CN102014967A - 芘携带肽穿过血脑屏障的用途 - Google Patents
芘携带肽穿过血脑屏障的用途 Download PDFInfo
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- CN102014967A CN102014967A CN2009801166660A CN200980116666A CN102014967A CN 102014967 A CN102014967 A CN 102014967A CN 2009801166660 A CN2009801166660 A CN 2009801166660A CN 200980116666 A CN200980116666 A CN 200980116666A CN 102014967 A CN102014967 A CN 102014967A
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Abstract
描述了用于穿过血脑屏障投递肽制剂的方法,包括对受试者施用包含(i)肽制剂和芘的偶联物,和相关检测和治疗方法。
Description
相关申请
本申请要求2008年3月21日提交的美国临时申请61/038,634的优先权的权益,本文通过提及而完整收录全部内容。
发明领域
一般而言,本发明涉及穿过血脑屏障(BBB)投递肽、蛋白质和抗体的领域。更具体而言,本发明涉及使用芘-制剂偶联物(agent conjugate)来穿过BBB投递肽、蛋白质或抗体的方法。
发明背景
神经病症的检测和治疗由于内源和外源施用的成分对脑的不透性(由于血脑屏障(BBB))而常常是困难的。BBB有效地将脑与周围制剂,诸如肽、蛋白质、大的大分子、非肽性分子、离子、和水溶性非电解质分开。例如,一般公认带电荷的或亲水性的分子以及具有大于约700kDa分子量的分子不能穿过BBB。一般还公认肽,诸如约21个氨基酸残基的肽不能有效穿过BBB,较长的肽诸如40个残基的Aβ40蛋白和42个残基的Aβ42蛋白(两者均与阿耳茨海默氏病(Alzheimer’s disease)有关)也不能。如此,BBB阻止检测剂以及治疗剂(其在其它方面可用于诊断和治疗多种神经病学病症)的投递。
在将制剂有效转运至脑上的先前尝试已经包括将制剂偶联至载体模块,使用脂质体配制剂、和使用纳米颗粒。例示性载体模块包括天然存在的多胺(美国专利5,670,477)、载体诸如溶菌酶、血红蛋白、细胞色素-c和物质-P(美国专利5,604,198)、和糖类(美国专利5,260,308)。在将Aβ蛋白有效转运到脑上的先前尝试已经使用与载体诸如OX26或腐胺偶联的Aβ40或更小的片段,诸如Aβ1-30。还已经提出高度糖基化终产物(RAGE)的受体用于介导穿过BBB的转运,特别对于Aβ蛋白。
然而,仍需要用于穿过BBB投递肽制剂(包括肽、蛋白质和抗体)的方法、制剂和试剂盒。
发明概述
根据一个实施方案,本发明提供了一种用于穿过血脑屏降投递肽偶联物的方法,包括对受试者施用偶联物,其包含肽制剂和芘。在一些实施方案中,所述肽制剂是能够鉴定与神经病学病症有关的蛋白质或结构的检测剂。在另一个实施方案中,所述肽制剂是可用于治疗神经病症的治疗剂。在一些实施方案中,所述肽制剂包括与靶蛋白中经历从α-螺旋构象向β-片层构象的构象变化的区域对应的氨基酸序列,但是不包括所述靶蛋白的全长序列。在其它实施方案中,所述肽制剂是对与神经病症有关的蛋白质或结构特异性的抗体。在一个实施方案中,所述偶联物进一步包含可检测标记物。在另一个实施方案中,所述偶联物包含芘衍生物,诸如烷基化的芘类似物、芘丁酸盐(酯)、PEG化的芘、芘-清蛋白类似物、包含游离羧基的芘衍生物和包含游离氨基的芘衍生物。在一些实施方案中,所述偶联物包含两个或更多个芘模块(moieties)。
根据另一个实施方案,本发明提供了一种体内检测方法,包括对受试者施用包含肽检测剂和芘的偶联物,并检测位于受试者的脑中的偶联物。在一个实施方案中,所述检测剂能够鉴定与神经病症有关的蛋白质或结构。在一些实施方案中,所述偶联物包含两个或更多个芘模块。在一些实施方案中,至少一种芘模块是包含游离羧基的芘衍生物,而至少一种芘模块是包含游离氨基的芘衍生物。在一个实施方案中,所述芘至少在肽的N端或C端,或在肽的N和C端两者与肽检测剂偶联。在又一个实施方案中,所述检测剂能够鉴定处于自我聚集的特定构象或状态的蛋白质。在另一个实施方案中,定位的偶联物的检测牵涉检测芘激基缔合物(excimers)。
在又一个实施方案中,本发明提供了一种体内检测方法,包括对受试者施用包含肽检测剂、芘和可检测标记物的偶联物,并检测已经位于所述受试者的脑中的偶联物。在一些实施方案中,所述标记物是荧光团、MRI造影剂、离子发射体、和放射性标志物。
在其它实施方案中,本发明提供了一种用于治疗神经病症的方法。该方法包括对受试者施用治疗有效量的偶联物,其包含肽治疗剂和芘。在一个实施方案中,所述肽制剂是抗淀粉样剂(anti-amyloid agent)。
附图简述
图1显示了通过对转基因小鼠鼻内施用的媒介物、肽-制剂芘偶联物、或芘丁酸盐(酯)(pyrene butyrate)每mm2检测的Aβ斑数目。
图2显示了通过鼻内施用的偶联物(AD185)荧光(-)对硫黄素S染色(▲)在皮层中检测的Aβ斑之间的相关性。
图3显示了通过静脉内施用的偶联物(AD185)荧光(-)对硫黄素S染色(■)在皮层(图3A)和海马(图3B)中检测的Aβ斑之间的相关性。
发明详述
在描述和公开本发明的具体实施方案前,要理解本文中所描述的具体的材料、方法和组合物仅作为例子呈现,而并不限制本发明的范围。除非另有定义,本文中所使用的技术和科学术语具有本发明所属技术领域普通技术人员通常理解的意义。本文通过提及完整收录列出提及的已知方法的出版物和其它材料,就像全文列出一样。
列出重组DNA技术的一般原理的标准参考著作包括Sambrook,J.等(1989)Molecular Cloning:A Laboratory Manual,第2版,Cold Spring HarborLaboratory Press,Planview,N.Y;McPherson,M.J.编(1991)DirectedMutagenesis:A Practical Approach,IRL Press,Oxford;Jones,J.(1992)AminoAcid and Peptide Synthesis,Oxford Science Publications,Oxford;Austen,B.M.和Westwood,O.M.R.(1991)Protein Targeting and Secretion,IRL Press,Oxford。可以在实施本发明中利用对于本领域普通技术人员已知的任何合适的材料和/或方法。然而,描述了优选的材料和方法。除非另有指明,以下描述和实施例中提及的材料、试剂等从商业来源可获得。
如本文中所使用的,除非明确规定仅指单数,单数形式(a,an)“一个”、“一种”、和“该”,“所述”(the)指单数和复数两者。
一般而言,术语“约”和范围的使用(无论是否通过术语约量化)指所理解的数字不限于本文中所列的精确数字,并且意图指基本上在所引用范围内的范围,而不偏离本发明的范围。如本文中所使用的,“约”是本领域普通技术人员理解的,并且会根据使用其的上下文在一定程度上变化。如果使用该术语之处本领域普通技术人员参考上下文无法清楚其使用,那么“约”会表示具体术语的多至+/-10%。
如本文中所使用的,“受试者”指需要检测或治疗性处理的任何动物,包括人和驯养动物,诸如猫、狗、猪、牛、绵羊、山羊、马、兔等。“受试者”还包括研究背景中使用的动物,包括小鼠和其它小的哺乳动物。典型的受试者可以有神经病症、疾病或病症的风险或怀疑患有此类状况,或者可以渴望测定关于特定状况的风险或状态。如本文中所使用的,“治疗性”处理包括施用治疗剂以治疗存在的状况,或预防受试者有风险或形成的状况,或者用于健康维持。
如本文中所使用的,短语“治疗有效量”指在受试者中提供特定药理学响应的药物剂量,对于所述特定的药理学响应,在需要此类治疗的患者中施用药物。强调的是,治疗有效量在治疗本文中所描述的状况/疾病中不会总是有效的,即使本领域技术人员将此类剂量视为治疗有效量。
如本文中所使用的,“肽”指经由肽键连接的两个或更多个单独的氨基酸(无论是否天然存在)的任何聚合物。如本文中所使用的,术语“肽制剂”包括肽、蛋白质、和抗体。肽包括全长蛋白质的片段,其中片段可以包括全长蛋白质的至少5个连续的氨基酸、至少10个连续的氨基酸、至少15个连续的氨基酸、至少20个连续的氨基酸、或至少25个连续的氨基酸。肽还包括合成肽。
如本文中所使用的,“构象”或“构象约束(conformational constraint)”指特定蛋白质构象,例如α-螺旋、平行和反平行β链、亮氨酸拉链、锌指等的存在。另外,构象约束可以包括没有额外结构信息的氨基酸序列信息。作为一个例子,“-C-X-X-C-”是一种构象约束,其指明两个半胱氨酸残基必须由两个其它氨基酸残基分开,其中每个的身份在此特定约束的语境中是无关的。“构象变化”是从一种构象向另一种的变化。
术语“Aβ蛋白”在本文中用于指所有形式的Aβ蛋白,包括Aβ34、Aβ37、Aβ38、Aβ40和Aβ42。
“重组蛋白或肽”指通过重组DNA技术生成,即从通过编码期望蛋白质或多肽的外源重组DNA表达构建体转化的细胞、微生物或哺乳动物生成的蛋白质或肽。大多数细菌培养物中表达的蛋白质或肽通常会是没有聚糖的。酵母中表达的蛋白质或肽可具有与哺乳动物细胞中表达的蛋白质或肽不同的糖基化样式。
如本文中所使用的,术语“天然存在的”或“天然的”就肽制剂而言指身体中存在的或自自然界中存在的来源回收的制剂(例如肽、蛋白质和抗体)。天然的肽制剂可以进行化学或酶促修饰,包括翻译后修饰,包括但不限于乙酰化、糖基化、磷酸化、脂质偶联、酰化和羰基化。
如本文中所使用的,术语“合成的”就肽制剂而言规定制剂不是天然存在的,但是可以通过其它手段诸如化学合成、生化方法、或重组方法来获得。
术语“类似物”、“片段”、“衍生物”、和“变体”在本文中提及肽时指此类肽的类似物、片段、衍生物、和变体,其保留与参照肽基本上类似的功能活性或基本上相同的生物学功能或活性,如本文中所描述的。“类似物”包括多肽原,其包含肽的氨基酸序列。
“片段”是肽的一部分,其与参照肽相比保留基本上类似的功能活性或基本上相同的生物学功能或活性,如本文中所公开的体外测定法中所显示的。
“衍生物”包括对本发明肽的所有修饰,其基本上保留本文中所公开的功能,而且包括别的结构和附带功能,例如PEG化的肽或融合有清蛋白质的肽。
“变体”包括具有与参照肽的氨基酸序列足够相似的氨基酸序列。术语“足够相似的”指序列具有共同的结构域(例如序列同源性)和/或共同的功能活性。例如,本文中将包含至少约45%、至少约50%、至少约55%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%、至少约99%、或至少约100%相同的共同结构域的氨基酸序列定义为足够相似的。变体包括由在严格条件下与编码参照多肽的多核苷酸的互补物杂交的多核苷酸编码的肽。此类变体一般保留参照肽的功能活性。变体还包括氨基酸序列上由于诱变而所有不同的肽。
“基本上相似的功能活性”和“基本上相同的生物学功能或活性”各指在通过相同方法或测定法来测定每种肽的生物学活性时,生物学活性的程度在由参照肽所表明的生物学活性的约50%至100%内或更多,在80%至100%内或更多,或约90%至100%内或更多。例如,制剂的类似物或衍生物可以与所指制剂在性质上展现出相同的生物学活性,虽然它可以在数量上展现出或多或少的活性。可以通过常规的筛选方法来证实制剂的给定类似物或衍生物的适合性以确认类似物或衍生物展现出与所指制剂的活性基本上相似的感兴趣活性。类似物或衍生物可以拥有别的结构特征和/或展现出别的功能特性,诸如PEG化的制剂,其包含PEG模块,而且可以展现出更长的体内循环半衰期。
通过比较氨基酸序列来测定两种肽之间的“相似性”。一种多肽的氨基酸与第二种多肽的对应氨基酸相似,若它是相同或保守的氨基酸替代的话。保守替代包括那些记载于Dayhoff,M.O.编,The Atlas of Protein Sequence andStructure 5,National Biomedical Research Foundation,Washington,D.C.(1978),和Argos,P.(1989)EMBO J.8:779-785中的。例如,属于下组之一的氨基酸表示保守变化或替代:
-Ala、Pro、Gly、Gln、Asn、Ser、Thr;
-Cys、Ser、Tyr、Thr;
-Val、Ile、Leu、Met、Ala、Phe;
-Lys、Arg、His;
-Phe、Tyr、Trp、His;和
-Asp、Glu。
本发明的一些方面涉及与蛋白质的特定结构状态诸如蛋白质的特定构象或自我聚集状态有关的疾病和状况的诊断和治疗。本文通过提及而完整收录PCT申请PCT/US2007/016738(WO 2008/013859)和美国专利申请11/828,953,其披露了相关的实施方案。本发明的一些方面提供了用于体内检测特定结构状态的蛋白质(包括错折叠的蛋白质和自我聚集的蛋白质,诸如那些与疾病状态有关的蛋白质)的偶联物和方法,及用于治疗那些疾病状态的偶联物和方法。在一些实施方案中,蛋白质与致淀粉样病(amyloidogenicdisease)有关。
在它们采用特定构象或自我聚集状态时与人或动物疾病有关的蛋白质是本领域中已知的。此类疾病的例子包括致淀粉样病,包括阿耳茨海默氏病(AD)、脑淀粉样血管病(cerebral amyloid angiopathy,CAA)、和脑血管疾病(CVD)。如本文中所使用的,“致淀粉样病”是如下的疾病,其中在身体中形成淀粉样斑或淀粉样沉积物。在多种病症中找到淀粉状蛋白形成,诸如糖尿病、AD、痒病(scrapie)、牛海绵样脑病(bovine spongiform encephalopathy,BSE)、克罗伊茨费尔特-雅各布病(Creutzfeldt-Jakob disease,CJD)、慢性消耗性疾病(chronic wasting disease,CWD)、相关的传染性海绵样脑病(transmissible spongiform encephalopathy,TSEs)。
多种疾病与蛋白质的特定结构形式有关(例如“错折叠的蛋白质”或自我聚集的蛋白质),而处于不同结构形式的蛋白质(例如“正常的蛋白质”)是无害的。在许多情况中,正常的蛋白质是可溶的,而错折叠的蛋白质形成不溶性聚集物。此类不溶性蛋白质的例子包括传染性海绵样脑病(TSE)中的阮病毒;阿耳茨海默氏病(AD)、脑淀粉样血管病(CAA)、和脑血管疾病(CVD)的淀粉样斑中的Aβ肽;帕金森氏病(Parkinson’s disease)的Lewy小体中的α-突触核蛋白沉积物、额颞痴呆(frontal temporal dementia)和皮克氏病(Pick’sdisease)中神经原纤维缠结中的tau;肌萎缩性脊髓侧索硬化(amylotrophiclateral sclerosis)中的超氧化物歧化酶;和亨延顿氏病(Huntington’s disease)中的亨延顿蛋白。参见例如Glenner等,J.Neurol.Sci.94:1-28,1989;Haan等,Clin.Neurol.Neurosurg.92(4):305-310,1990。
这些不溶性蛋白质常常形成聚集物,其由具有β-折叠片构象的共同特征的非分支原纤维构成。在CNS中,淀粉状蛋白可以存在于脑和脑膜血管中(脑血管沉积物)和脑实质中(斑)。人和动物模型中的神经病理学研究指明接近淀粉样沉积物的细胞在其正常功能上是扰乱的。参见例如Mandybur,ActaNeuropathol.78:329-331,1989;Kawai等,Brain Res.623:142-146,1993;Martin等,Am.J.Pathol.145:1348-1381,1994;Kalaria等,Neuroreport 6:477-80,1995;Masliah等,J.Neurosci.16:5795-5811,1996。另外,其它研究指明淀粉样原纤维实际上可能启动神经变性。参见例如Lendon等,J.Am.Med.Assoc.277:825-831,1997;Yankner,Nat.Med.2:850-852,1996;Selkoe,J.Biol.Chem.271:18295-18298,1996;Hardy,Trends Neurosci.20:154-159,1997。
虽然导致蛋白质错折叠的潜在分子机制没有得到充分了解,但是所有上文所提及的神经病学病症的共同特征是聚集以形成β片层结构的原纤维的形成。原纤维形成和随后与斑沉积物有关的二级β片层结构的形成经由复杂的机制发生,所述复杂的机制牵涉成核阶段,其中蛋白质单体结合以形成原纤维,接着原纤维在每个末端延伸。如此,能够破坏原纤维形成的肽、蛋白质或抗体探针会阻止疾病行进,并且如此是治疗重要性的。另外,能够结合病态蛋白质的特定自我结合状态的制剂是有用的诊断工具以检测和量化错折叠蛋白质的特定形式,以及领会疾病的行进。如此,能够结合特定自我聚集状态的特定蛋白质的高度选择性肽制剂可用作检测剂,也可用于治疗应用。
A.用于穿过BBB投递肽制剂的方法
申请人已经发现了与芘载体偶联的药学相关肽制剂(例如肽、蛋白质和抗体)显示在对受试者施用时穿过血脑屏障(BBB)的能力增强。
在一个实施方案中,提供了一种用于穿过BBB投递肽制剂的方法,其包括对受试者施用偶联物,其包含(i)肽制剂和(ii)芘。在一些实施方案中,肽制剂是肽、蛋白质、或抗体。在一些实施方案中,肽制剂是检测剂或治疗剂。在具体的实施方案中,肽制剂是能够鉴定与神经病症有关的靶蛋白或结构(诸如自我聚集的特定构象或状态)的检测剂。在其它实施方案中,肽制剂是可用于治疗神经病症的治疗剂。如本文中所使用的,“能够鉴定”指肽制剂选择性且优先地结合靶蛋白或结构。
可以在适合于对受试者施用的任何组合物(诸如包含偶联物和药学可接受载体的组合物)中配制偶联物。偶联物可以通过任何合适的手段施用,包括通过鼻内、静脉内、腹膜内、动脉内、肌肉内、皮下、口服、含服、或经皮施用,并且可以相应地进行配制。例如,药学可接受载体可以是液体,使得组合物适宜胃肠外施用,或者可以是为口服配制的固体,即加有媒介物的胶囊壳、片剂、丸剂等。或者,药学可接受载体可以为可喷雾液体或固体形式,使得组合物适宜吸入。药学可接受载体是本领域中已知的,并且可以包括但不限于溶解剂或悬浮剂,诸如水或天然存在的植物油,如芝麻、花生、或棉籽油或合成的脂肪媒介物,如油酸乙酯等。缓冲液、防腐剂、抗氧化剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂和芳香剂也可以包含在组合物中。
在本文中所描述的方法中,可以使用一种或多种包含相同或不同检测剂、治疗剂、芘模块和/或标记物的偶联物,其中在同一组合物中或在可以通过相同路径或通过一种或多种不同路径同时或序贯施用的一种或多种不同组合物中提供每种偶联物。
在一些实施方案中,芘偶联的肽制剂展现出穿过BBB的通透性,其实质上大于非偶联的活性剂的通透性,诸如比非偶联的活性剂的通透性大至少3倍、至少5倍、至少10倍、至少15倍、至少20倍、或更多。
穿过BBB的通透性的一种测量是相对于注射量和相对于进入其它组织的量(%IDI)的进入脑的偶联物量。在一些实施方案中,芘-偶联物具有1-10之间的辛醇/水分配系数。
认为一些用于提高肽穿过BBB的通透性的载体还具有提高肽-载体偶联物的半衰期的效果。例如,将显著量的结构大小添加至肽-载体偶联物的载体可以降低肽的降解或清除率。在外周和脑两者中降解Aβ40肽(例如在正常的生理学条件下)。然而,使用例如腐胺或OX26作为载体的偶联物显著提高Aβ40的半衰期。虽然升高的半衰期可以具有一些优点,诸如促成脑中的浓度升高,但是它也可能具有显著的缺点,诸如脑中非特异性定位的升高。如果例如非特异性定位的偶联物促成降低体内成像的灵敏性和/或选择性的高背景,那么这可能是一个特别的顾虑。
本文中所描述的偶联物没有遭受此缺点。例如,用包含在两端都用芘标记的Aβ肽的偶联物进行的实验显示了偶联物在施用后6小时被清除,如通过脑脊液分析所测定的,其没有揭示循环偶联物的证据。
可以凭实验评估偶联物的定位和清除或降解速率,例如通过对小鼠施用偶联物,并将它们处死以在施用后不同时间时(诸如在施用后的时间期限,包括2分钟、10分钟、30分钟、60分钟、1小时、2小时、3小时、4小时、5小时、6小时、或更长时)分析来进行。
可以凭实验证实偶联物的非毒性,例如使用本领域中已知的体外测定法和体内啮齿类毒性研究来进行。
B.肽制剂
在包含氨基酸残基外,肽制剂的性质是不受限制的。肽制剂可以是合成的或天然存在的肽,包括天然存在的肽的变体或衍生物。肽可以是线性肽、环肽、约束肽(constrained peptide)、或模拟肽(peptidomimetic)。用于生成环肽的方法是本领域中公知的。例如,可以以头尾方式、侧链到N或C端残基、以及使用接头的环化来实现环化。环肽的选择性和活性取决于环肽的控制其三维结构的总体环大小。如此,环化提供了一种用于探查疾病状态的行进以及靶向病态蛋白质的特定自我聚集状态的有力工具。
在一些实施方案中,肽制剂特异性结合与神经病症有关的靶蛋白或结构。根据这些实施方案,本发明为诊断或治疗提供了可用于选择性靶向与神经病症有关的靶蛋白或结构的制剂。
在一些实施方案中,肽制剂是一种肽探针,如记载于PCT申请PCT/US2007/016738(WO 2008/013859)和美国专利申请11/828,953中的,本文通过提及而完整收录其全部内容。如其中所描述的,此类肽探针可以用作检测剂和/或治疗剂。PCT申请PCT/US2007/016738(WO 2008/013859)和美国专利申请11/828,953中所描述的例示性肽探针包括与靶蛋白中经历从α-螺旋构象向β-片层构象的构象变化的区域对应的氨基酸序列,并且肽探针自身经历从α-螺旋构象向β-片层构象的构象变化,但是不包括靶蛋白的全长序列。例如,肽探针可以由来自靶蛋白序列的至少5个,或约10个至约25个连续氨基酸,包括来自靶蛋白序列的至少5个、至少10个、多至约25个和多至约50个,诸如5至50、10至50、5至25或10至25个连续氨基酸组成。在一些实施方案中,在与处于β-片层构象的靶蛋白接触时,肽探针可以经历构象变化。
如PCT申请PCT/US2007/016738(WO 2008/013859)和美国专利申请11/828,953中所描述的,其中所描述的肽探针可用于在样品中或在体内检测蛋白质,并可用于检测处于特定结构状态(例如靶结构状态)诸如自我聚集的特定构象或状态的蛋白质。例如,可以将肽探针与芘偶联,使得在肽探针是α-螺旋或无规卷曲构象(或可溶性状态)时它不形成激基缔合物,但是在肽探针处于β-片层构象(或不溶性聚集状态)时确实形成激基缔合物。靶结构状态可以与疾病有关,而不同结构状态与疾病无关。靶结构状态可以引起疾病,可以是疾病症状中的一个因素,可以由于其它因素而在样品中或在体内出现,或者可以在其它方面与疾病有关。
在一些实施方案中,肽制剂包含PCT申请PCT/US2007/016738 WO2008/013859)和美国专利申请11/828,953的氨基酸序列SEQ ID NO 34。在一些实施方案中,肽制剂包含PCT申请PCT/US2007/016738 WO 2008/013859)和美国专利申请11/828,953的氨基酸序列SEQ ID NO:35、SEQ ID NO:36、SEQ IDNO:37、SEQ ID NO:38、或SEQ ID NO:45,其在检测和治疗AD的背景中是有用的。在一些实施方案中,肽制剂选自WO 2008/013859的SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、或SEQ ID NO:45。在其它实施方案中,肽制剂不同于WO 2008/013859的SEQ ID NO 34、SEQ IDNO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、或SEQ ID NO:45。在一些实施方案中,肽选自WO 2008/013859的SEQ ID NO:36或SEQ IDNO:38。在一些实施方案中,肽不同于WO 2008/013859的SEQ ID NO:36或SEQ ID NO:38,包括选自WO 2008/013859的SEQ ID NO 34、SEQ ID NO:35、SEQ ID NO:37、或SEQ ID NO:45的肽或另一种肽。在一些实施方案中,肽是WO 2008/013859的SEQ ID NO:36。在一些实施方案中,肽不同于WO2008/013859的SEQ ID NO:36,包括选自WO 2008/013859的SEQ ID NO 34、SEQ ID NO:35、SEQ ID NO:37、或SEQ ID NO:45的肽或另一种肽。在一些实施方案中,肽是WO 2008/013859的SEQ ID NO:38。在一些实施方案中,肽不同于WO 2008/013859的SEQ ID NO:38,包括选自WO 2008/013859的SEQ ID NO 34、SEQ ID NO:35、SEQ ID NO:37、或SEQ ID NO:45的肽或另一种肽。
SEQ ID NO:1(WO 2008/013859的SEQ ID NO:34)
Val Val Ala Gly Ala Ala Ala Ala Gly Ala Val His Lys Leu Asn Thr Lys Pro
Lys Leu Lys His Val Ala Gly Ala Ala Ala Ala Gly Ala Val Lys
SEQ ID NO:2(WO 2008/013859的SEQ ID NO:35)
Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Leu
Met
SEQ ID NO:3(WO 2008/013859的SEQ ID NO:36)
Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly
Leu Met
SEQ ID NO:4(WO 2008/013859的SEQ ID NO:37)
Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Leu
Met Lys
SEQ ID NO:5(WO 2008/013859的SEO ID NO:38)
Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly
Leu Met Lys
SEO ID NO:6(WO 2008/013859的SEQ ID NO:45)
Glu Val His His Gln Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys
Gly Ala Ile Ile Gly Leu Met Val Gly Gly Val Val Ile Ala
在其它实施方案中,肽制剂特异性结合与其它神经病症,诸如中风、脑血管疾病、癫痫、传染性海绵样脑病(TSE)有关的靶蛋白或结构;阿耳茨海默氏病(AD)、脑淀粉样血管病(CAA)、和脑血管疾病(CVD)的淀粉样斑中的Aβ肽;帕金森氏病的Lewy小体中的α-突触核蛋白沉积物、额颞痴呆和皮克氏病中神经原纤维缠结中的tau;肌萎缩性脊髓侧索硬化中的超氧化物歧化酶;及亨延顿氏病和良性和癌性脑肿瘤诸如成胶质细胞瘤(glioblastoma’s)、垂体瘤(pituitary tumor)、或脑膜瘤(meningioma)中的亨延顿蛋白。
在一些实施方案中,肽制剂经历与上文所讨论的α-螺旋向β-片层变化不同的构象变化,诸如β-片层向α-螺旋变化、非结构化(unstructured)向β-片层变化等。此类肽制剂在与与神经病症有关的靶肽或结构相互作用后可以经历此类构象变化。
在其它实施方案中,肽制剂是特异性结合与神经病症有关的靶蛋白或结构,诸如与致淀粉样病有关的靶蛋白或结构(诸如自我聚集的特定构象或状态)的抗体,诸如抗淀粉样抗体E610和NG8。其它抗淀粉样抗体是本领域中已知的,特异性结合与其它神经病症有关的蛋白质或结构的抗体亦然。
其它肽检测剂包括荧光蛋白,诸如绿色荧光蛋白(GFP)、链霉抗生物素蛋白、酶、酶底物,和本领域中已知的其它肽检测剂。
例示性肽治疗剂包括肽大分子和小肽。例如,神经营养性蛋白在本文中所描述的方法的背景中作为肽制剂是有用的。神经营养性蛋白包括神经生长因子(NGF)、脑源性神经营养因子(BDNF)、神经营养蛋白-3(NT-3)、神经营养蛋白-4(NT-4)、神经营养蛋白-5(NT-5)、胰岛素样生长因子(IGF-I和IGF-II)、神经胶质细胞系衍生的神经营养因子(GDNF)、成纤维细胞生长因子(FGF)、睫状神经营养因子(CNTF)、表皮生长因子(EGF)、神经胶质衍生的连接蛋白(GDN)、转化生长因子(TGF-α和TGF-β)、白介素、血小板源性生长因子(PDGF)和S100β蛋白、以及其生物活性衍生物和类似物。
神经活性肽还包括下丘脑释放激素、垂体后叶激素、垂体肽、无脊椎动物肽、胃肠肽、那些在心脏中找到的肽的亚类一诸如心房钠尿肽,和其它神经活性肽。
下丘脑释放激素的亚类包括作为合适例子的促甲状腺素释放激素、促性腺激素释放激素、促生长素抑制素、促肾上腺皮质激素释放激素和生长激素释放激素。
垂体后叶激素的亚类以诸如加压素、催产素、和后叶激素运载蛋白等化合物例示。
垂体肽的亚类以促肾上腺皮质激素、β-内啡肽、α-促黑色素细胞激素、促乳素、黄体化激素、生长激素、和促甲状腺激素例示。
合适的无脊椎动物肽以FMRF酰胺、水螅头激活剂、直肠肽、小的心脏肽、肌调蛋白、Buccolin、产卵激素和袋细胞肽(bag cell peptide)例示。
胃肠肽包括此类神经学活性化合物,诸如血管活性肠肽、缩胆囊素、胃泌素、神经降压肽、甲硫氨酸脑啡肽、亮氨酸脑啡肽、胰岛素和胰岛素样生长因子I和II、胰高血糖素、肽组氨酸异亮氨酸酰胺、铃蟾肽,促胃动素和胰泌素。
其它神经活性肽的例子包括血管紧张肽II、缓激肽、强啡肽、Opiocortin、睡眠肽(sleep peptide)、降钙素、CGRP(降钙素基因相关肽)、神经肽Y、神经肽Yy、甘丙肽、物质K(神经激肽)、泡蛙肽、肛褶蛙肽、耳腺蛙肽、章鱼唾腺精(eledoisin)和心房钠尿肽。
肽制剂还包括与突触囊泡膜有关的蛋白质,诸如钙结合蛋白和其它突触囊泡蛋白。钙结合蛋白的亚类包括细胞骨架相关蛋白,诸如钙调结合蛋白、膜联蛋白、钙电蛋白(哺乳动物)、钙电蛋白(电鳐)、依钙蛋白I、依钙蛋白复合物、依钙蛋白II、内联蛋白I、内联蛋白II、蛋白II、会联蛋白I;和酶调节物,诸如p65。
其它突触囊泡蛋白包括活动化抑制剂(诸如突触蛋白Ia,b和突触蛋白IIa,b)、可能的融合蛋白诸如突触泡蛋白、和未知功能的蛋白质诸如p29、VAMP-1,2(小突触泡蛋白)、VAT1、rab 3A、和rab 3B。
肽制剂还包括α-、β-和γ-干扰素、Epoetin、非格司亭(Fligrastim)、沙格司亭(Sargramostin)、CSF-GM、人IL、TNF和其它生物技术药物。
肽制剂还包括使用重组生物技术方法获得的肽、蛋白质和抗体。
肽制剂还包括“抗淀粉样剂”或“抗致淀粉样剂”,其直接或间接抑制蛋白质聚集和/或形成淀粉样斑或沉积物和/或促进淀粉样斑或沉积物的解聚或降低。抗淀粉样剂还包括一般在本领域中称为“淀粉样切除机(buster)”或“斑切除机”的制剂。这些包括作为模拟肽并与淀粉样原纤维相互作用以将它们缓慢溶解的药物。“模拟肽”指生物分子模拟另一种生物学活性肽分子的活性。“淀粉样切除机”或“斑切除机”还包括吸收淀粉样原纤维保持稳定所必需的辅助因子的制剂。
抗淀粉样剂包括抗体和肽探针,如记载于PCT申请PCT/US2007/016738(WO 2008/013859)和美国专利申请11/828,953中的,本文通过提及而完整收入其全部内容。如其中所描述的,针对给定靶蛋白的肽探针特异性结合所述蛋白质,而且可以优先结合靶蛋白的特定结构形式。虽然不想要限于任何理论,认为肽探针结合靶蛋白会阻止靶蛋白的高级装配物的形成,由此预防或治疗与靶蛋白有关的疾病和/或预防疾病的进一步行进。例如,肽探针对靶蛋白单体的结合会阻止靶蛋白的自我聚集。类似地,肽探针对可溶性寡聚体或不溶性聚集物的结合会阻止进一步聚集和初原纤维和原纤维形成,而肽探针对初原纤维或原纤维的结合会阻止该结构的进一步延伸。在阻断进一步聚集外,这种结合还能将平衡移回到更有利于可溶性单体的状态,进一步使疾病的行进停止,并减轻疾病症状。
本领域技术人员会认可上文描述为例示性检测剂的肽制剂中许多作为治疗剂也是有用的,并且上文描述为例示性治疗剂的肽制剂中许多作为检测剂也是有用的。如此,这些描述符决不是限制性的。
在一些实施方案中,肽制剂是上文所描述肽制剂的变体,具有一个或多个氨基酸替代、添加、或缺失,诸如一个或多个保守氨基酸替代、添加、或缺失,和/或一个或多个氨基酸替代、添加、或缺失,其进一步增强偶联物穿过BBB的通透性。例如,产生更疏水性氨基酸序列的氨基酸替代、添加、或缺失可以进一步增强偶联物穿过BBB的通透性。
C.芘
芘可以是在与非肽制剂偶联时改善制剂穿过BBB的通透性的芘或任何芘衍生物或类似物。
芘由四个融合的苯环构成:
“芘”衍生物或类似物指包含芘的四个融合苯环的分子,其中一个或多个芘碳原子被取代或与别的模块偶联。例示性芘衍生物包括烷基化芘,其中一个或多个芘碳原子用线性或分支的、取代的或未取代的烷基、烯基、炔基或酰基基团,诸如C1-C20、线性或分支的、取代的或未取代的烷基、烯基、炔基或酰基基团取代,其中所述基团可以用例如包括O、N或S原子(例如羰基、胺、硫氢基)的模块或用卤素取代。在一些实施方案中,芘衍生物包括一个或多个游离的羧基基团和/或一个或多个游离的胺基团,其中每个可以直接附着至芘碳原子或附着至线性或分支的、取代的或未取代的烷基、烯基、炔基或酰基基团上的任何位置,如上文所描述的,诸如在与芘碳分隔1个或多个,诸如1至3、1至5、或更多个原子的碳原子上附着。在一些实施方案中,用一个或多个乙酸模块和/或一个或多个乙胺(ethylamine)模块取代芘。在一些实施方案中,用单个甲基、乙基、丙基或丁基基团取代芘衍生物。在一些实施方案中,用短链脂肪酸取代芘,诸如芘丁酸盐(酯)。在另一个实施方案中,将芘与清蛋白、运铁蛋白或抗体的Fc片段偶联。在一些实施方案中,经由碳-碳连接、氨基基团、肽键、醚、硫醚、二硫化物、或酯连接将取代基附着至芘。
可以通过本领域中已知的方法来生成芘衍生物。例如,可以使用取代的芘来将脂肪酸附着至四环支架。合适的试剂(包括芘的官能化烷基衍生物)和衍生化反应是本领域中已知的。例如氨基芘可以与1,4-丁二酸甲酯起反应以产生芘的丁酸衍生物。或者,1-氰硫基芘可以与4-氨基丁酸甲酯起反应以产生芘的硫取代的丁酸衍生物。其它备选的反应还包括使芘硼酸与取代的脂肪酸起反应以产生芘的脂肪酸衍生物。
在其它实施方案中,芘衍生物是PEG化的芘,即与聚乙二醇(PEG)偶联的芘。此类芘衍生物可以展现出更长的体内循环半衰期。在其它实施方案中,芘衍生物是与清蛋白偶联的芘。
在一些实施方案中,与芘相比,芘衍生物展现出降低的毒性。在一些实施方案中,与芘相比,芘衍生物展现出延长的体内循环半衰期,诸如上文所讨论的PEG化的芘。在一些实施方案中,与芘相比,芘衍生物展现出甚至更大的升高的穿过BBB的通透性,诸如偶联有清蛋白的芘。在一些实施方案中,芘衍生物具有1-10之间的辛醇/水分配系数。
D.偶联物
可以通过本领域中已知的任何手段,包括化学(共价)偶联将肽制剂偶联至芘。在一些实施方案中,经由侧链残基将肽制剂直接偶联至芘。在一个实施方案中,经由赖氨酸残基的ε-氨基基团将芘偶联至肽制剂。可以经由钯催化的交叉偶联反应将芘的衍生物诸如氯芘偶联至赖氨酸的ε-氨基基团。在其它实施方案中,经由接头将肽制剂偶联至芘。作为接头使用的化合物是本领域中公知的,包括任选取代的C1-C20烷基基团、链烷酸、链烯酸、炔酸(alkynoicacid)、醇盐基团、氨基链烷酸、烷基胺、烷氧基基团、双功能性亚氨酯、戊二醛、环氧乙烷聚合物(PEG),任选取代的芳香基基团、炔基吡啶基、炔基联吡啶、邻苯二甲酸、苹果酸和马来酸、N-羟基琥珀酰亚胺酯、异双功能试剂和基团特异性反应剂诸如马来酰亚胺模块、二硫模块(SH)和碳二亚胺模块。
可以通过化学合成或生物工程方法,诸如包括在活的生物体中与制剂一起表达芘的方法来形成偶联物。此类生物工程方法包括直接工程化改造合成的生物学过程或进化,并筛选芘-制剂偶联物组合。
在一些实施方案中,将肽制剂偶联至单一芘模块。在其它实施方案中,将肽制剂偶联至两个或更多个芘模块。在将肽制剂偶联至两个或更多个芘模块时,可以将每个芘模块偶联至制剂(直接地或经由接头)。
在一个实施方案中,将芘模块偶联至肽制剂,在其N或C端处。在另一个实施方案中,将芘模块在内部(非末端)氨基酸残基处偶联至肽制剂。在具有两个芘模块的实施方案中,可以将一个芘模块偶联至肽制剂的每个末端,可以将一个芘模块偶联至N或C端,而另一个在内部残基上偶联,或者可以将两个都在内部残基上偶联。在将超过两个芘模块偶联至肽制剂时,可以以末端和内部残基的任何排列或组合放置模块。在一些实施方案中,芘模块彼此接近地偶联,而在其它实施方案中,它们位于肽制剂上分开或远离的位置处。在其它实施方案中,将一个或多个芘模块偶联(直接地或经由接头)至一个或多个芘模块,将其中至少一个偶联(直接地或经由接头)至肽制剂。
不管芘模块的位置,偶联物可以展现出制剂穿过BBB的通透性增强。
在一些实施方案中,用芘标记偶联物,使得它们能够形成芘激基缔合物。也就是说,以如下方式将肽制剂偶联至芘模块,使得容许与肽制剂的相同或不同分子偶联的芘模块间的激基缔合物形成,其可能是想要的。根据这些实施方案,可以将两个或更多个芘模块偶联至同一肽制剂分子,使得容许通过同一肽制剂分子上的芘模块间的相互作用进行激基缔合物形成,诸如例如可以与肽制剂的特定构象结合。或者,激基缔合物形成可以是由于不同肽制剂分子上的芘模块间的相互作用,诸如例如可以与肽制剂分子间的定位、结合和/或相互作用有关。
在一些实施方案中,使用不同芘衍生物,其中至少一种包括一个或多个游离的羧基基团(诸如乙酸模块),并且其中至少一个包括一个或多个游离的胺基团(诸如乙胺模块),如上文所讨论的。根据此实施方案,一个芘衍生物上的游离的羧基基团与另一个芘衍生物上的游离的胺基团之间的相互作用可以稳定芘衍生物间的相互作用,诸如经由盐桥的形成,而且可以稳定激基缔合物形成加合物和/或使激基缔合物荧光最大化。根据这些实施方案,可以将两种不同的芘衍生物偶联至同一肽制剂分子,诸如以通过同一肽制剂分子上的不同芘衍生物间的相互作用来稳定激基缔合物形成,诸如例如可以与肽制剂的特定构象结合。或者,可以将一个芘衍生物偶联至一个肽制剂分子,并可以将不同的芘衍生物偶联至不同肽制剂分子,诸如以通过不同肽制剂分子间的相互作用来稳定激基缔合物形成,诸如例如可以与肽制剂分子间的定位、结合和/或相互作用有关。
在一些实施方案中,用可检测标记物标记偶联物。例如,偶联物可以包含与标记物共价或非共价偶联或融合的肽制剂。在肽制剂是检测剂的实施方案中,可检测标记物可以提供改善的检测或在别的环境下的检测。在肽制剂是治疗剂的实施方案中,在由治疗剂提供的疗法外,可检测标记物还可以提供检测。
如本文中所使用的,“可检测标记物”包括可以检测的任何模块。选定的具体标记物可以广泛变化,这取决于要用于分析的分析技术。标记物可以在肽制剂的氨基或羧基末端或者在接近肽制剂的氨基或羧基末端处复合或共价键合,所述肽制剂可以用短的、疏水性肽序列末端加帽。在本发明的一些方面,肽制剂的氨基和羧基末端两者都用大小范围为约1个至约5个氨基酸的小的疏水性肽末端加帽。这些肽可以是天然的或合成的,但是常常是天然的(即源自靶蛋白)。可以在肽的氨基和/或羧基末端或者在接近肽的氨基和/或羧基末端处或者在任何其它合适的位置附着标记物。
如本文中所使用的,“可检测标记物”是可用于标记偶联物的化学或生物化学模块。“可检测标记物”可以包括荧光剂(例如荧光团、荧光蛋白、荧光半导体纳米晶体)、磷光剂、化学发光剂、显色剂、猝灭剂、染料、放射性核素、金属离子、金属溶胶、配体(例如生物素、链霉抗生物素蛋白半抗原等)、酶(例如β-半乳糖苷酶、辣根过氧化物酶、葡萄糖氧化酶、碱性磷酸酶等)、酶底物、酶辅因子(例如NADPH)、酶抑制剂、闪烁剂、抑制剂、磁性颗粒、寡核苷酸、和本领域中已知的其它模块。
若试剂或标记物是荧光团,则可以使用荧光团的一种或多种特性来评估经标记的偶联物的状态。例如,基于偶联物是结合的还是游离的,荧光团的激发波长可以有所不同。在一些实施方案中,荧光的发射波长、强度、或极化也可以随偶联物的状态而变化。
如本文中所使用的,“荧光团”是一种可由光激发以发射荧光或磷光的化学基团。“猝灭剂”是能够猝灭来自荧光供体的荧光信号的试剂。第一荧光团可以发射激发第二荧光团的荧光信号。第一荧光团可以发射由第二荧光团猝灭的信号。本文中所公开的探针可以经历荧光共振能量转移(FRET)。
荧光团和猝灭剂可以包括下列试剂(或以下列商品名称出售的荧光团和猝灭剂):1,5 IAEDANS;1,8-ANS;伞形酮(例如4-甲基伞形酮);吖啶酯、5-羧基-2,7-二氯荧光素;5-羧基荧光素(5-FAM);5-羧基四甲基若丹明(5-TAMRA);5-FAM(5-羧基荧光素);5-HAT(羟基色胺);5-羟基色胺(HAT);5-ROX(羧基-X-若丹明);5-TAMRA(5-羧基四甲基若丹明);6-羧基若丹明6G;6-CR 6G;6-JOE;7-氨基-4-甲基香豆素;7-氨基放线菌素D(7-AAD);7-羟基-4-甲基香豆素;9-氨基-6-氯-2-甲氧基吖啶;ABQ;酸性品红;ACMA(9-氨基-6-氯-2-甲氧基吖啶);吖啶橙;吖啶红;吖啶黄;吖啶黄素(Acriflavin);吖啶黄素福尔根SITSA;Alexa Fluor 350TM;Alexa Fluor 430TM;Alexa Fluor488TM;Alexa Fluor 532TM;Alexa Fluor 546TM;Alexa Fluor 568TM;Alexa Fluor594TM;Alexa Fluor 633TM;Alexa Fluor 647TM;Alexa Fluor 660TM;Alexa Fluor680TM;茜素Complexon;茜素红;别藻蓝蛋白(APC);AMC;AMCA-S;AMCA(氨甲基香豆素);AMCA-X;氨基放线菌素D;氨基香豆素;氨甲基香豆素(AMCA);苯胺蓝;Anthrocyl硬脂酸酯;APC(别藻蓝蛋白);APC-Cy7;APTS;Astrazon亮红4G;Astrazon橙R;Astrazon红6B;Astrazon黄7 GLL;米帕林(Atabrine);ATTO-TAGTM CBQCA;ATTO-TAGTM FQ;金胺;AurophosphineG;Aurophosphine;BAO 9(二氨基苯基二唑);硫酸黄连素;β-内酰胺酶;BFP蓝移GFP(Y66H);蓝色荧光蛋白;BFP/GFP FRET;Bimane;双苯甲酰胺;双苯甲亚胺(Hoechst);Blancophor FFG;Blancophor SV;BOBOTM-1;BOBOTM-3;Bodipy 492/515;Bodipy 493/503;Bodipy 500/510;Bodipy505/515;Bodipy 530/550;Bodipy 542/563;Bodipy 558/568;Bodipy 564/570;Bodipy 576/589;Bodipy 581/591;Bodipy 630/650-X;Bodipy 650/665-X;Bodipy 665/676;Bodipy FL;Bodipy FL ATP;Bodipy Fl-神经酰胺;Bodipy R6GSE;Bodipy TMR;Bodipy TMR-X偶联物;Bodipy TMR-X,SE;Bodipy TR;Bodipy TR ATP;Bodipy TR-X SE;BO-PROTM-1;BO-PROTM-3;亮硫黄素(Sulphoflavin)FF;钙黄绿素;钙黄绿素蓝;钙CrimsonTM;钙绿(CalciumGreen);钙橙(Calcium Orange);Calcofluor白;羧基-X-若丹明(5-ROX);CascadeBlueTM;Cascade Yellow;儿茶酚胺;CCF2(GeneBlazer);CFDA;CFP-青色荧光蛋白;CFP/YFP FRET;叶绿素;色霉素A;CL-NERF(比率染料(RatioDye),pH);CMFDA;腔肠素(Coelenterazine)f;腔肠素fcp;腔肠素h;腔肠素hcp;腔肠素ip;腔肠素n;腔肠素O;香豆素鬼笔环肽;C-藻蓝蛋白;CPM甲基香豆素;CTC;CTC甲臜(Formazan);Cy2TM;Cy3.18;Cy3.5TM;Cy3TM;Cy5.18;Cy5.5TM;Cy5TM;Cy7TM;青色GFP;环AMP氟传感器(FiCRhR);Dabcyl;Dansyl;Dansyl胺;Dansyl尸胺;绿化Dansyl;Dansyl DHPE;氟化Dansyl;DAPI;Dapoxyl;Dapoxyl 2;Dapoxyl 3;DCFDA;DCFH(二氯二氢荧光素二乙酸酯);DDAO;DHR(二氢罗丹明123);Di-4-ANEPPS;Di-8-ANEPPS(非比率);DiA(4-Di-16-ASP);二氯二氢荧光素二乙酸酯(DCFH);DiD-亲脂性示踪剂;DiD(DiIC18(5));DIDS;二氢罗丹明123(DHR);DiI(DiIC18(3));二硝基苯酚;DiO(DiOC18(3));DiR;DiR(DiIC18(7));DNP;多巴胺;DsRed;DTAF;DY-630-NHS;DY-635-NHS;EBFP;ECFP;EGFP;ELF 97;曙红;藻红(Erythrosin);藻红ITC;溴化乙锭;乙锭同二聚物(Ethidium homodimer)-1(EthD-1);Euchrysin;EukoLight;氯化铕(III);EYFP;快速蓝(Fast Blue);FDA;福尔根(碱性副品红);FITC;Flazo橙;Fluo-3;Fluo-4;荧光素(FITC);荧光素二乙酸酯;Fluoro-Emerald;Fluoro-Gold(羟芪巴脒);Fluor-Ruby;FluorX;FM 1-43TM;FM 4-46;FuraRedTM;Fura RedTM/Fluo-3;Fura-2;Fura-2/BCECF;Genacryl亮红B;Genacryl亮黄10GF;Genacryl粉红3G;Genacryl黄5GF;GeneBlazer(CCF2);荧光蛋白(例如GFP(S65T);GFP红移(rsGFP);GFP野生型,非UV激发(wtGFP);GFP野生型,UV激发(wtGFP);和GFPuv;Gloxalic Acid;Granular蓝;血卟啉;Hoechst 33258;Hoechst 33342;Hoechst 34580;HPTS;羟基香豆素;羟基芪脒(Hydroxystilbamidine)(FluoroGold);羟色胺;Indo-1;吲哚二碳菁(Indodicarbocyanine)(DiD);吲哚三碳菁(Indotricarbocyanine)(DiR);IntrawhiteCf;JC-1;JO-JO-1;JO-PRO-1;Laurodan;LDS 751(DNA);LDS 751(RNA);Leucophor PAF;Leucophor SF;Leucophor WS;丽丝胺若丹明;丽丝胺若丹明B;钙黄绿素/乙锭同二聚物;LOLO-1;LO-PRO-1;萤光黄;鲁米诺、LysoTracker蓝;Lyso Tracker蓝-白;Lyso Tracker绿;Lyso Tracker红;Lyso Tracker黄;LysoSensor蓝;LysoSensor绿;LysoSensor黄/蓝;Mag绿;Magdala红(根皮红B);Mag-Fura红;Mag-Fura-2;Mag-Fura-5;Mag-Indo-1;Magnesium绿;Magnesium橙;Malachite绿;Marina蓝;Maxilon亮黄素10GFF;Maxilon亮黄素8 GFF;部花青(Merocyanin);甲氧基香豆素;Mitotracker绿FM;Mitotracker橙;Mitotracker红;光神霉素(Mitramycin);Monobromobimane;Monobromobimane(mBBr-GSH);Monochlorobimane;MPS(甲基绿派洛宁芪(Methyl Green Pyronine Stilbene));NBD;NBD胺;Nile红;NEDTM;硝基苯二唑(Nitrobenzoxadidole);去甲肾上腺素;核快红(Nuclear Fast Red);核黄(Nuclear Yellow);Nylosan Brilliant IaVin E8G;Oregon绿;Oregon绿488-X;Oregon绿TM;Oregon绿TM 488;Oregon绿TM 500;Oregon绿TM 514;Pacific蓝;碱性副品红(Feulgen);PBFI;PE-Cy5;PE-Cy7;PerCP;PerCP-Cy5.5;PE-德克萨斯红[红613];根皮红B(苏丹红);Phorwite AR;Phorwite BKL;PhorwiteRev;Phorwite RPA;膦3R;藻红蛋白B[PE];藻红蛋白R[PE];PKH26(Sigma);PKH67;PMIA;Pontochrome蓝黑;POPO-1;POPO-3;PO-PRO-1;PO-PRO-3;樱草灵(Primuline);普施安黄(Procion Yellow);碘化丙啶(PI);PyMPO;芘;派若宁(Pyronine);派若宁B;Pyrozal亮黄素7GF;QSY 7;芥子奎吖因(Quinacrine Mustard);红613[PE-德克萨斯红];试卤灵(Resorufin);RH 414;Rhod-2;罗丹明;罗丹明110;罗丹明123;罗丹明5 GLD;罗丹明6G;罗丹明B;罗丹明B 200;特级罗丹明B;罗丹明BB;罗丹明BG;罗丹明绿;罗丹明类鬼笔环肽;罗丹明鬼笔环肽;罗丹明红;罗丹明WT;玫瑰红;R-藻蓝蛋白;R-藻红蛋白(PE);RsGFP;S65A;S65C;S65L;S65T;Sapphire GFP;SBFI;5-羟色胺;Sevron亮红2B;Sevron亮红4G;Sevron亮红B;Sevron橙;Sevron黄L;sgBFPTM;sgBFPTM(super glow BFP);sgGFPTM;sgGFPTM(超级发光GFP);SITS;SITS(樱草灵);SITS(芪异硫磺酸(Stilbene IsothiosulphonicAcid));SNAFL钙黄绿素;SNAFL-1;SNAFL-2;SNARF钙黄绿素;SNARF1;钠绿(Sodium Green);SpectrumAqua;SpectrumGreen;SpectrumOrange;Spectrum Red;SPQ(6-甲氧基-N-(3-磺丙基)喹啉);芪(Stilbene);硫基罗丹明(Sulphorhodamine)B can C;特级硫基罗丹明G;SYTO 11;SYTO 12;SYTO13;SYTO 14;SYTO 15;SYTO 16;SYTO 17;SYTO 18;SYTO 20;SYTO21;SYTO 22;SYTO 23;SYTO 24;SYTO 25;SYTO 40;SYTO 41;SYTO42;SYTO 43;SYTO 44;SYTO 45;SYTO 59;SYTO 60;SYTO 61;SYTO62;SYTO 63;SYTO 64;SYTO 80;SYTO 81;SYTO 82;SYTO 83;SYTO84;SYTO 85;SYTOX蓝;SYTOX绿;SYTOX橙;TETTM;四环素;四甲基罗丹明(TRITC);德克萨斯红TM;德克萨斯红-XTM偶联物;硫代二羰花青(Thiadicarbocyanine)(DiSC3);噻嗪红R;噻唑橙;硫黄素5;硫黄素S;硫黄素TCN;Thiolyte;噻唑橙;Tinopol CBS(Calcofluor White);TMR;TO-PRO-1;TO-PRO-3;TO-PRO-5;TOTO-1;TOTO-3;TriColor(PE-Cy5);TRITC四甲基罗丹明异硫氰酸酯(TetramethylRodamineIsoThioCyanate);真蓝(TrueBlue);TruRed;Ultralite;荧光素钠B;Uvitex SFC;wt GFP;WW 781;X-罗丹明;XRITC;二甲苯橙(Xylene Orange);Y66F;Y66H;Y66W;黄色GFP;YFP;YO-PRO-1;YO-PRO-3;YOYO-1;YOYO-3;及其盐类。
试剂可以包括荧光团的衍生物,其已经进行过修饰以促进与另一种反应性分子的偶联。因此,试剂可以包括试剂的胺反应性衍生物诸如异硫氰酸酯衍生物和/或琥珀酰亚胺酯衍生物。
在用于体内检测的实施方案中,可以使用可用于体内检测的试剂。例如,可以使用可用于磁性共振成像的试剂诸如氟-18,也可以是化学发光剂。
在一个实施方案中,标记物是PET或MRI图像造影剂。虽然最初希望MRI提供一种非侵入性地进行明确诊断的手段,在许多情况中造影剂的添加改善了针对所成像组织的灵敏性和/或特异性。MRI造影剂可以包括阳性或阴性剂。阳性剂一般包括顺磁性分子或短的T1松弛剂(relaxation agent),虽然也使用两种的组合。顺磁性阳性GI造影剂的典型包括氯化铁、柠檬酸铁铵、和钆-DTPA(有和没有甘露醇)。短的T1松弛时间造影剂包括矿物油、油乳剂、和蔗糖聚酯。使用抗磁剂作为阴性造影剂,例如高岭土和膨润土的混合物。另一种抗磁性造影剂是硫酸钡的悬浮液。另外,也可以使用全氟化学剂诸如全氟溴辛烷(Perfluoroctylbromide,PFOB)作为阴性MRI造影剂。可以使用超顺磁剂作为口服阴性MRI造影剂。一般使用诸如磁铁矿清蛋白微球、口服磁性颗粒(Nycomed A/S,奥斯陆,挪威)、和超顺磁氧化铁(AMI121,AdvancedMagnetics,Cambridge,Mass.)等化合物。这些化合物含有直径为约250至350埃的小的氧化铁晶体,并且是Fe2O3和Fe3O4的混合物。
在另一个实施方案中,制剂是放射性试剂。例如,制剂可以提供要由目前用于此目的的机器检测的足够能量的正电子发射。此类实体的一个例子包含氧-15(一种通过正电子发射衰变的氧同位素)。另一个例子是具有氟-18的化合物诸如F-18氟-L-多巴(FDOPA)、F-18氟代酪氨酸(FTYR)、氟脱氧葡萄糖(FDG)以及含有C11原子的化合物(例如C-11甲硫氨酸(MET))。
如上文所指明的,探针可以包含在融合蛋白中,所述融合蛋白还包括在探针的N端或C端处偶联的荧光蛋白。荧光蛋白可以经由肽接头偶联,如记载于技术(U.S.6,448,087;Wurth等,J.Mol.Biol.319:1279-1290(2002);及Kim等,J.Biol.Chem.280:35059-35076(2005)中的,本文通过提及而将其完整收录)。在一些实施方案中,合适的接头可以长约约8-12个氨基酸。在别的实施方案中,接头的大于约75%的氨基酸残基选自丝氨酸、甘氨酸、和丙氨酸残基。
可检测标记物还包括寡核苷酸。例如,肽探针可以偶联至寡核苷酸标签,其可以通过本领域中已知的方法(例如扩增测定法诸如PCR、TMA、b-DNA、NASBA等)来检测。
若制剂或标记物是荧光团,则可以使用荧光团的一种或多种特性来评估经标记的偶联物的状态。例如,基于偶联物是结合的还是游离的,荧光团的激发波长可以有所不同。在一些实施方案中,荧光的发射波长、强度、或极化也可以随偶联物的状态而变化。
E.用肽偶联物的体内检测
还提供了用于检测已经穿过BBB并且位于脑中的偶联物的体内检测(包括体内成像)方法。如本文中所使用的,“位于脑中”指已经穿过血脑屏障,并且包括位于脑周围的流体中。
在一个实施方案中,方法包括(a)对受试者施用包含(i)肽检测剂和(ii)芘的偶联物,并(b)检测已经位于受试者的脑中的偶联物。在一些实施方案中,肽检测剂特异性结合位于脑中的蛋白质或结构,由此提供对蛋白质或结构的选择性靶向。在一些实施方案中,偶联物特异性结合位于脑中且与神经病症有关的蛋白质或结构,诸如与阿耳茨海默氏病有关的错折叠的Aβ蛋白或Aβ斑,或与其它神经病症有关的其它蛋白质或结构,如上文所讨论的,由此提供对蛋白质或结构的选择性靶向。
在另一个实施方案中,方法包括(a)对受试者施用包含(i)肽制剂和(ii)芘的偶联物,其中所述偶联物是用可检测标记物标记的,并(b)检测已经位于受试者的脑中的偶联物。在一些实施方案中,偶联物特异性结合位于脑中的蛋白质或结构,诸如与神经病症有关的蛋白质或结构,诸如与阿耳茨海默氏病有关的错折叠的Aβ蛋白或Aβ斑,或与其它神经病症有关的其它蛋白质或结构,如上文所讨论的,由此提供对蛋白质或结构的选择性靶向。
例如,检测剂或标记物可以是荧光团、MRI造影剂、离子发射体(PET)、放射性(闪烁计数器)等。可以通过适合于检测检测剂或标记物的手段,诸如傅里叶变换红外线、紫外线、MRI、PET、闪烁计数器、或荧光、光散射、荧光共振能量转移(FRET)、荧光猝灭、和本领域普通技术人员常规使用的多种层析方法来检测偶联物。
在一些实施方案中,检测步骤包括检测芘激基缔合物形成。激基缔合物是一种加合物,其不必是共价的,而且在已经由光子激发的分子实体与相同的未激发分子实体之间形成。加合物在自然界中是瞬时的,而且一直存在直到它通过发射光子来发荧光。激基缔合物表示两个荧光团的相互作用,所述荧光团在用特定波长的光激发后发射不同波长的光,该光在量级(magnitude)上与由单独起作用的荧光团发射的光也是不同的。有可能通过产生比通常的发射光谱的波长长的波长的新荧光条带认出激基缔合物(或激基缔合物的形成)。激基缔合物可以与荧光共振能量转移区别,因为激发光谱与单体的光谱相同。激基缔合物的形成依赖于荧光团的几何排列,而且受它们之间的距离严重影响。
在一个实施方案中,芘模块存在于肽制剂的每个末端处,并且荧光团之间的激基缔合物形成是可忽略的,只要总体肽构象是α-螺旋或无规卷曲,但是在肽制剂经历结构变化(诸如构象变化)时形成激基缔合物,从而使得芘模块彼此接近。存在于肽上其它位置的芘模块在此背景中也可以是有用的,只要激基缔合物形成是构象依赖性的。此外,激基缔合物形成的量级与存在的蛋白质分析物的量直接相关。例如,在肽制剂是肽探针时,如记载于PCT申请PCT/US2007/016738(WO 2008/013859)和美国专利申请11/828,953中的,肽制剂可以经受构象改变,这导致在其与靶蛋白或结构诸如β-片层构象或自我聚集的特定状态的淀粉样蛋白进行接触或相互作用时的激基缔合物形成。如此,本发明的方法容许通过检测激基缔合物形成来进行脑中靶蛋白或结构的检测和体内成像。
可以通过光学特性的变化来检测激基缔合物的形成。可以通过已知的荧光测定技术(包括UV、IR、CD、NMR、或荧光等,这取决于附着至探针的荧光团)来测量此类变化。光学特性的这些变化的量级与已经采用与该变化有关的结构状态的偶联物的量直接相关,而且与存在的靶蛋白或结构的量直接相关。
本文中所描述的偶联物在其它体内检测方法中也是有用的。例如,可以使用偶联物来在任何其它体内位置,诸如任何器官(包括心脏、肺、肝、肾)或任何组织中检测靶蛋白或结构(诸如自我聚集的特定构象或状态)。感兴趣的特定区域还可以包括血管组织或淋巴组织。本文中所描述的偶联物在活体显微术方法中在检测和成像靶蛋白或结构中也是有用的。
在一些实施方案中,可以在FRET方法中与芘偶联物一起使用包含不同荧光标记物(诸如例如GFP)的偶联物。荧光共振能量转移(FRET)牵涉能量从“供体”荧光团到合适放置的“接受体”荧光团的非辐射转移。可以发生FRET的距离限于1-10nm之间,并且因此使用此技术来证明用供体荧光团和接受体荧光团标记的两种类型的分子是否在彼此10nm内出现。通过共焦成像测量FRET使分子相互作用的细胞内位置能被测定。
可以在供体荧光团的发射光谱与接受体的吸收光谱显著交叠(>30%)时发生FRET。经CFP和YFP标记的融合蛋白的组合已经被广泛用于活细胞中的FRET测量。已经用于FRET的其它供体和接受体荧光团对包括CFP和dsRED、BFP和GFP、GFP或YFP和dsRED、Cy3和Cy5、Alexa488和Alexa555、Alexa488和Cy3、FITC和罗丹明(TRITC)、YFP和TRITC或Cy3。
在一些实施方案中,偶联物包含用如下放置的芘模块和另一荧光团标记的肽,使得FRET可以在肽采用特定构象,诸如β-片层构象时发生,诸如可以在如上文所描述的肽探针与靶蛋白或结构相互作用时发生。对受试者施用所述偶联物容许通过检测FRET信号来检测定位的偶联物。
F.用肽偶联物的疗法
还提供了治疗神经病学病症的方法,包括投递治疗剂穿过BBB。在一个实施方案中,方法包括(a)对受试者施用包含(i)肽治疗剂和(ii)芘的偶联物。在另一个实施方案中,所述偶联物是用可检测标记物标记的,并且方法进一步包括检测已经位于受试者的脑中的偶联物。在一些实施方案中,所述肽治疗剂是抗淀粉样剂。在一些实施方案中,方法包括施用治疗有效量的偶联物。在一些实施方案中,偶联物特异性结合位于脑中的蛋白质或结构,诸如与神经病症有关的蛋白质或结构,诸如与阿耳茨海默氏病有关的错折叠的Aβ蛋白或Aβ斑,或与其它神经病症有关的其它蛋白质或结构,如上文所讨论的,由此提供对蛋白质或结构的选择性靶向。
实施例
下列实施例提供了本发明的进一步例示而非进行限制。
实施例1
以下例示了肽-芘偶联物穿过BBB的能力。可以使用类似的方法来确认根据本文中所描述的方法使用的给定的偶联物的适合性和/或确认与非偶联的制剂相比,偶联物展现出穿过BBB的通透性增强。
以下例示了肽制剂偶联物在体内靶向Aβ斑(例如与阿耳茨海默氏病有关的Aβ蛋白的不溶性自我聚集体)的能力。使用对与Aβ蛋白的残基16-35(SEQID NO:3)对应的Aβ特异性的且在每个末端用芘标记的肽制剂,所述Aβ蛋白的残基16-35(SEQ ID NO:3)具有用于偶联芘的添加的C端赖氨酸残基(例如SEQ ID NO:5)。
SEQ ID NO:3:
Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly
Leu Met
SEQ ID NO:5:
Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly
Leu Met Lys
体内研究使用四只纯合的hAPP751SL转基因10个月龄小鼠和四只同窝出生者对照(不携带转基因的同胞)。以每次施用10μl液体(0.1至2.0mg/ml的浓度)鼻内施用经标记的肽制剂偶联物,施用时间间隔为计划的半小时,其根据处理后动物的状况进行调节。
在处理结束时,处死小鼠,并提取CSF和脑。(通过标准的吸入麻醉、异氟烷、七氟烷来使所有的小鼠镇静)。
通过钝剥离并暴露枕大孔来获得脑脊液。暴露后,将巴斯德移液管以0.3-1mm的近似深度插入枕大孔中。通过抽吸和毛细作用来收集CSF,直至流动完全停止。将CSF立即冷冻,并于-80℃保持,直至使用。
CSF取样后,快速取出胃、胃内容物和脑。将脑切成对半,并将所有小鼠的右半球在新鲜生成的4%低聚甲醛/PBS(pH 7.4)中于室温浸没固定1小时,并转移至15%蔗糖/PBS溶液达24小时以确保防冷冻。此后,在第二天将脑在液体异戊烷中冷冻,并于-80℃贮存,直至用于组织学调查。立即将另一半脑在液体异戊烷中休克冷冻,用于未来使用。
自用最高剂量的肽制剂偶联物处理的转基因小鼠和对照小鼠和转基因媒介物对照(例如用于肽制剂偶联物的稀释剂)记录图像以确认肽制剂偶联物穿过血脑屏障(BBB)(它确实如此)。
为了评估肽制剂偶联物染色的特异性,使用显微镜的UV-2A和B-1E滤光器来激发荧光以检测下部光谱中可探查的自身荧光。在连续切片中记录荧光部分以确保杂质(例如灰尘)不引起荧光。用ThioflavinS对转基因切片染色以评估斑负荷(plaque load)。
如上文所指明的,hAPP751SL转基因小鼠在脑外周的某些血管中表达hAPP。肽制剂偶联物结合脑中血管外部的淀粉状蛋白和团块(agglomerate)。在非转基因小鼠中,肽制剂偶联物达到嗅球,但不结合可指明的形态学结构。
实施例2
以下实施例确认上文所描述的Aβ肽-制剂偶联物在鼻内施用后选择性靶向脑中的Aβ斑的能力。
用媒介物(10%DMSO)、上文所描述的Aβ肽-制剂偶联物、或芘丁酸盐(酯)处理三组的三只hAPP转基因小鼠。小鼠在1小时期间里以20分钟时间间隔接受三次10μl注射。6小时后处死小鼠,并收集组织。使用固定的冷冻组织和装备有UV-2A滤光器的显微镜进行矢状切片中的荧光。使用图像Pro-Plus软件(Media Cybernetics,Inc.,Bethesda,MD)对数字图像进行所有斑计数。
如图1中所看到的,仅用偶联物(“芘-肽偶联物”)处理的小鼠显示Aβ斑的荧光标记,而用媒介物或芘丁酸盐(酯)处理的小鼠不然。仅展示背景水平的荧光的偶联物处理组中的小鼠几乎不含Aβ斑,如通过抗Aβ抗体(6E10抗体)或硫黄素S(其对淀粉样斑特异性的)染色所测定的。图2显示了偶联物荧光(AD185)和硫黄素S染色间的相关性。在海马(数据未显示)和皮层(图2中绘图的)两者中找到正相关,其中r2=0.555和p=0.005。
用6E10抗体或硫黄素S对连续的矢状脑(sequential sagital brain)切片染色,并与来自经偶联物标记的切片的荧光图像合并(co-merge)。这些数据显示了与抗体和硫黄素S斑染色一致的偶联物荧光,这进一步证明偶联物对Aβ斑的特异性。
实施例3
以下实施例确认上文所描述的Aβ肽-制剂偶联物在静脉内施用后选择性靶向脑中的Aβ斑的能力。
经由尾静脉以30mg/kg的剂量对hAPP转基因小鼠静脉内施用上文所描述的Aβ肽-制剂偶联物。施用偶联物后6小时时处死小鼠,并制备脑切片以进行成像,如上文所描述的。在偶联物荧光方面对切片成像后,对其进行荧光漂白,并用硫黄素S染料进行染色。数据揭示了皮层(图3A)和海马(图3B)两者中偶联物荧光(AD185)与硫黄素S染色之间的显著相关性。
本领域技术人员会显而易见的是,可以在不背离本发明的范围或精神的前提下在本发明的实践中进行各种修饰和变型。通过考虑本发明的说明书和实践,本发明的其它实施方案对于本领域技术人员会是显而易见的。意图认为说明书和实施例仅为例示性的,本发明的真正范围和精神由所附权利要求书指明。
Claims (27)
1.一种用于穿过血脑屏障投递肽制剂的方法,包括对受试者施用偶联物,其包含
肽制剂;和
芘。
2.权利要求1的方法,其中所述肽制剂是治疗剂或检测剂。
3.权利要求2的方法,其中所述肽制剂能够鉴定与神经病症有关的靶蛋白。
4.权利要求3的方法,其中所述肽制剂选择性结合与神经病症(neurological condition)有关的蛋白质或结构。
5.权利要求4的方法,其中所述肽制剂包括与所述靶蛋白中经历从α-螺旋构象向β-片层构象的构象变化的区域对应的氨基酸序列,但是不包括所述靶蛋白的全长序列。
6.权利要求5的方法,其中所述检测剂包含SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5或SEQ ID NO:6。
7.权利要求4的方法,其中所述肽制剂是对与神经病症有关的蛋白质或结构特异性的抗体。
8.权利要求2的方法,其中所述肽制剂是可用于治疗神经病症的治疗剂。
9.权利要求1的方法,其中所述偶联物进一步包含可检测标记物。
10.权利要求1的方法,其中所述芘是芘的衍生物。
11.权利要求9的方法,其中所述芘的衍生物选自下组:烷基芘、氨基芘、芘羧酸盐(酯)(pyrene carboxylate)、芘丁酸盐(酯)、清蛋白-芘、PEG化的芘、包含游离羧基的芘衍生物和包含游离氨基的芘衍生物。
12.权利要求1的方法,其中所述偶联物包含两个或更多个芘模块。
13.权利要求1的方法,其中与所述肽相比,偶联物展现出穿过所述血脑屏障的通透性增强。
14.一种体内检测方法,包括
(a)对受试者施用包含(i)肽检测剂和(ii)芘的偶联物,并
(b)检测位于所述受试者的脑中的偶联物。
15.权利要求14的方法,其中所述偶联物包含两个或更多个芘模块。
16.权利要求14的方法,其中所述肽检测剂在选自如下的位置与芘偶联:所述肽检测剂的C端和N端的至少一处。
17.权利要求16的方法,其中所述肽检测剂在所述肽检测剂的C端和N端的每处与芘模块偶联。
18.权利要求17的方法,其中步骤(b)包括检测芘激基缔合物形成。
19.权利要求15的方法,其中至少一种芘模块是包含游离羧基的芘衍生物,而至少一种芘模块是包含游离氨基的芘衍生物。
20.权利要求14的方法,其中所述肽检测剂能够鉴定与神经病症有关的蛋白质或结构。
21.权利要求14的方法,其中肽检测剂能够鉴定处于自我聚集的特定构象或状态的蛋白质。
22.权利要求14的方法,其中所述检测剂包含SEQ ID NO:2、SEQ IDNO:3、SEQ ID NO:4、SEQ ID NO:5或SEQ ID NO:6。
23.权利要求14的方法,其中所述偶联物进一步包含可检测标记物。
24.权利要求23的方法,其中所述标记物选自下组:荧光团、MRI造影剂、离子发射体、和放射性标记物。
25.一种治疗神经病症的方法,包括对有所需要的受试者施用治疗有效量的偶联物,其包含(i)肽治疗剂和(ii)芘。
26.权利要求25的方法,其中所述肽治疗剂可用于治疗神经病症。
27.权利要求25的方法,其中所述肽治疗剂是抗淀粉样剂。
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- 2009-01-30 CN CN2009801166660A patent/CN102014967A/zh active Pending
Cited By (2)
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CN110759974A (zh) * | 2018-07-25 | 2020-02-07 | 中国医学科学院药物研究所 | 一种磷脂-聚乙二醇-狂犬病毒衍生肽聚合物,其制备方法及应用 |
CN110759974B (zh) * | 2018-07-25 | 2021-11-09 | 中国医学科学院药物研究所 | 一种磷脂-聚乙二醇-狂犬病毒衍生肽聚合物,其制备方法及应用 |
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CA2718860A1 (en) | 2009-09-24 |
JP2011517666A (ja) | 2011-06-16 |
EP2268314A2 (en) | 2011-01-05 |
US20090238754A1 (en) | 2009-09-24 |
WO2009117041A3 (en) | 2010-01-07 |
MX2010010266A (es) | 2010-12-14 |
AU2009226161A1 (en) | 2009-09-24 |
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