。
8.根据权利要求6所述的药物组合物,其中所述组合物被配制成用于经口、肠胃外、吸入(喷雾剂、散剂或气雾剂)、表面、经直肠、经鼻、经颊、经阴道施用或通过植入装置。
9.根据权利要求6所述的药物组合物,其中所述组合物还包含抗肿瘤剂,优选选自(i)生物碱、(ii)烷化剂、(iii)抗生素及类似物、(iv)抗代谢剂、(v)免疫调节剂、(vi)铂复合物以及(vii)抗肿瘤激素或类似物。
10.长度等于或小于5个氨基酸的肽或其衍生物,所述肽或其衍生物包含:序列DKY,优选XDKY(SEQ ID No.7)或DKYX(SEQ ID No.8),
或者序列DRY,优选XDRY(SEQ ID No.9)或DRYX(SEQ ID No.10),
其中X是任意氨基酸。
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