CN113412116A - 用于心脏保护的经修饰的轴突生长诱向因子-1肽和组合物 - Google Patents
用于心脏保护的经修饰的轴突生长诱向因子-1肽和组合物 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
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Abstract
本文公开了经修饰的轴突生长诱向因子‑1肽及其组合物,以及使用其赋予心脏保护作用的方法。在一些实施方案中,本发明提供了使用一种或多种经修饰的轴突生长诱向因子‑1肽及其组合物的方法。在一些实施方案中,本发明提供了刺激、增加或增强内皮细胞产生一氧化氮的方法,其包括向内皮细胞施用一种或多种经修饰的轴突生长诱向因子‑1肽或其组合物。
Description
相关申请的交叉引用
本申请要求2018年12月12日提交的美国专利申请号62/778,406的权益,该申请全文以引用方式并入本文。
经由EFS-WEB提交的序列表的引用
6.12kb大小的名为“20181210_034044_194P1_seq_ST25”的序列表的ASCII文本文件的内容创建于2018年12月11日,并且随同本申请一起经由EFS-Web以电子方式提交,其全文以引用方式并入本文。
鸣谢政府支持
本发明受政府支持在美国国家卫生研究院颁发的资助号HL119968下进行。美国政府享有本发明的某些权利。
背景技术
1.技术领域
本发明整体涉及经修饰的轴突生长诱向因子-1肽及其组合物,以及其使用方法。
2.相关技术
轴突生长诱向因子及其受体是本领域熟知的,如在以下中所例示的:US 5,565,331;US 6,096,866;US 6,017,714;US 6,309,638;US 6,670,451;和US 8,168,593;以及US20060019896和US20060025335。
轴突生长诱向因子-1是分泌性分子,众所周知,它在指导神经元发育中的脊椎动物连合轴突中发挥明确的作用。参见Kennedy等人(1994)Cell 78:425-35;Serafini等人(1994)Cell 78:409-24;以及Serafini等人(1996)Cell 87:1001-14。最近的研究已进一步证实轴突生长诱向因子-1除了在上皮细胞的形态发生中起关键作用之外,还在内皮细胞增殖、迁移和血管生成信号传导中起关键作用。参见Park等人(2004)PNAS USA 101:16210-5;Carmeliet等人(2005)Nature 436:193-200;Nguyen等人(2006)PNAS USA 103:6530-5;Wilson等人(2006)Science 313:640-4;Liu等人(2004)Curr Biol 14:897-905。至少八种轴突生长诱向因子受体已在哺乳动物的神经元、血管系统和其他细胞类型中得到表征。这些包括在结肠直肠癌(DCC)、UNC5A、B、C、D、再生蛋白、α6β4和α3β1整联蛋白中缺失的。参见Tessier-LaVigne等人(1996)Science 274:1123-33;Huber等人(2003)Annu Rev Neurosci26:509-63;Cirulli等人(2007)Nat Rev Mol Cell Biol 8:296-306;和Yebra等人(2003)Dev Cell 5:695-707。轴突生长诱向因子-1与DCC的结合介导轴突的有吸引力的生长,以及内皮细胞中的阳性血管生成信号传导。相比之下,UNC5B受体似乎具有排斥性,从而介导细胞效应,诸如丝状伪足回缩,特别是在发育的毛细血管中。参见Lu等人(2004)Nature 432:179-86;和Larrivee等人(2007)Genes Dev 21:2433-47。
发明内容
在一些实施方案中,本发明提供了如本文所述的经修饰的轴突生长诱向因子-1肽及其组合物。
在一些实施方案中,本发明提供了使用一种或多种经修饰的轴突生长诱向因子-1肽及其组合物的方法。在一些实施方案中,本发明提供了刺激、增加或增强内皮细胞产生一氧化氮的方法,包括向内皮细胞施用一种或多种经修饰的轴突生长诱向因子-1肽或其组合物。在一些实施方案中,本发明提供了刺激或诱导内皮细胞中的ERK1/2和/或eNOS的磷酸化的方法,包括向内皮细胞施用一种或多种经修饰的轴突生长诱向因子-1肽或其组合物。在一些实施方案中,本发明提供了治疗、抑制或减轻具有内皮细胞的组织或器官的损伤的方法,包括在损伤之前、期间和/或之后,通过向内皮细胞施用一种或多种经修饰的轴突生长诱向因子-1肽或其组合物,来刺激、增加或增强内皮细胞产生一氧化氮并且/或者刺激或诱导内皮细胞中的ERK1/2、eNOS或这两者的磷酸化。在一些实施方案中,内皮细胞是血管内皮细胞。在根据本发明的一些方法中,向内皮细胞的施用是体内施用。在一些实施方案中,损伤是由超氧化物产生、缺血/再灌注或心肌梗塞引起的。在一些实施方案中,组织是心脏组织。在一些实施方案中,器官是心脏。在一些实施方案中,损伤是由心肌梗塞引起的,并且施用减小了心脏的梗塞面积。在一些实施方案中,本发明涉及治疗或抑制受试者的再狭窄,包括在血管中的内皮细胞损伤之前、期间或之后,向受试者施用治疗有效量的一种或多种经修饰的轴突生长诱向因子-1肽。在一些实施方案中,本发明提供了治疗、抑制或减轻受试者的器官(例如,心脏)的缺血/再灌注损伤的方法,包括将治疗有效量的一种或多种经修饰的轴突生长诱向因子-1肽或其组合物施用于受试者,从而治疗、抑制或减轻缺血/再灌注损伤。在一些实施方案中,本发明提供了减少或减小因缺血/再灌注损伤而导致的受试者心脏梗塞面积的方法,包括将治疗有效量的一种或多种经修饰的轴突生长诱向因子-1肽或其组合物施用于受试者,从而减少或减小梗塞面积。在一些实施方案中,受试者是哺乳动物受试者。在一些实施方案中,受试者是动物模型,例如,小鼠。在一些实施方案中,受试者是人。在一些实施方案中,用一种或多种根据本发明的经修饰的轴突生长诱向因子-1肽或组合物治疗的受试者是对其有需要的受试者。对其有需要的受试者包括可以受益于刺激、增加或增强一氧化氮产生的那些,可以受益于刺激或诱导ERK1/2和/或eNOS的磷酸化的那些,具有或可能具有由反应性氧物质或氧化应激的产生增加、缺血/再灌注或心肌梗塞引起的组织或器官损伤的那些,以及将暴露于或将可能暴露于超氧化物的产生增加、缺血/再灌注状况或心肌梗塞的那些。
在一些实施方案中,本发明提供了人造包装,例如,套件,其中包括一种或多种经修饰的轴突生长诱向因子-1肽或其组合物。在一些实施方案中,该人造包装还包括药物递送装置。在一些实施方案中,本发明提供了一种装置,其中包括一种或多种经修饰的轴突生长诱向因子-1肽或其组合物。
前面的一般描述和下面的详细描述都仅仅是示例性和解释性的,并且旨在提供对所要求保护的本发明的进一步解释。包括任何附图以提供对本发明的进一步理解,并且任何附图被结合在本说明书中并构成本说明书的一部分,展示了本发明的几个实施方案,并且连同说明书一起用于解释本发明的原理。
具体实施方式
以前,发现轴突生长诱向因子-1和轴突生长诱向因子-1肽片段在施用于受试者时表现出心脏保护活性。参见PCT/US2011/038277、PCT/US2015/023248和Li&Cai(2015)Am JPhysiol Cell Physiol 309:C100-106,其全文以引用方式并入本文。现有技术的轴突生长诱向因子-1肽片段在本文中称为“现有技术肽”。当递送至心脏时,现有技术肽激活由轴突生长诱向因子-1开启的保护途径,即ERK1/2和eNOS的DCC依赖性激活。ERK1/2和eNOSs1177(人/小鼠为1177个残基,而牛为1179个残基)磷酸化在培养的内皮细胞中通过现有技术肽以时间依赖性方式增加,据信这将增加一氧化氮(NO)的产生以发挥心脏保护作用。
如本文所公开的,本发明人进一步修饰了现有技术肽,并且测定了它们对抗缺血再灌注(I/R)损伤的心脏保护功效。对I/R后梗塞面积的分析表明,在用经修饰的轴突生长诱向因子-1肽治疗之后,心肌损伤显著减少。事实上,与现有技术肽相比,经修饰的轴突生长诱向因子-1肽以显著更大的程度减小了梗塞面积—梗塞面积减小的程度增加了约14%至40%。
因此,本发明提供了经修饰的轴突生长诱向因子-1肽及其组合物和方法。如本文所用,“经修饰的轴突生长诱向因子-1肽”是指包含如下的SEQ ID NO:1、基本上由其组成或由其组成的肽或蛋白质:
X1-X2-X3-C-X4-X5-X6-X7-T-X8-G(SEQ ID NO:1)
其中
X1为Ala、Asn、Cys、Ser或Thr,优选地X1为Cys、Ser或Thr,其中当X1为Cys时,它共价或非共价地经由二硫键连接(例如附接)到第四个氨基酸位置处的半胱氨酸残基,或者共价或非共价地连接(例如附接)到环氧乙烷化合物;
X2存在或不存在,并且如果存在,X2为Ala、Asp、Ile、Leu、Met、Phe、Pro、Trp或Val,优选地X2为Leu或Pro;
X3存在或不存在,并且如果存在,X3为Asn、Arg、Asp、Cys、Gln、Glu、Gly、Ser、Thr或Tyr,优选地X3为Asn或Asp;
X4为Arg、His或Lys,优选地X4为Arg或Lys;
X5为Arg、Asp、Glu、His、Lys、Phe、Trp或Tyr,优选地X5为Asn、Asp或His;
X6为Asn、Cys、Gln、Gly、Ser、Thr、Tyr或Val,优选地X6为Asn或Gly;
X7存在或不存在,并且如果存在,X7为Asn、Gly、His、Ile、Thr或Val,优选地X7为Val;并且
X8存在或不存在,并且如果存在,X8为Ala、Asn、Ile、Leu、Met、Phe、Pro、Thr、Trp或Val,优选地X8为Ala;并且
其中存在X2、X3或X2和X3两者。
在一些实施方案中,环氧乙烷化合物为聚乙二醇(PEG)、聚环氧乙烷(PEO)和聚氧乙烯(POE)、甲氧基聚乙二醇(MPEG)或单甲氧基聚乙二醇(mPEG),或者二乙二醇(mini-PEG),优选地环氧乙烷化合物为mini-PEG。
在一些实施方案中,经修饰的轴突生长诱向因子-1肽的长度为约8-60个、约8-55个、约8-50个、约8--45个、约8-40个、约8-35个、约8-30个、约8-25个、约8-20个、约8-15个、约8--12个、8-11个、约9-60个、约9-55个、约9-50个、约9-45个、约9-40个、约9-35个、约9-30个、约9-25个、约9-20个、约9-15个、约9-12个、或9-11个氨基酸残基。在一些实施方案中,经修饰的轴突生长诱向因子-1肽的长度为8个、9个、10个或11个氨基酸残基。
如本文所用,“包含”给定序列的肽意味着该肽可以在N末端、C末端或这两者处包括附加的氨基酸残基、氨基酸异构体和/或氨基酸类似物。这些附加的残基可以改变,也可以不改变给定序列的活性或功能,即,具有这些附加的残基、异构体或类似物的肽与给定序列本身(没有这些附加的残基、异构体或类似物)相比可以具有不同的活性或功能。如本文所用,“基本上由”给定序列“组成”的肽意味着该肽可以在N末端、C末端或这两者处包括附加的氨基酸残基、氨基酸异构体和/或氨基酸类似物,只要它们不实质上改变给定序列的功能或活性,即,具有这些附加的残基、异构体或类似物的肽具有与给定序列本身基本上相似的活性和功能。如本文所用,“由”给定序列“组成”的肽意味着该肽在N末端和C末端处不包括附加的氨基酸残基、氨基酸异构体和/或氨基酸类似物。
在一些实施方案中,经修饰的轴突生长诱向因子-1肽可以是分离的。如本文所用,“分离的”化合物是指从其天然环境中分离的化合物。例如,分离的肽是不具有对应于全长多肽的位于N末端、C末端或这两者的侧翼的天然氨基酸的肽。例如,分离的Vl-9aa肽是指具有Vl的氨基酸残基(304至312位aa)的肽,该肽可以在其N端、C端或这两者处具有非天然氨基酸,但是在其C端处的第9个氨基酸残基之后不具有脯氨酸氨基酸残基,或者在其N端处的半胱氨酸氨基酸残基之前不具有缬氨酸氨基酸残基,或这两者都有。作为另一个实例,分离的肽可以是固定至不与该肽天然结合的底物的肽。作为进一步的实例,分离的肽可以是连接到不与该肽天然结合的另一个分子(例如PEG化合物,例如mPEG)的肽。
在一些实施方案中,经修饰的轴突生长诱向因子-1肽可以包括一种或多种天然氨基酸、非天然氨基酸,或它们的组合。肽的氨基酸残基可以是D-异构体、L-异构体或这两者。肽可以由α-氨基酸、β-氨基酸、天然氨基酸、非天然氨基酸、氨基酸类似物或它们的组合构成。氨基酸类似物包括β-氨基酸和其中氨基基团或羧基基团被类似的反应性基团取代(例如,用仲胺或叔胺取代伯胺,或用酯取代羧基基团)的氨基酸。
β-氨基酸类似物的实例包括环状β-氨基酸类似物;β-丙氨酸;I-β-苯基丙氨酸;I-l,2,3,4-四氢-异喹啉-3-乙酸;I-3-氨基-4-(1-萘基)-丁酸;I-3-氨基-4-(2,4-二氯苯基)丁酸;I-3-氨基-4-(2-氯苯基)-丁酸;I-3-氨基-4-(2-氰基苯基)-丁酸;I-3-氨基-4-(2-氟苯基)-丁酸;I-3-氨基-4-(2-呋喃基)-丁酸;I-3-氨基-4-(2-甲基苯基)-丁酸;I-3-氨基-4-(2-萘基)-丁酸;I-3-氨基-4-(2-噻吩基)-丁酸;I-3-氨基-4-(2-三氟甲基苯基)-丁酸;I-3-氨基-4-(3,4-二氯苯基)丁酸;I-3-氨基-4-(3,4-二氟苯基)丁酸;I-3-氨基-4-(3-苯并噻吩基)-丁酸;I-3-氨基-4-(3-氯苯基)-丁酸;I-3-氨基-4-(3-氰基苯基)-丁酸;I-3-氨基-4-(3-氟苯基)-丁酸;I-3-氨基-4-(3-甲基苯基)-丁酸;I-3-氨基-4-(3-吡啶基)-丁酸;I-3-氨基-4-(3-噻吩基)-丁酸;I-3-氨基-4-(3-三氟甲基苯基)-丁酸;I-3-氨基-4-(4-溴苯基)-丁酸;I-3-氨基-4-(4-氯苯基)-丁酸;I-3-氨基-4-(4-氰基苯基)-丁酸;I-3-氨基-4-(4-氟苯基)-丁酸;I-3-氨基-4-(4-碘苯基)-丁酸;I-3-氨基-4-(4-甲基苯基)-丁酸;I-3-氨基-4-(4-硝基苯基)-丁酸;I-3-氨基-4-(4-吡啶基)-丁酸;I-3-氨基-4-(4-三氟甲基苯基)-丁酸;I-3-氨基-4-五氟-苯基丁酸;I-3-氨基-5-己烯酸;I-3-氨基-5-己炔酸;I-3-氨基-5-苯基戊酸;I-3-氨基-6-苯基-5-己烯酸;(S)-1,2,3,4-四氢-异喹啉-3-乙酸;(S)-3-氨基-4-(1-萘基)-丁酸;(S)-3-氨基-4-(2,4-二氯苯基)丁酸;(S)-3-氨基-4-(2-氯苯基)-丁酸;(S)-3-氨基-4-(2-氰基苯基)-丁酸;(S)-3-氨基-4-(2-氟苯基)-丁酸;(S)-3-氨基-4-(2-呋喃基)-丁酸;(S)-3-氨基-4-(2-甲基苯基)-丁酸;(S)-3-氨基-4-(2-萘基)-丁酸;(S)-3-氨基-4-(2-噻吩基)-丁酸;(S)-3-氨基-4-(2-三氟甲基苯基)-丁酸;(S)-3-氨基-4-(3,4-二氯苯基)丁酸;(S)-3-氨基-4-(3,4-二氟苯基)丁酸;(S)-3-氨基-4-(3-苯并噻吩基)-丁酸;(S)-3-氨基-4-(3-氯苯基)-丁酸;(S)-3-氨基-4-(3-氰基苯基)-丁酸;(S)-3-氨基-4-(3-氟苯基)-丁酸;(S)-3-氨基-4-(3-甲基苯基)-丁酸;(S)-3-氨基-4-(3-吡啶基)-丁酸;(S)-3-氨基-4-(3-噻吩基)-丁酸;(S)-3-氨基-4-(3-三氟甲基苯基)-丁酸;(S)-3-氨基-4-(4-溴苯基)-丁酸;(S)-3-氨基-4-(4-氯苯基)丁酸;(S)-3-氨基-4-(4-氰基苯基)-丁酸;(S)-3-氨基-4-(4-氟苯基)丁酸;(S)-3-氨基-4-(4-碘苯基)-丁酸;(S)-3-氨基-4-(4-甲基苯基)-丁酸;(S)-3-氨基-4-(4-硝基苯基)-丁酸;(S)-3-氨基-4-(4-吡啶基)-丁酸;(S)-3-氨基-4-(4-三氟甲基苯基)-丁酸;(S)-3-氨基-4-五氟-苯基丁酸;(S)-3-氨基-5-己烯酸;(S)-3-氨基-5-己炔酸;(S)-3-氨基-5-苯基戊酸;(S)-3-氨基-6-苯基-5-己烯酸;1,2,5,6-四氢吡啶-3-羧酸;1,2,5,6-四氢吡啶-4-羧酸;3-氨基-3-(2-氯苯基)-丙酸;3-氨基-3-(2-噻吩基)-丙酸;3-氨基-3-(3-溴苯基)-丙酸;3-氨基-3-(4-氯苯基)-丙酸;3-氨基-3-(4-甲氧基苯基)-丙酸;3-氨基-4,4,4-三氟-丁酸;3-氨基己二酸;D-β-苯基丙氨酸;β-亮氨酸;L-β-高丙氨酸;L-β-高天冬氨酸γ-苄基酯;L-β-高谷氨酸δ-苄基酯;L-β-高异亮氨酸;L-β-高亮氨酸;L-β-高甲硫氨酸;L-β-高苯丙氨酸;L-β-高脯氨酸;L-β-高色氨酸;L-β-高缬氨酸;L-Nω-苄氧基羰基-β-高赖氨酸;Nω-L-β-高精氨酸;O-苄基-L-β-高羟脯氨酸;O-苄基-L-β-高丝氨酸;O-苄基-L-β-高苏氨酸;O-苄基-L-β-高酪氨酸;γ-三苯甲基-L-β-高天冬酰胺;I-β-苯丙氨酸;L-β-高天冬氨酸γ-叔丁酯;L-β-高谷氨酸δ-叔丁酯;L-Nω-β-高赖氨酸;Nδ-三苯甲基-L-β-高谷氨酰胺;Nω-2,2,4,6,7-五甲基-二氢苯并呋喃-5-磺酰基-L-β-高精氨酸;O-叔丁基-L-β-高羟基-脯氨酸;O-叔丁基-L-β-高丝氨酸;O-叔丁基-L-β-高苏氨酸;O-叔丁基-L-β-高酪氨酸;2-氨基环戊烷羧酸;和2-氨基环己烷羧酸。
丙氨酸、缬氨酸、甘氨酸和亮氨酸的氨基酸类似物的实例包括α-甲氧基甘氨酸;α-烯丙基-L-丙氨酸;α-氨基异丁酸;α-甲基-亮氨酸;β-(1-萘基)-D-丙氨酸;β-(1-萘基)-L-丙氨酸;β-(2-萘基)-D-丙氨酸;β-(2-萘基)-L-丙氨酸;β-(2-吡啶基)-D-丙氨酸;β-(2-吡啶基)-L-丙氨酸;β-(2-噻吩基)-D-丙氨酸;β-(2-噻吩基)-L-丙氨酸;β-(3-苯并噻吩基)-D-丙氨酸;β-(3-苯并噻吩基)-L-丙氨酸;β-(3-吡啶基)-D-丙氨酸;β-(3-吡啶基)-L-丙氨酸;β-(4-吡啶基)-D-丙氨酸;β-(4-吡啶基)-L-丙氨酸;β-氯-L-丙氨酸;β-氰基-L-丙氨酸;β-环己基-D-丙氨酸;β-环己基-L-丙氨酸;β-环戊烯-1-基-丙氨酸;β-环戊基-丙氨酸;β-环丙基-L-Ala-OH.二环己基铵盐;β-叔丁基-D-丙氨酸;β-叔丁基-L-丙氨酸;γ-氨基丁酸;L-α,β-二氨基丙酸;2,4-二硝基-苯基甘氨酸;2,5-二氢-D-苯基甘氨酸;2-氨基-4,4,4-三氟丁酸;2-氟-苯基甘氨酸;3-氨基-4,4,4-三氟-丁酸;3-氟-缬氨酸;4,4,4-三氟-缬氨酸;4,5-脱氢-L-leu-OH.二环己基铵盐;4-氟-D-苯基甘氨酸;4-氟-L-苯基甘氨酸;4-羟基-D-苯基甘氨酸;5,5,5-三氟-亮氨酸;6-氨基己酸;环戊基-D-Gly-OH.二环己基铵盐;环戊基-Gly-OH.二环己基铵盐;D-α,β-二氨基丙酸;D-α-氨基丁酸;D-α-叔丁基甘氨酸;D-(2-噻吩基)甘氨酸;D-(3-噻吩基)甘氨酸;D-2-氨基己酸;D-2-茚满基甘氨酸;D-烯丙基甘氨酸-二环己基铵盐;D-环己基甘氨酸;D-正缬氨酸;D-苯基甘氨酸;β-氨基丁酸;β-氨基异丁酸;(2-溴苯基)甘氨酸;(2-甲氧基苯基)甘氨酸;(2-甲基苯基)甘氨酸;(2-噻唑基)甘氨酸;(2-噻吩基)甘氨酸;2-氨基-3-(二甲氨基)-丙酸;L-α,β-二氨基丙酸;L-α-氨基丁酸;L-α-叔丁基甘氨酸;L-(3-噻吩基)甘氨酸;L-2-氨基-3-(二甲氨基)-丙酸;L-2-氨基己酸二环己基-铵盐;L-2-茚满基甘氨酸;L-烯丙基甘氨酸.二环己基铵盐;L-环己基甘氨酸;L-苯基甘氨酸;L-炔丙基甘氨酸;L-正缬氨酸;N-α-氨基甲基-L-丙氨酸;D-α,γ-二氨基丁酸;L-α,γ-二氨基丁酸;β-环丙基-L-丙氨酸;(N-β-(2,4-二硝基苯基))-L-α,β-二氨基丙酸;(N-β-l-(4,4-二甲基-2,6-二氧代亚环己-1-基)乙基)-D-α,β-二氨基丙酸;(N-β-1-(4,4-二甲基-2,6-二氧代亚环己-1-基)乙基)-L-α,β-二氨基丙酸;(N-β-4-甲基三苯甲基)-L-α,β-二氨基丙酸;(N-β-烯丙氧基羰基)-L-α,β-二氨基丙酸;(N-γ-1-(4,4-二甲基-2,6-二氧代亚环己-l-基)乙基)-D-α,γ-二氨基丁酸;(N-γ-1-(4,4-二甲基-2,6-二氧代亚环己-l-基)乙基)-L-α,γ-二氨基丁酸;(N-γ-4-甲基三苯甲基)-D-α,γ-二氨基丁酸;(N-γ-4-甲基三苯甲基)-L-α,γ-二氨基丁酸;(N-γ-烯丙氧基羰基)-L-α,γ-二氨基丁酸;D-α,γ-二氨基丁酸;4,5-脱氢-L-亮氨酸;环戊基-D-Gly-OH;环戊基-Gly-OH;D-烯丙基甘氨酸;D-高环己基丙氨酸;L-1-芘基丙氨酸;L-2-氨基己酸;L-烯丙基甘氨酸;L-高环己基丙氨酸;和N-(2-羟基-4-甲氧基-Bzl)-Gly-OH。
精氨酸和赖氨酸的氨基酸类似物的实例包括瓜氨酸;L-2-氨基-3-胍基丙酸;L-2-氨基-3-脲基丙酸;L-瓜氨酸;Lys(Me)2-OH;Lys(N3)-OH;Nδ-苄氧基羰基-L-鸟氨酸;Nω-硝基-D-精氨酸;Nω-硝基-L-精氨酸;α-甲基-鸟氨酸;2,6-二氨基庚二酸;L-鸟氨酸;(Nδ-1-(4,4-二甲基-2,6-二氧代-亚环己-1-基)乙基)-D-鸟氨酸;(Nδ-1-(4,4-二甲基-2,6-二氧代-亚环己-1-基)乙基)-L-鸟氨酸;(Nδ-4-甲基三苯甲基)-D-鸟氨酸;(Nδ-4-甲基三苯甲基)-L-鸟氨酸;D-鸟氨酸;L-鸟氨酸;Arg(Me)(Pbf)-OH;Arg(Me)2-OH(非对称);Arg(Me)2-OH(对称);Lys(ivDde)-OH;Lys(Me)2-OH.HCl;Lys(Me3)-OH氯化物;Nω-硝基-D-精氨酸;和Nω-硝基-L-精氨酸。
天冬氨酸和谷氨酸的氨基酸类似物的实例包括α-甲基-D-天冬氨酸;α-甲基-谷氨酸;α-甲基-L-天冬氨酸;γ-亚甲基-谷氨酸;(N-γ-乙基)-L-谷氨酰胺;[N-α-(4-氨基苯甲酰基)]-L-谷氨酸;2,6-二氨基庚二酸;L-α-氨基辛二酸;D-2-氨基己二酸;D-α-氨基辛二酸;α-氨基庚二酸;亚氨基二乙酸;L-2-氨基己二酸;苏-β-甲基-天冬氨酸;γ-羧基-D-谷氨酸γ,γ-二叔丁酯;γ-羧基-L-谷氨酸γ,γ-二叔丁酯;Glu(Oall)-OH;L-Asu(OtBu)—OH;和焦谷氨酸。
半胱氨酸和甲硫氨酸的氨基酸类似物的实例包括Cys(法尼基)-OH、Cys(法尼基)-Ome、α-甲基-甲硫氨酸、Cys(2-羟乙基)-OH、Cys(3-氨基丙基)-OH、2-氨基-4-(乙硫基)丁酸、丁硫氨酸、丁硫氨酸亚砜亚胺、乙硫氨酸、甲硫氨酸甲磺酰氯、硒代甲硫氨酸、半胱氨酸、[2-(4-吡啶基)乙基]-DL-青霉胺、[2-(4-吡啶基)乙基]-L-半胱氨酸、4-甲氧基苄基-D-青霉胺、4-甲氧基苄基-L-青霉胺、4-甲基苄基-D-青霉胺、4-甲基苄基-L-青霉胺、苄基-D-半胱氨酸、苄基-L-半胱氨酸、苄基-DL-高半胱氨酸、氨基甲酰基-L-半胱氨酸、羧乙基-L-半胱氨酸、羧甲基-L-半胱氨酸、二苯基甲基-L-半胱氨酸、乙基-L-半胱氨酸、甲基-L-半胱氨酸、叔丁基-D-半胱氨酸、三苯甲基-L-高半胱氨酸、三苯甲基-D-青霉胺、胱硫醚、高胱氨酸、L-高胱氨酸、(2-氨基乙基)-L-半胱氨酸、硒-L-胱氨酸、胱硫醚、Cys(StBu)-OH和乙酰氨基甲基-D-青霉胺。
苯丙氨酸和酪氨酸的氨基酸类似物的实例包括β-甲基-苯基丙氨酸、β-羟基苯基丙氨酸、α-甲基-3-甲氧基-DL-苯基丙氨酸、α-甲基-D-苯基丙氨酸、α-甲基-L-苯基丙氨酸、1,2,3,4-四氢异喹啉-3-羧酸、2,4-二氯-苯基丙氨酸、2-(三氟甲基)-D-苯基丙氨酸、2-(三氟甲基)-L-苯基丙氨酸、2-溴-D-苯基丙氨酸、2-溴-L-苯基丙氨酸、2-氯-D-苯基丙氨酸、2-氯-L-苯基丙氨酸、2-氰基-D-苯基丙氨酸、2-氰基-L-苯基丙氨酸、2-氟-D-苯基丙氨酸、2-氟-L-苯基丙氨酸、2-甲基-D-苯基丙氨酸、2-甲基-L-苯基丙氨酸、2-硝基-D-苯基丙氨酸、2-硝基-L-苯基丙氨酸、2,4,5-三羟基-苯基丙氨酸、3,4,5-三氟-D-苯基丙氨酸、3,4,5-三氟-L-苯基丙氨酸、3,4-二氯-D-苯基丙氨酸、3,4-二氯-L-苯基丙氨酸、3,4-二氟-D-苯基丙氨酸、3,4-二氟-L-苯基丙氨酸、3,4-二羟基-L-苯基丙氨酸、3,4-二甲氧基-L-苯基丙氨酸、3,5,3'-三碘-L-甲状腺原氨酸、3,5-二碘-D-酪氨酸、3,5-二碘-L-酪氨酸、3,5-二碘-L-甲状腺原氨酸、3-(三氟甲基)-D-苯基丙氨酸、3-(三氟甲基)-L-苯基丙氨酸、3-氨基-L-酪氨酸、3-溴-D-苯基丙氨酸、3-溴-L-苯基丙氨酸、3-氯-D-苯基丙氨酸、3-氯-L-苯基丙氨酸、3-氯-L-酪氨酸、3-氰基-D-苯基丙氨酸、3-氰基-L-苯基丙氨酸、3-氟-D-苯基丙氨酸、3-氟-L-苯基丙氨酸、3-氟-酪氨酸、3-碘-D-苯基丙氨酸、3-碘-L-苯基丙氨酸、3-碘-L-酪氨酸、3-甲氧基-L-酪氨酸、3-甲基-D-苯基丙氨酸、3-甲基-L-苯基丙氨酸、3-硝基-D-苯基丙氨酸、3-硝基-L-苯基丙氨酸、3-硝基-L-酪氨酸、4-(三氟甲基)-D-苯基丙氨酸、4-(三氟甲基)-L-苯基丙氨酸、4-氨基-D-苯基丙氨酸、4-氨基-L-苯基丙氨酸、4-苯甲酰基-D-苯基丙氨酸、4-苯甲酰基-L-苯基丙氨酸、4-双(2-氯乙基)氨基-L-苯基丙氨酸、4-溴-D-苯基丙氨酸、4-溴-L-苯基丙氨酸、4-氯-D-苯基丙氨酸、4-氯-L-苯基丙氨酸、4-氰基-D-苯基丙氨酸、4-氰基-L-苯基丙氨酸、4-氟-D-苯基丙氨酸、4-氟-L-苯基丙氨酸、4-碘-D-苯基丙氨酸、4-碘-L-苯基丙氨酸、高苯丙氨酸、甲状腺素、3,3-二苯基丙氨酸、甲状腺原氨酸、乙基-酪氨酸和甲基-酪氨酸。
脯氨酸的氨基酸类似物的实例包括3,4-脱氢-脯氨酸、4-氟-脯氨酸、顺式-4-羟基-脯氨酸、噻唑烷-2-羧酸和反式-4-氟-脯氨酸。
丝氨酸和苏氨酸的氨基酸类似物的实例包括3-氨基-2-羟基-5-甲基己酸、2-氨基-3-羟基-4-甲基戊酸、2-氨基-3-乙氧基丁酸、2-氨基-3-甲氧基丁酸、4-氨基-3-羟基-6-甲基庚酸、2-氨基-3-苄氧基丙酸、2-氨基-3-苄氧基丙酸、2-氨基-3-乙氧基丙酸、4-氨基-3-羟基丁酸和α-甲基丝氨酸。
色氨酸的氨基酸类似物的实例包括α-甲基-色氨酸;β-(3-苯并噻吩基)-D-丙氨酸;β-(3-苯并噻吩基)-L-丙氨酸;1-甲基-色氨酸;4-甲基-色氨酸;5-苄氧基-色氨酸;5-溴-色氨酸;5-氯-色氨酸;5-氟-色氨酸;5-羟基-色氨酸;5-羟基-L-色氨酸;5-甲氧基-色氨酸;5-甲氧基-L-色氨酸;5-甲基-色氨酸;6-溴-色氨酸;6-氯-D-色氨酸;6-氯-色氨酸;6-氟-色氨酸;6-甲基-色氨酸;7-苄氧基-色氨酸;7-溴-色氨酸;7-甲基-色氨酸;D-1,2,3,4-四氢-去甲哈尔满-3-羧酸;6-甲氧基-1,2,3,4-四氢去甲哈尔满-1-羧酸;7-氮杂色氨酸;L-1,2,3,4-四氢-去甲哈尔满-3-羧酸;5-甲氧基-2-甲基-色氨酸;和6-氯-L-色氨酸。
在一些实施方案中,经修饰的轴突生长诱向因子-1肽可以包含一种或多种非必需氨基酸。非必需氨基酸残基可以是能够从多肽的野生型序列改变而不消除或基本上不改变其基本生物学或生物化学活性(例如,受体结合或激活)的残基。
在一些实施方案中,经修饰的轴突生长诱向因子-1肽可以包含一个或多个保守氨基酸取代。在一些实施方案中,保守氨基酸取代是其中氨基酸残基被具有侧链的氨基酸残基替换的取代。具有碱性侧链的氨基酸包括Arg、His和Lys,具有酸性侧链的氨基酸包括Asp和Glu,具有不带电荷的极性侧链的氨基酸包括Asn、Cys、Gln、Gly、Ser、Thr和Tyr,具有非极性侧链的氨基酸包括Ala、Ile、Leu、Met、Phe、Pro、Trp和Val,具有I-支链侧链的氨基酸包括Ile、Thr和Val,并且具有芳香侧链的氨基酸包括His、Phe、Trp和Tyr。在一些实施方案中,保守氨基酸取代是如下表中所示的非常高度保守的取代、高度保守的取代或保守取代:
经修饰的轴突生长诱向因子-1肽优于全长轴突生长诱向因子-1蛋白,因为它们的尺寸更短,因此,可能1)方便且成功地大量生产,2)更实惠,3)在具有与全长轴突生长诱向因子-1相比较小或减小的副作用的情况下激活保护途径,4)更容易递送到受试者的靶器官,以及5)在治疗期间更稳定且更有活性,以具有更大的保护作用。经修饰的轴突生长诱向因子-1肽优于现有技术肽,因为经修饰的轴突生长诱向因子-1肽表现出优于现有技术肽的优异活性。
基于本文举例说明的经修饰的轴突生长诱向因子-1肽与现有技术肽之间的序列相似性和差异,据信第一个氨基酸残基(如本文所述的SEQ ID NO:1的X1,和第一个半胱氨酸,即现有技术肽的“核心序列”的位置1处的氨基酸残基)的取代负责赋予经修饰的轴突生长诱向因子-1肽优异的活性。X1氨基酸位置所赋予的优异活性是出乎意料的,因为本领域技术人员认为丝氨酸是半胱氨酸的非常高度保守的取代。因此,本领域技术人员预期,将现有技术肽V1修饰为在氨基酸位置1处具有丝氨酸而不是半胱氨酸,将导致基本上相似的活性。然而,如表3所示,用丝氨酸替代半胱氨酸导致梗塞面积的减少量增加了接近30%((71—55)/55=29%)。
因为经修饰的轴突生长诱向因子-1肽被证实显著减少了心脏组织的梗塞面积,所以一种或多种经修饰的轴突生长诱向因子-1肽可以用于治疗受试者的急性心肌梗塞。在一些实施方案中,一种或多种经修饰的轴突生长诱向因子-1肽可以用于治疗、抑制或减轻受试者心脏组织的缺血/再灌注损伤。如本文所用,术语“缺血/再灌注损伤”(I/R损伤)是指器官(例如,心脏)的由将器官置于缺血状态(诸如由于血栓栓塞事件、外科手术或心脏停顿)而引起的损伤。临床相关情况包括在心肌梗塞(缺血)期间发生的冠状动脉/分支的闭塞。采用经皮经腔冠状动脉成形术(PTCA)规程进行治疗产生了已知会引起额外损伤的再灌注状况,然而这可以通过药理学后调节(在再灌注阶段施用经修饰的轴突生长诱向因子-1肽)来保护。因此,在一些实施方案中,本发明还涉及通过单独施用或与PTCA/药物洗脱支架结合施用一种或多种经修饰的轴突生长诱向因子-1肽(例如,静脉内)来对心肌梗塞进行急性治疗。在一些实施方案中,经修饰的轴突生长诱向因子-1肽可以用于减少或抑制心脏组织的梗塞面积,并且/或者治疗、抑制或减轻由心肌梗塞引起的对心脏组织的损伤。
因为经修饰的轴突生长诱向因子-1肽像现有技术肽一样减少心脏组织的梗塞面积,除了减少的量显著大于现有技术肽所观察到的减少量之外,预期经修饰的轴突生长诱向因子-1肽将诱导ERK1/2、eNOSs1177和/或eNOSs1179的磷酸化,并且诱导一氧化氮产生到至少与现有技术肽相同的程度。因此,在一些实施方案中,一种或多种经修饰的轴突生长诱向因子-1肽用于在受试者中诱导ERK1/2、eNOSs1177和/或eNOSs1179的磷酸化。类似地,据信经修饰的轴突生长诱向因子-1肽可以诱导一氧化氮产生到至少与现有技术肽相同的程度。因此,在一些实施方案中,一种或多种经修饰的轴突生长诱向因子-1肽用于增加受试者中一氧化氮的产生。
肽组合物和递送
施用一种或多种经修饰的轴突生长诱向因子-1肽可以通过直接施用来完成,或者通过施用一种或多种编码一种或多种经修饰的轴突生长诱向因子-1肽的核酸分子来完成。
在一些实施方案中,将治疗有效量的一种或多种根据本发明的肽片段施用于受试者。如本文所用,“治疗有效量”是指与对照(诸如安慰剂)相比,可以用于治疗、减轻、改善、预防或抑制受试者的给定的疾病或病症(诸如I/R损伤或其症状)的量。例如,在一些实施方案中,治疗有效量是在受试者中对心脏组织的I/R损伤的体征和/或症状具有有益作用的量。在一些实施方案中,治疗有效量是与对照相比,抑制或减轻I/R损伤的体征和/或症状的量。对心脏组织的I/R损伤的体征和症状是本领域已知的,并且包括突发胸痛(通常向左臂或颈部左侧放射)、气短、恶心、呕吐、心悸、出汗和焦虑。在一些实施方案中,治疗有效量是与对照相比,足以在受试者中增加ERK1/2、eNOS或这两者的磷酸化以及/或者增加一氧化氮产生的量。在一些实施方案中,治疗有效量是与对照相比,足以激活受试者的心脏保护机制的量。在一些实施方案中,一种或多种经修饰的轴突生长诱向因子-1肽的治疗有效量在下述范围内:约1ng/kg至约100mg/kg体重、约0.001mg/kg至约100mg/kg体重、约0.01mg/kg至约10mg/kg体重、约0.01mg/kg至约5mg/kg体重、约0.01mg/kg至约3mg/kg体重、约0.01mg/kg至约2mg/kg体重、约0.01mg/kg至约1mg/kg体重、或约0.01mg/kg至约0.5mg/kg体重。在一些实施方案中,在受试者缺血和再灌注或I/R损伤时或紧接其之后立即将约5mg/kg至约10mg/kg体重的一种或多种经修饰的轴突生长诱向因子-1肽施用于受试者。在一些实施方案中,在给定的时段,例如,约4周,每日施用约1ng/kg体重至约25ng/kg体重、优选地约10ng/kg体重至约20ng/kg体重,以及更优选地约15ng/kg体重的一种或多种经修饰的轴突生长诱向因子-1肽,以治疗、预防或抑制血管成形术后再狭窄。
应当指出的是,用治疗有效量治疗受试者可以作为单一剂量或作为一系列的若干剂量施用。用于治疗的剂量在给定治疗的过程中可以增加或减少。对于给定的一组病症和给定的受试者的最佳剂量可以由本领域技术人员使用本领域的剂量测定试验和/或诊断测定来确定。剂量测定试验和/或诊断测定可以用于在治疗过程期间监测和调整剂量。在一些实施方案中,一种或多种轴突生长诱向因子-1化合物以组合物的形式施用。
在一些实施方案中,这些组合物包含一种或多种经修饰的轴突生长诱向因子-1肽、基本上由其组成或由其组成。如本文所用,“包含”一种或多种经修饰的轴突生长诱向因子-1肽的组合物意味着该组合物可以包含其他化合物,包括不是经修饰的轴突生长诱向因子-1肽的蛋白质(例如,现有技术肽)。如本文所用,“基本上由”一种或多种经修饰的轴突生长诱向因子-1肽“组成”的组合物意味着该组合物可以包含除经修饰的轴突生长诱向因子-1肽之外的蛋白质,只要这些附加的蛋白质不实质上改变包含在该组合物中的经修饰的轴突生长诱向因子-1肽的活性或功能即可。如本文所用,“由”一种或多种经修饰的轴突生长诱向因子-1肽“组成”的组合物意味着该组合物除了一种或多种经修饰的轴突生长诱向因子-1肽之外不包含蛋白质。由一种或多种经修饰的轴突生长诱向因子-1肽组成的组合物可以包含不是蛋白质的成分,例如,药学上可接受的载体、表面活性剂、防腐剂等。在一些实施方案中,由一种或多种经修饰的轴突生长诱向因子-1肽组成的组合物可以包含微量污染物,其可以包括肽污染物,例如,一种或多种经修饰的轴突生长诱向因子-1肽的较小片段,这些较小片段可能来自例如一种或多种经修饰的轴突生长诱向因子-1肽的合成、后续加工、储存条件和/或蛋白质降解。
在一些实施方案中,这些组合物可以包含一种或多种纯化过的经修饰的轴突生长诱向因子-1肽、基本上由其组成或由其组成。如本文所用,“纯化过的”经修饰的轴突生长诱向因子-1肽意味着已从经修饰的轴突生长诱向因子-1肽中除去了一定量的与经修饰的轴突生长诱向因子-1肽天然缔合的大分子组分。如本文所用,包含一种或多种纯化过的经修饰的轴突生长诱向因子-1肽、基本上由其组成或由其组成的组合物意味着该组合物不包含一定量的与一种或多种经修饰的轴突生长诱向因子-1肽天然缔合的大分子组分和/或用于合成经修饰的轴突生长诱向因子-1肽的试剂。在一些实施方案中,从一种或多种经修饰的轴突生长诱向因子-1肽中除去的量(或不存在于组合物中)为大分子组分和/或试剂的至少约60%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约96%、至少约96%、至少约97%、至少约98%、至少约99%或100%。在一些实施方案中,组合物中除去了至少约60%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约96%、至少约96%、至少约97%、至少约98%、至少约99%或100%的与一种或多种经修饰的轴突生长诱向因子-1肽天然缔合的大分子组分和/或用于合成一种或多种经修饰的轴突生长诱向因子-1肽的试剂。在一些实施方案中,本发明的组合物仅由一种或多种经修饰的轴突生长诱向因子-1肽(例如,固体或结晶形式的一种或多种经修饰的轴突生长诱向因子-1肽)组成。
在一些实施方案中,根据本发明的组合物包含一种或多种经修饰的轴突生长诱向因子-1肽和药学上可接受的载体。如本文所用的术语“药学上可接受的载体”,是指通过人工添加到组合物中的载体或稀释剂,其通常对预期接受者无毒并且不显著抑制被包含在组合物中的一种或多种经修饰的轴突生长诱向因子-1肽的活性。在一些实施方案中,根据本发明的组合物可以包含一种或多种赋形剂、稀释剂、助剂、防腐剂、增溶剂、缓冲剂、增稠剂、胶凝剂、发泡剂、表面活性剂、粘合剂、悬浮剂、崩解剂、润湿剂、溶剂、增塑剂、填充剂、着色剂、分散剂、矫味剂,和/或本领域已知的类似物。
根据本发明的组合物通常包含约0.1%至99%的一种或多种经修饰的轴突生长诱向因子-1肽。在一些实施方案中,根据本发明的组合物包含一种或多种经修饰的轴突生长诱向因子-1肽和一种或多种现有技术肽。在一些实施方案中,根据本发明的组合物包含一种或多种经修饰的轴突生长诱向因子-1肽和全长轴突生长诱向因子-1。在一些实施方案中,所述组合物是协同组合物,例如,以协同量包含根据本发明的经修饰的轴突生长诱向因子-1肽和第二蛋白质的组合物,该第二蛋白质可以是第二种根据本发明的经修饰的轴突生长诱向因子-1肽,或者例如全长轴突生长诱向因子-1蛋白质或现有技术肽。
在一些实施方案中,一种或多种经修饰的轴突生长诱向因子-1肽以游离酸或游离碱的形式包含在本发明的组合物中。在一些实施方案中,一种或多种经修饰的轴突生长诱向因子-1肽以药学上可接受的盐(诸如酸加成盐或碱加成盐)的形式包含在组合物中。药学上可接受的盐是指一种或多种经修饰的轴突生长诱向因子-1肽的任何盐形式,其通常对预期接受者无毒,并且不显著抑制被包含在组合物中的一种或多种经修饰的轴突生长诱向因子-1肽或其他活性剂的活性。在一些实施方案中,一种或多种经修饰的轴突生长诱向因子-1肽以水合物或前药的形式提供。
包含一种或多种经修饰的轴突生长诱向因子-1肽的组合物可以通过全身途径和/或通过局部途径施用。合适的施用途径示例性地包括静脉内、口服、口腔、肠胃外、鞘内、脑室内、腹膜内、心内、动脉内、膀胱内、经眼、眼内、直肠、阴道、皮下、皮内、透皮、肌内、局部、鼻内和经粘膜。在一些实施方案中,一种或多种经修饰的轴突生长诱向因子-1肽及其组合物以静脉内方式或通过心室内注射来施用,例如,在用于急性MI治疗或心脏直视手术的血管成形术期间。
在一些实施方案中,根据本发明的经修饰的轴突生长诱向因子-1肽和组合物可以使用本领域已知的方法和组合物来修饰,以改善它们的生物半衰期、稳定性、功效、生物利用度、生物活性,或这些性质的组合。
例如,在一些实施方案中,经修饰的轴突生长诱向因子-1肽可以进行环化,以产生对蛋白水解降解具有抗性的环肽。可以使用本领域已知的方法,通过二硫键、羊毛硫氨酸、二碳代、肼或内酰胺桥在肽序列的侧链或末端之间进行环化。
在一些实施方案中,经修饰的轴突生长诱向因子-1肽可以缀合至分子诸如维生素B12、脂质或环氧乙烷化合物,例如,聚乙二醇(PEG)、聚环氧乙烷(PEO)和聚氧乙烯(POE)、甲氧基聚乙二醇(MPEG)、单甲氧基聚乙二醇(mPEG)、二乙二醇(mini-PEG)等。环氧乙烷化合物可以进一步用例如胺结合末端官能团诸如N-羟基琥珀酰亚胺酯、N-羟基琥珀酰亚胺碳酸酯和脂族醛,或硫醇结合基团诸如马来酰亚胺、吡啶基二硫化物和乙烯基磺酸盐官能化。由于氨基基团(α-氨基和ε-赖氨酸氨基)和半胱氨酸残基非常适于缀合,所以经修饰的轴突生长诱向因子-1肽可以进一步包含一个或多个用于缀合至环氧乙烷分子或本领域中已知的载体化合物的氨基酸残基。缀合肽的药代动力学特性和药效学特性可以通过使用特定的接头来进一步修饰。例如,丙基接头和戊基接头可以用于提供具有松散构象的缀合物,而苯基接头可以用于提供更致密的构象以及邻近C末端的屏蔽结构域。值得注意的是,相对于松散构象,致密构象通常在维持生物活性、延长血浆半衰期、降低蛋白水解敏感性和免疫原性方面更有效。
在一些实施方案中,经修饰的轴突生长诱向因子-1肽可以使用本领域中已知的方法(例如,原位化学反应或定点诱变)进行高糖基化。高糖基化可以导致N-连接或O-连接的蛋白质糖基化。给定的经修饰的轴突生长诱向因子-1肽的清除率可以通过选择特定的糖类来优化。例如,聚唾液酸(PSA)能够以不同的尺寸获得,并且其清除率取决于聚合物的类型和分子大小。因此,例如,具有高分子量的PSA可能适用于递送低分子量的经修饰的轴突生长诱向因子-1肽,而具有低分子量的PSA可能适用于递送具有高分子量的经修饰的轴突生长诱向因子-1肽。糖类的类型可以用于将经修饰的轴突生长诱向因子-1肽靶向特定的组织或细胞。例如,与甘露糖缀合的经修饰的轴突生长诱向因子-1肽可以被甘露糖特异性凝集素(例如,甘露糖受体和甘露聚糖结合蛋白)识别,并且被肝脏摄取。在一些实施方案中,经修饰的轴突生长诱向因子-1肽可以被高糖基化以提高它们在不同环境条件下的物理稳定性和化学稳定性,例如,以抑制应激条件下的失活并且减少由生产条件和储存条件引起的聚集。
在一些实施方案中,可以使用药物递送系统,诸如微粒、纳米颗粒(具有在10nm至1000nm范围内的大小的颗粒)、纳米乳剂、脂质体等,来提供对敏感蛋白质的保护、延长释放、降低施用频率、提高患者依从性和控制血浆水平。可以使用各种天然或合成的微粒和纳米颗粒,它们可以是生物可降解聚合物和/或生物相容性聚合物。微粒和纳米颗粒可以由脂质、聚合物和/或金属制成。聚合物微粒和纳米颗粒可以由天然或合成的聚合物制成,诸如淀粉、藻酸盐、胶原、壳聚糖、聚己内酯(PCL)、聚乳酸(PLA)、聚(丙交酯-共-乙交酯)(PLGA)等。在一些实施方案中,纳米颗粒是固体脂质纳米颗粒(SLN)、碳纳米管、纳米球、纳米胶囊等。在一些实施方案中,聚合物是亲水的。在一些实施方案中,聚合物是硫醇化聚合物。
由于药物从微粒和纳米颗粒中释放的速率和程度可能取决于聚合物的组成和制造方法,因此可以选择给定的组成和制造方法,例如,喷雾干燥、冻干、微挤出和复乳剂,来赋予期望的药物释放曲线。由于掺入微粒或纳米颗粒之中或之上的肽片段在制剂开发期间可能易于在水-有机界面处变性,因此可以使用不同的稳定赋形剂和组合物来防止聚集和变性。例如,可以将PEG和糖(例如,PEG(MW 5000)和麦芽糖)与α-胰凝乳蛋白酶一起添加到组合物中,以减少聚集和变性。此外,可以采用经化学修饰的肽片段,例如,缀合的肽片段和高糖基化的肽片段。
蛋白质稳定性也可以通过选择的制造方法来实现。例如,为了防止水-有机界面处的降解,可以使用称为技术的非水方法。固态肽片段也可以使用水包油包固体(s/o/w)方法封装,例如,喷雾干燥或喷雾冷冻干燥的肽片段或者负载肽的固体纳米颗粒可以使用s/o/w方法封装在微球中。疏水离子配对(HIP)络合可以用于增强蛋白质稳定性并且提高微粒和纳米颗粒的封装效率。在疏水离子配对(HIP)络合中,肽的可电离官能团与含有带相反电荷官能团的离子配对剂(例如,表面活性剂或聚合物)络合,导致形成HIP络合物,其中亲水性蛋白质分子以疏水络合物形式存在。
在一些实施方案中,合成或天然来源的和各种大小(例如,20nm至几百微米)的脂质体可以用于递送肽片段。根据制备方法的不同,脂质体可以是小单层囊泡(25nm至50nm)、大单层囊泡(100nm至200nm)、巨大单层囊泡(1μm至2μm)和多层囊泡(MLV;1μm至2μm)。被递送的肽片段可以被封装到脂质体中或被吸附在表面上。脂质体的大小和表面特性可以被优化以获得期望的结果。例如,单层脂质体和多层脂质体在血管内施用之后数小时至数天提供持续释放。延长药物释放可以通过多囊泡脂质体(也称为技术)来实现。与ULV和MLV不同,多囊泡脂质体由被脂质层网络包围的非同心的多个水性室构成,其中脂质层网络赋予增加的稳定性水平和更长的药物释放持续时间。脂质体可以被进一步修饰,以获得期望的结果。例如,脂质体可以被聚乙二醇化或具有其他表面修饰,以便干扰网状内皮系统的识别和摄取并且提供增加的循环时间。
适合根据本发明使用的示例性脂质体包括多层囊泡(MLV)、寡层囊泡(OLV)、单层囊泡(UV)、小单层囊泡(SUV)、中等大小的单层囊泡(MUV)、大单层囊泡(MUV)、大单层囊泡(LUV)、巨大单层囊泡(GUV)、多囊囊泡(MW)、通过反相蒸发法制备的单层或寡层囊泡(REV)、通过反相蒸发法制备的多层囊泡(MLV-REV)、稳定的复层囊泡(SPLV)、冷冻和解冻的MLV(FATMLV)、通过挤出方法制备的囊泡(VET)、用弗氏压滤法制备的囊泡(FPV)、通过融合制备的囊泡(FUV)、脱水-再水化囊泡(DRV)和泡囊(BSV)。
脂质体可以包含附加的脂质,例如,载体脂质,包括棕榈酰磷脂酰胆碱(DPPC)、磷脂酰胆碱(PC;卵磷脂)、磷脂酸(PA)、磷脂酰甘油(PG)、磷脂酰乙醇胺(PE)、磷脂酰丝氨酸(PS)、二硬脂酰磷脂酰胆碱(DSPC)、二肉豆蔻酰磷脂酰胆碱(DMPC)、二棕榈酰磷脂酰甘油(DPPG)、二硬脂酰磷脂酰甘油(DSPG)、二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酸(DPPA);二肉豆蔻酰磷脂酸(DMPA)、二硬脂酰磷脂酸(DSPA)、二棕榈酰磷脂酰丝氨酸(DPPS)、二肉豆蔻酰磷脂酰丝氨酸(DMPS)、二硬脂酰磷脂酰丝氨酸(DSPS)、二棕榈酰磷脂酰乙醇胺(DPPE)、二肉豆蔻酰磷脂酰乙醇胺(DMPE)、二硬脂酰磷脂酰乙醇胺(DSPE)等,或它们的组合。在一些实施方案中,脂质体还包含甾醇(例如,胆固醇)。
在一些实施方案中,胶束可以用于递送经修饰的轴突生长诱向因子-1肽。磷脂诸如DSPE-PEG、共聚体系PEG-PE、PLA-PEG和超支化聚([胺-酯]-共-[d,l-丙交酯])以及聚离子络合物可以用于增强稳定性和药代动力学特性。
热敏凝胶可以用于递送经修饰的轴突生长诱向因子-1肽。包含PEG、PCL、PLA、聚(乙交酯)、PLGA、聚(N-异丙基丙烯酰胺)、聚环氧乙烷、壳聚糖等的热可逆嵌段共聚物可以用于提供肽片段的受控释放。热敏凝胶的实例包括PLGA-PEG-PLGA三嵌段共聚物凝胶和Pluronic F-127(PF 127)。聚电解质络合物和/或聚乙二醇化可以用于提供蛋白质从凝胶的持续释放。微粒和/或纳米颗粒也可以与凝胶组合使用,以提供持续的药物递送。
经修饰的轴突生长诱向因子-1肽可以以化学方式合成,或者在细胞系统或无细胞系统中通过重组表达。合成方法包括液相合成、固相合成和微波辅助肽合成。肽片段可以通过下列方式来修饰:酰化、烷基化、酰胺化、精氨酰化、聚谷氨酰化、聚糖基化、丁酰化、γ-羧基化、糖基化、丙二酰化、羟基化、碘化、核苷酸加成(例如,ADP-核糖基化)、氧化、磷酸化、腺苷酰化、丙酰化、S-谷胱甘肽化、S-亚硝基化、琥珀酰化、硫酸化、糖化、棕榈酰化、豆蔻酰化、异戊二烯化或异戊烯化(例如,法尼基化或香叶基香叶基化)、糖基磷脂酰肌醇化、脂酰化、黄素部分(例如,FMN或FAD)附着、、血红素C附着、磷酸泛酰巯基乙胺化、亚视黄基席夫碱形成、白喉酰胺形成、乙醇胺磷酸甘油附着、羧腐胺赖氨酸残基(hypusine)形成、生物素化、聚乙二醇化、ISG化、SUMU化、泛素化、拟素化、原核类泛素化、瓜氨酸化、脱酰胺化、消去化(eliminylation)、氨甲酰化,或它们的组合。
包含一种或多种经修饰的轴突生长诱向因子-1肽的组合物可以经受本领域已知的一轮或多轮纯化步骤或浓缩步骤,以除去杂质并且/或者将肽片段浓缩。因此,在一些实施方案中,本发明提供了具有自然界中不存在的纯度和/或组成的肽组合物。在一些情况下,该肽组合物为至多30%、40%、50%、60%、70%、80%、90%、95%、99%、99.9%或100%纯的肽片段。在一些情况下,该肽组合物为至少30%、40%、50%、60%、70%、80%、90%、95%、99%、99.9%或100%纯的肽片段。在一些情况下,该组合物不含杂质。在一些情况下,肽组合物中的肽片段的量至多为总组合物重量的30%、40%、50%、60%、70%、80%、90%、95%、99%、99.9%或100%。在一些情况下,肽组合物中的肽片段的量按总组合物的重量计至少为30%、40%、50%、60%、70%、80%、90%、95%、99%、99.9%或100%。
本发明的组合物包括含有一种或多种经修饰的轴突生长诱向因子-1肽的药物组合物。术语“药物组合物”是指适用于受试者中的药物用途的组合物。药物组合物通常包含有效量的活性剂,例如,一种或多种根据本发明的经修饰的轴突生长诱向因子-1肽,以及药学上可接受的载体。术语“有效量”是指足以产生期望的结果的剂量或量。期望的结果可以包括剂量或量的接受者的客观或主观改善,例如,长期生存率、疾病状态的有效预防,等等。在一些实施方案中,“有效量”小于治疗有效量。在一些实施方案中,药物组合物包含治疗有效量的一种或多种轴突生长诱向因子-1化合物。根据本发明的药物组合物可以还包含一种或多种补充剂。
一种或多种根据本发明的经修饰的轴突生长诱向因子-1肽可以优选地以药物组合物的形式施用于受试者。优选地,受试者是哺乳动物,更优选地,受试者是人。优选的药物组合物是包含至少一种治疗有效量的经修饰的轴突生长诱向因子-1肽和药学上可接受的媒介物的那些。
本发明的药物组合物可以使用本领域中已知的方法被配制用于预期的递送途径,包括静脉内、肌内、腹膜内、皮下、眼内、鞘内、关节内、滑膜内、脑池、肝内、病灶内注射、颅内注射、输注和/或吸入施用途径。根据本发明的药物组合物可以包含以下一者或多者:pH缓冲溶液、助剂(例如,防腐剂、润湿剂、乳化剂和分散剂)、脂质体制剂、纳米颗粒、分散体、悬浮液或乳液,以及用于复溶为无菌可注射溶液剂或分散体的无菌粉末。本发明的组合物和制剂可以使用本领域中的方法进行优化以提高稳定性和功效。参见例如,Carra等人(2007)Vaccine 25:4149-4158。
本发明的组合物可以通过任何合适的途径施用于受试者,包括口服、透皮、皮下、鼻内、吸入、肌内和血管内施用。应当理解,优选的施用途径和药物制剂将随受试者的病症和年龄、待治疗的病症的性质、期望的治疗效果和所使用的特定的经修饰的轴突生长诱向因子-1肽而变化。
如本文所用,“药学上可接受的媒介物”或“药学上可接受的载体”可互换使用,是指与药物施用相容并且符合适用的标准和法规(例如,美国药典和国家处方集(USP-NF)书中列出的用于药物施用的药典标准)的溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。因此,例如,未消毒的水被排除作为至少用于静脉内施用的药学上可接受的载体。药学上可接受的媒介物包括本领域已知的那些。参见例如,Remington:TheScience and Practice of Pharmacy.第20版,(2000)Lippincott Williams&Wilkins.Baltimore,MD。
本发明的药物组合物可以以剂量单位形式提供。如本文所用,“剂量单位形式”是指适合作为用于待治疗受试者的单位剂量的物理离散单位;每个单位包含经计算以产生期望的治疗效果的预定量的一种或多种经修饰的轴突生长诱向因子-1肽,以及所需的药学上可接受的载体。本发明的剂量单位形式的规格由给定的经修饰的轴突生长诱向因子-1肽的独特特性和要实现的期望治疗效果以及本领域中在配混用于治疗个体的这种活性化合物方面固有的限制决定,并且直接取决于前述各项。
根据本发明的经修饰的轴突生长诱向因子-1肽及其组合物的毒性和治疗功效可以使用细胞培养物和/或实验动物和本领域的药物规程来确定。例如,可以通过本领域中的方法确定致死剂量LC50(使群体的50%致死的剂量,表示为浓度×暴露时间)或LD50(使群体的50%致死的剂量),以及ED50(在群体的50%中治疗有效的剂量)。毒性与治疗效果之间的剂量比为治疗指数,它可以表示为LD50/ED50之比。表现出大治疗指数的经修饰的轴突生长诱向因子-1肽是优选的。虽然可以使用导致毒副作用的经修饰的轴突生长诱向因子-1肽,但是应当小心设计将此类化合物靶向治疗部位的递送系统,以使对未感染细胞的潜在损害最小化,并由此减少副作用。
从细胞培养测定和动物研究获得的数据可以用于制定一系列用于人的剂量。优选的剂量提供了包括ED50在内的一系列循环浓度,几乎没有或完全没有毒性。剂量可以根据所采用的剂型和所利用的施用途径而变化。根据本发明的一种或多种经修饰的轴突生长诱向因子-1肽的治疗有效量和剂量可以由细胞培养测定初步估计。可以在动物模型中制定剂量以实现循环血浆浓度范围,该范围包括在细胞培养中确定的IC50(即,实现症状的半数最大抑制的测试化合物的浓度)。这种信息可以用于更准确地确定人体的有用剂量。例如,可以通过高效液相色谱法来测量血浆中的水平。此外,适合于给定受试者的剂量可以由主治医师或有资格的执业医生基于各种临床因素来确定。
以下实施例旨在举例说明本发明,而非对其进行限制。
经修饰的轴突生长诱向因子-1肽诱导出乎意料的对抗缺血/再灌注损伤的优异心脏保护作用
轴突生长诱向因子-1和现有技术肽V1、V2和V3是心脏中的经由DCC/ERKl/2/eNOSs1177/NO信号传导进行的心脏保护性物质。当在缺血/再灌注损伤之前施用时,用V1、V2或V3灌注的心脏的梗塞面积显著减小(对照I/R:39.3±0.3%对比I/R+V1:14.6±2.3%对比I/R+V2:23.0±2.8%对比I/R+V3:18.8±0.8%,p<0.001)。因此,V1、V2和V3现有技术肽在诱导对抗缺血/再灌注损伤的心脏保护作用方面非常有效。另外,当在缺血/再灌注损伤之后施用时,所有三种现有技术肽还诱导对抗I/R损伤的强效心脏保护作用(对照I/R:37.6±1.3%对比I/R+V1:17.6±3.2%对比I/R+V2:20.6±1.7%对比I/R+V3:15.8±2.0%,p<0.001)。
与对照组相比,现有技术肽的片段(例如,Vl-9aa、V2-10aa和V3-11aa)也显著减小了梗塞面积(对照I/R:37.6±1.3%对比I/R+Vl-9aa:16.8±2.2%;I/R+V2-10aa:18.6±1.7%;I/R+V3-11aa:16.7±3.0%,p<0.001)。参见表1:
表1
因此,类似地测量了经修饰的轴突生长诱向因子-1肽减小梗塞面积的能力,并且结果汇总在表2中:
表2
经修饰的轴突生长诱向因子-1肽所赋予的梗塞面积的减少百分比与最接近的现有技术肽所赋予的梗塞面积的减少百分比之间的比较证明,经修饰的轴突生长诱向因子-1肽的活性显著优于现有技术肽的活性,如表3所示:
表3
比较 | MI减少的改善% |
V1P对比Vl-9aa | (77-55)/55=40% |
V2P对比V2-10aa | (58-51)/51=14% |
V3P对比V3-llaa | (70-58)/70=25% |
V1S对比Vl-9aa | (71-55)/55=29% |
V1T对比Vl-9aa | (64-55)/55=16% |
V1C对比Vl-9aa | (74-55)/55=35% |
因此,在一些实施方案中,本发明提供一种或多种经修饰的轴突生长诱向因子-1肽,其可以用于治疗受试者的急性心肌梗塞。在一些实施方案中,本发明涉及在受试者中治疗心肌梗塞、减少或抑制梗塞面积以及/或者减轻或抑制I/R损伤,其包括在心肌梗塞或者缺血或再灌注之前、期间或之后,将治疗有效量的一种或多种经修饰的轴突生长诱向因子-1肽施用于受试者。
预期经修饰的轴突生长诱向因子-1肽对内皮损伤后新生内膜形成表现出稳健的抑制作用,其以类似于全长轴突生长诱向因子-1肽的方式模拟PCTA后的临床再狭窄。此外,预期经修饰的轴突生长诱向因子-1肽经由增强内皮祖细胞(EPC)功能以增强创伤区域(例如,由血管成形术规程引起的冠状动脉内皮细胞损伤)处的再内皮化并且增加一氧化氮产生以抑制血管平滑肌细胞(VSMC)的增殖和迁移来减弱再狭窄。因此,在一些实施方案中,本发明涉及治疗或抑制受试者的再狭窄,其包括在血管中的内皮细胞损伤之前、期间或之后,向受试者施用治疗有效量的一种或多种一种或多种经修饰的轴突生长诱向因子-1肽。
肽序列
以下是本文举例说明的经修饰的轴突生长诱向因子-1肽的氨基酸序列:
V1P:(mini-PEG)-CDCRHNTAG(SEQ ID NO:2)
V2P:(mini-PEG)-CLNCRHNTAG(SEQ ID NO:3)
V3P:(mini-PEG)-CPCKDGVTIGIT(SEQ ID NO:4)
V1S:SDCRHNTAG(SEQ ID NO:5)
V1T:TDCRHNTAG(SEQ ID NO:6)
V1C:CDCRHNTAG(SEQ ID NO:7),其中半胱氨酸残基通过二硫键连接
以下是本文举例说明的现有技术肽的氨基酸序列:
V1:CKCNGHAARCVRDRDDSLVCDCRHNTAGPECDRCKPFHYDRPWQRATAREANEC(SEQ ID NO:8)
V2:CNCNLHARRCRFNMELYKLSGRKSGGVCLNCRHNTAGRHCHYCKEGYYRDMGKPITHRKAC(SEQID NO:9)
V3:CDCHPVGAAGKTCNQTTGQCPCKDGVTGITCNRCAKGYQQSRSPIAPC(SEQ ID NO:10)
Vl-9aa:CDCRHNTAG(SEQ ID NO:11)
V2-10aa:CLNCRHNTAG(SEQ ID NO:12)
V3-11aa:CPCKDGVTGIT(SEQ ID NO:13)
阴性对照V3-16aa:HPVGAAGKTCNQTTGQ(SEQ ID NO:14)
全长轴突生长诱向因子-1人序列的登录号是GI 148613884。
材料和方法
可以采用PCT/US2011/038277和PCT/US2015/023248中所公开的各种方法。因为本文的实验表明举例说明的经修饰的轴突生长诱向因子-1肽表现出优于现有技术肽的优异活性,所以经修饰的轴突生长诱向因子-1肽可以用于代替或补充采用轴突生长诱向因子-1或其他轴突生长诱向因子-1衍生物(诸如现有技术肽)的治疗性治疗。
材料
经纯化的小鼠轴突生长诱向因子-1购自R&D Systems(Minneapolis,MN,USA)。肽片段V1(人轴突生长诱向因子-1的285-338氨基酸)、V2(341-401aa)、V3(404-451aa)、Vl-9aa(304-312aa)、V2-10aa(368-377aa)、V3-16aa(407-422aa)和V3-11aa(423-433aa)由GenicBio Limited(中国上海市)合成。对磷酸化ERK1/2、ERK1/2和eNOSs1179具有特异性的多克隆抗体获自Cell Signaling Technology(Danvers,MA,USA)。eNOS的单克隆抗体购自BDBiosciences(San lose,CA,USA)。
细胞培养
在含有10%胎牛血清(FBS)的培养基199中培养牛主动脉内皮细胞(BAEC,CellSystems,Kirkland,WA,USA),如前所述。参见Chalupsky和Cai,PNAS USA 2005;102:9056-9061;以及Nguyen和Cai,PNAS USA 2006;103:6530-6535。汇合后一天,将细胞在含有5%FBS的培养基中饥饿过夜,然后用轴突生长诱向因子-1蛋白质或不同的肽片段刺激,并且在不同的时间点收获。
蛋白质印迹
对于蛋白质印迹,将大约20μg至40μg的蛋白质通过10%SDS-PAGE分离,转移到硝酸纤维素膜,并且使用本领域中已知的方法用磷酸化的ERK1/2、ERK1/2、eNOS和eNOSs1179(1:1,000)抗体进行探测。参见例如,Gao等人,Journal of Molecular and CellularCardiology.2009;47:752-760。
兰根多夫(LANGENDORFF)灌注
雄性C57BL/6J小鼠(8至12周龄)获自Charles River Laboratories(Wilmington,MA,USA)。在用腹膜内注射戊巴比妥(60mg/kg)麻醉之后,立即收获小鼠心脏,并用20号不锈钢钝头针给主动脉插管,并且转移到兰根多夫装置中,并用改良的Krebs-Henseleit缓冲液(KHB)立即逆行灌注30分钟,如前所述。参见Bouhidel等人Front Biosci(Landmark Ed)2014;19:566-570,以及Zhang等人,J Mol Cell Cardiol.2010;48:1060-1070。然后,在经受缺血/再灌注(I/R)损伤(20分钟全心缺血,之后是60分钟再灌注,其中使用或不使用轴突生长诱向因子-1或不同的肽片段)之前,使用或不使用轴突生长诱向因子-1(100ng/ml)或与轴突生长诱向因子-1相同摩尔浓度1.47nmol/L的不同肽片段将心脏预灌注45分钟。然后收获心脏用于分析梗塞面积。对于使用肽片段进行的后调节处理,心脏经历了40分钟的KHB灌注、20分钟的全心缺血和60分钟用不同肽片段进行的再灌注。
梗塞面积分析
在I/R方案结束时,将心脏以1mm的间隔垂直于心脏的长轴切片,并且在室温下用1%氯化三苯基四氮唑(TTC)的PBS溶液染色10分钟。在用PBS洗涤一次之后,将心脏的切片在10%福尔马林中固定过夜。然后使用NIH Image 1.62对心脏切片进行数字化摄影,以进行面积测量。梗塞面积表示为梗塞与风险区的比率(风险区是该全心缺血模型中的整个心室容积)。
统计分析
蛋白质印迹的光密度数据通过软件Image J获得。分组数据通过软件GradpadPrism 6进行分析。所有值均表示为平均值±SEM。使用单向ANOVA分析和Newman-Keuls检验作为事后检验对两个以上的组执行比较。统计学显著性被设定为p<0.05。
除非另外指明,否则本申请中使用的所有科学术语和技术术语均具有本领域常用的含义。
如本文所用,术语“受试者”、“患者”和“个体”可互换使用,以指代人和非人动物。术语“非人动物”包括所有脊椎动物,例如,哺乳动物和非哺乳动物,诸如非人灵长类动物、马、绵羊、狗、奶牛、猪、鸡,以及其他兽医受试者和试验动物。在本发明的一些实施方案中,受试者是哺乳动物。在本发明的一些实施方案中,受试者是人。
如本文所用,术语“诊断”是指向另一方(例如,患者)通知(即,口头沟通或通过书写(在例如纸张或电子媒介上))诊断的物理和主动步骤。类似地,“提供预后”是指向另一方(例如,患者)通知(即,口头沟通或通过书写(在例如纸张或电子媒介上))预后的物理和主动步骤。
除非另有特别说明,否则单数的使用可以包括复数。如说明书和所附权利要求书中所用,单数形式“一个”、“一种”和“该”可以包括多个指代物,除非上下文另有明确规定。
如本文所用,“和/或”意味着“和”或者“或”。例如,“A和/或B”意味着“A、B或A和B两者”,“A、B、C和/或D”意味着“A、B、C、D,或它们的组合”,并且所述“A、B、C、D,或它们的组合”意味着A、B、C和D的任何子集,例如,单成员子集(例如,A或B或C或D)、双成员子集(例如,A和B;A和C;等),或三成员子集(例如,A、B和C;或A、B和D;等),或所有四个成员(例如,A、B、C和D)。
如本文所用,短语“……中的一者或多者”,例如,“A、B和/或C中的一者或多者”意味着“A中的一者或多者”、“B中的一者或多者”、“C中的一者或多者”、“A中的一者或多者和B中的一者或多者”、“B中的一者或多者和C中的一者或多者”、“A中的一者或多者和C中的一者或多者”以及“A中的一者或多者、B中的一者或多者和C中的一者或多者”。
短语“包含A、基本上由A组成或由A组成”用作避免页面和翻译费超额的工具,并且意味着在一些实施方案中,所讨论的给定事物:包含A、基本上由A组成或由A组成。例如,句子“在一些实施方案中,组合物包含A、基本上由A组成或由A组成”应当被解释为如同写成以下三个单独的句子:“在一些实施方案中,组合物包含A。在一些实施方案中,组合物基本上由A组成。在一些实施方案中,组合物由A组成。”
类似地,叙述一串替代词的句子应当被解释为如同提供了一串句子,使得每个给定的替代词在句子中由其自身提供。例如,句子“在一些实施方案中,组合物包含A、B或C”应当被解释为如同写成以下三个单独的句子:“在一些实施方案中,组合物包含A。在一些实施方案中,组合物包含B。在一些实施方案中,组合物包含C。”作为另一个实例,句子“在一些实施方案中,组合物至少包含A、B或C”应当被解释为如同写成以下三个单独的句子:“在一些实施方案中,组合物至少包含A。在一些实施方案中,组合物至少包含B。在一些实施方案中,组合物至少包含C。”
如本文所用,术语“蛋白质”、“多肽”、“肽”和“肽片段”可互换使用,以指代连接在一起的两个或更多个天然氨基酸和/或非天然氨基酸,并且本文的序列和式中使用单字母氨基酸命名。如本文所用,“aa”是用于“氨基酸”的缩写。例如,“Vl-9aa”的“9aa”表示该肽的长度为9个氨基酸残基。
在理解或完成本发明的公开内容所必需的程度上,本文提及的所有出版物、专利和专利申请均以引用方式明确地并入本文,其程度如同每个出版物、专利和专利申请均单独地并入本文一样。
尽管已经如此描述了本发明的示例性实施方案,但是本领域的技术人员应当注意,公开内容仅仅是示例性的,并且在本发明的范围内可以做出各种其他的替代、改编和修改。因此,本发明不限于如本文所展示的具体实施方案,而是仅受以下权利要求书的限制。
序列表
<110> 加利福尼亚大学董事会
<120> 用于心脏保护的经修饰的轴突生长诱向因子-1肽和组合物
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<221> MISC_FEATURE
<222> (1)..(1)
<223> 其中二乙二醇(mini-PEG)与之连接
<400> 2
Cys Asp Cys Arg His Asn Thr Ala Gly
1 5
<210> 3
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 基于人轴突生长诱向因子-1序列的肽
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> 其中二乙二醇(mini-PEG)与之连接
<400> 3
Cys Leu Asn Cys Arg His Asn Thr Ala Gly
1 5 10
<210> 4
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 基于人轴突生长诱向因子-1序列的肽
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> 其中二乙二醇(mini-PEG)与之连接
<400> 4
Cys Pro Cys Lys Asp Gly Val Thr Ile Gly Ile Thr
1 5 10
<210> 5
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 基于人轴突生长诱向因子-1序列的肽
<400> 5
Ser Asp Cys Arg His Asn Thr Ala Gly
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 基于人轴突生长诱向因子-1序列的肽
<400> 6
Thr Asp Cys Arg His Asn Thr Ala Gly
1 5
<210> 7
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 基于人轴突生长诱向因子-1序列的肽
<220>
<221> 二硫化物
<222> (1)..(3)
<400> 7
Cys Asp Cys Arg His Asn Thr Ala Gly
1 5
<210> 8
<211> 54
<212> PRT
<213> 人工序列
<220>
<223> 基于人轴突生长诱向因子-1序列的肽
<400> 8
Cys Lys Cys Asn Gly His Ala Ala Arg Cys Val Arg Asp Arg Asp Asp
1 5 10 15
Ser Leu Val Cys Asp Cys Arg His Asn Thr Ala Gly Pro Glu Cys Asp
20 25 30
Arg Cys Lys Pro Phe His Tyr Asp Arg Pro Trp Gln Arg Ala Thr Ala
35 40 45
Arg Glu Ala Asn Glu Cys
50
<210> 9
<211> 61
<212> PRT
<213> 人工序列
<220>
<223> 基于人轴突生长诱向因子-1序列的肽
<400> 9
Cys Asn Cys Asn Leu His Ala Arg Arg Cys Arg Phe Asn Met Glu Leu
1 5 10 15
Tyr Lys Leu Ser Gly Arg Lys Ser Gly Gly Val Cys Leu Asn Cys Arg
20 25 30
His Asn Thr Ala Gly Arg His Cys His Tyr Cys Lys Glu Gly Tyr Tyr
35 40 45
Arg Asp Met Gly Lys Pro Ile Thr His Arg Lys Ala Cys
50 55 60
<210> 10
<211> 48
<212> PRT
<213> 人工序列
<220>
<223> 基于人轴突生长诱向因子-1序列的肽
<400> 10
Cys Asp Cys His Pro Val Gly Ala Ala Gly Lys Thr Cys Asn Gln Thr
1 5 10 15
Thr Gly Gln Cys Pro Cys Lys Asp Gly Val Thr Gly Ile Thr Cys Asn
20 25 30
Arg Cys Ala Lys Gly Tyr Gln Gln Ser Arg Ser Pro Ile Ala Pro Cys
35 40 45
<210> 11
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 基于人轴突生长诱向因子-1序列的肽
<400> 11
Cys Asp Cys Arg His Asn Thr Ala Gly
1 5
<210> 12
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 基于人轴突生长诱向因子-1序列的肽
<400> 12
Cys Leu Asn Cys Arg His Asn Thr Ala Gly
1 5 10
<210> 13
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 基于人轴突生长诱向因子-1序列的肽
<400> 13
Cys Pro Cys Lys Asp Gly Val Thr Gly Ile Thr
1 5 10
<210> 14
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 基于人轴突生长诱向因子-1序列的肽
<400> 14
His Pro Val Gly Ala Ala Gly Lys Thr Cys Asn Gln Thr Thr Gly Gln
1 5 10 15
Claims (15)
1.一种肽,所述肽包括如下的SEQ ID NO:1、基本上由如下的SEQ ID NO:1组成或由如下的SEQ ID NO:1组成:
X1-X2-X3-C-X4-X5-X6-X7-T-X8-G(SEQ ID NO:1)
其中
X1为Ala、Asn、Cys、Ser或Thr,优选地X1为Cys、Ser或Thr,其中当X1为Cys时,其共价或非共价地经由二硫键连接到第四个氨基酸位置处的半胱氨酸残基,或者共价或非共价地连接到环氧乙烷化合物;
X2存在或不存在,并且如果存在,X2为Ala、Ile、Leu、Met、Phe、Pro、Trp或Val,优选地X2为Leu或Pro;
X3存在或不存在,并且如果存在,X3为Asn、Asp、Cys、Gln、Glu、Gly、Ser、Thr或Tyr,优选地X3为Asn或Asp;
X4为Arg、His或Lys,优选地X4为Arg或Lys;
X5为Arg、Asp、Glu、His、Lys、Phe、Trp或Tyr,优选地X5为Asp或His;
X6为Asn、Cys、Gln、Gly、Ser、Thr或Tyr,优选地X6为Asn或Gly;
X7存在或不存在,并且如果存在,X7为Ile、Thr或Val,优选地X7为Val;并且
X8存在或不存在,并且如果存在,X8为Ala、Ile、Leu、Met、Phe、Pro、Trp或Val,优选地X8为Ala;并且
其中存在X2、X3或X2和X3两者。
2.根据权利要求1所述的肽,其中所述环氧乙烷化合物为聚乙二醇(PEG)、聚环氧乙烷(PEO)和聚氧乙烯(POE)、甲氧基聚乙二醇(MPEG)或单甲氧基聚乙二醇(mPEG),优选地所述环氧乙烷化合物为mini-PEG。
3.根据权利要求1或权利要求2所述的肽,其中所述肽包括下列各项、基本上由下列各项组成或由下列各项组成:SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ IDNO:6或SEQ ID NO:7。
4.根据权利要求1-3中任一项所述的肽,其中所述肽的长度为约8-60个、约8-55个、约8-50个、约8-45个、约8-40个、约8-35个、约8-30个、约8-25个、约8-20个、约8-15个、约8-12个、约8-11个、约9-60个、约9-55个、约9-50个、约9-45个、约9-40个、约9-35个、约9-30个、约9-25个、约9-20个、约9-15个、约9-12个、或9-11个氨基酸残基。
5.根据权利要求1-3中任一项所述的肽,其中所述肽的长度为8个、9个、10个或11个氨基酸残基。
6.一种组合物,所述组合物包括一种或多种根据权利要求1-5中任一项所述的肽。
7.一种刺激、增加或增强内皮细胞产生一氧化氮的方法,所述方法包括向所述内皮细胞施用一种或多种根据权利要求1-5所述的肽或根据权利要求6所述的组合物。
8.一种刺激或诱导内皮细胞中的ERK1/2和/或eNOS的磷酸化的方法,所述方法包括向所述内皮细胞施用一种或多种根据权利要求1-5所述的肽或根据权利要求6所述的组合物。
9.一种治疗、抑制或减轻具有内皮细胞的组织或器官的损伤的方法,所述内皮细胞是血管内皮细胞,所述方法包括在所述损伤之前、期间和/或之后,通过向所述内皮细胞施用一种或多种根据权利要求1-5所述的肽或根据权利要求6所述的组合物,来刺激、增加或增强所述内皮细胞产生一氧化氮并且/或者刺激或诱导所述内皮细胞中的ERK1/2、eNOS或这两者的磷酸化。
10.根据权利要求7-9中任一项所述的方法,其中对所述内皮细胞的所述施用是体内施用。
11.根据权利要求10所述的方法,其中所述损伤是由超氧化物产生、缺血/再灌注或心肌梗塞引起的。
12.如权利要求11所述的方法,其中所述组织是心脏组织,或者所述器官是心脏。
13.如权利要求12所述的方法,其中所述损伤是由心肌梗塞引起的,并且所述施用减小了心脏的梗塞面积。
14.一种治疗、抑制或减轻受试者的心脏的缺血/再灌注损伤的方法,所述方法包括将治疗有效量的一种或多种根据权利要求1-5所述的肽或根据权利要求6所述的组合物施用于所述受试者,从而治疗、抑制或减轻所述缺血/再灌注损伤。
15.一种减少或减小因缺血/再灌注损伤而导致的受试者心脏梗塞面积的方法,所述方法包括将治疗有效量的一种或多种根据权利要求1-5所述的肽或根据权利要求6所述的组合物施用于所述受试者,从而减少或减小所述梗塞面积。
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US20060019896A1 (en) * | 2004-07-14 | 2006-01-26 | University Of Utah Research Foundation | Netrin-related compositions and uses |
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