CN116916971A - 用于外科操作中输尿管可视化的方法和组合物 - Google Patents
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Abstract
用于在外科操作期间对输尿管进行可视化,包括输尿管以及其他靶组织的荧光可视化的方法,其包括向对象施用包含肽和荧光部分的荧光缀合物。
Description
关于序列表的声明
与本申请相关的序列表以文本格式代替纸质副本提供,并在此通过引用并入本说明书中。包含序列表的文本文件的名称为110267_405WO_SEQUENCE_LISTING.txt。该文本文件为142KB,创建于2022年1月13日,并经由EFS-Web以电子方式提交。
领域
本发明一般涉及手术中的成像方法,并且更特别地涉及外科操作期间输尿管以及神经的荧光可视化。
背景
输尿管包含一对多层肌肉管–平均每个成年人的输尿管长约10至12英寸–其将尿液从肾脏输送到膀胱。输送依赖于蠕动运动,其由起搏器引发的输尿管壁的肌肉层收缩引起。当壁有节奏地收紧和放松时,尿液以脉动的运动通过输尿管流向膀胱。
因为输尿管从腹部延伸到骨盆,所以它们紧密靠近腹盆腔中的许多结构,诸如性腺和子宫血管、髂动脉、肠系膜下血管和乙状结肠血管,以及宫颈、结肠和直肠。此外,输尿管是薄壁管,其通常处于塌缩状态,且难以与周围组织区分。考虑到输尿管的位置和物理特性,在许多手术(包括妇科、泌尿科、结直肠和心血管外科操作)中,输尿管都有很大的损伤风险。参见例如,Engelsgjerd和LaGrange,2020,StatPearls,Treasure Island(FL):StatPearls Publishing;2020年7月10日;Ferrara和Kann,2019,Clin.Colon RectalSurg.32,196-203;Ahn等人,2019,Quant.Imaging Med.Surg.9,1056-1065;Gild等人,2018,Asian J.Urol.5,101-106。实际上,输尿管损伤在手术中往往没有被注意到,导致诊断延迟和治疗延误,在一些情况下,这可能导致长期并发症,如肾脏衰竭。Tan-Kim等人,2015,J.Minimally Invasive Gynecol.22,1278-1286;Al-Awadi等人,2005,Int.Urol.Nephrol.37,235-241。
因此,输尿管损伤会显著影响患者的发病率和伴随的医疗保健费用。在美国,每年进行约60万次子宫切除术和30万次结肠手术,输尿管损伤率分别高达2.5%和7.6%。参见Gild等人,2018,Asian J.Urol.5,101-106;Doll等人,2016,JAMA Surg.151,876-877;Teeluckdharry等人,2015,Obstet.Gynecol.126,1161-1169;Briggs和Goldberg,2011,Clin.Rectal.Rectal Surg.30,130-135。在下腹部外科操作中,医源性输尿管损伤(IUI)的发生率估计范围对于癌症手术为0.5%–1%,对于腹腔镜妇科手术为0.3%-2.5%,并且对于妇科肿瘤手术高达10%。参见例如,de Valk等人,2019,Nat.Commun.16,3118;Anderson等人,2015,Surg.Endosc.29,1406-1412;Engel等人,2015,Curr.Opin.Urol.25,331-335;Minas等人,2014,Obstet.Gynecol.16,19-28;Zafar等人,2014,JSLS.18,e2014.00158;Silva等人,2012,Asian J.Endosc.Surg.5,1050110;Delacroix和Winters,2010,Clin.Rectal Rectal Surg.23,104-112。仅在美国,输尿管损伤的总体经济影响就超过10亿美元,显示平均住院时间为4天,且每次损伤的费用超过30,000美元。
已经探索了几种方法来帮助降低手术期间输尿管损伤的风险。这些包括泌尿科操作(如将支架或照射导管插入输尿管中),但这些可能会扰乱手术流程,并引入不必要的延误,例如通过需要在手术中咨询泌尿科医生或其他专家。参见例如,Wood等人,1996,J.Am.Assoc.Gynecol.Laparosc,3,393-397;Chahin等人,2002,JSLS 6,49-52。其他方法包括施用或注射放射性染料或荧光团(或某些缀合物),以对输尿管进行可视化。然而,这种注射操作可能会带来额外的风险和复杂性,并且一些试剂可能具有有限的灵敏度、强度和作用时间。参见例如,Ikeda等人,2017,Am.J.Physiol.Renal Physiol.312,F629-F639;Al-Taher等人,2016,J.Laparoendosc.Adv.Surg.Tech.A.26,870-875;Verbeek等人,2014,Ann.Surg.Oncol.21,S528-S537;Hyun等人,2012,Contrast Media Mol.Imaging 7,516-524;Choi等人,2011,Angew Chem.Int.Ed.Engl.50,6258-6263;Tanaka,等人,2007,J.Urol.178,2197-2201;Cadeddu等人,2001,J.Endourology15,111-116。
本领域仍然需要鉴定具有所期望性质的组合物,其包括在外科操作期间对输尿管的可视化。本发明通过提供肽组合物,特别是荧光肽缀合物,满足了本领域的这些和其他需求,其允许施用后灵敏且延长的输尿管可视化,并且还可以支持神经可视化,包括同时进行的神经和输尿管可视化。
概述
本文公开了对输尿管进行可视化的方法,其包括用于外科操作期间输尿管的荧光可视化的方法。
在一方面,本公开涉及对对象的输尿管进行可视化的方法,所述方法包括:(a)向对象施用有效量的荧光缀合物,其中所述荧光缀合物包含肽和荧光部分,以及(b)检测施用后所述输尿管中荧光部分的荧光。在实施方案中,所述对象正经受外科操作。
在另一方面,本公开涉及方法,其包括:(a)向正经受外科操作的对象施用有效量的荧光缀合物,其中所述荧光缀合物包含肽和荧光部分;以及(b)通过检测输尿管中荧光部分的荧光,对所述对象中输尿管进行可视化。
在另一方面,本公开涉及减少输尿管损伤的方法,所述方法包括:(a)在外科操作前鉴定处于输尿管损伤风险中的对象;(b)向正经受外科操作的对象施用有效量的荧光缀合物,其中所述荧光缀合物包含肽和荧光部分;以及(c)通过检测所述输尿管中所述荧光部分的荧光,使所述输尿管可视化。在实施方案中,所述输尿管损伤由结扎、成角、横断、撕裂、挤压、局部缺血或切除术引起。
在所述方法的实施方案中,所述肽可以是神经靶向性肽。在任何方法中,所述肽可以由本文所公开的氨基酸序列中的任一种组成或包含本文所公开的氨基酸序列中的任一种,其包括第PCT/US2018/045054号国际专利申请和第PCT/US21/61821号国际专利申请中所列举的那些。在实施方案中,所述荧光缀合物的肽包含选自以下的氨基酸序列:SEQ IDNO:1-14、16、18-82和84-748。
在任何方法的实施方案中,所述荧光部分可直接或经由连接子间接与所述肽的N-末端、C-末端或N-末端和C-末端两者缀合。在任何方法的实施方案中,如本文公开的,所述荧光部分选自荧光蛋白、荧光肽、荧光染料或以上的组合。
在实施方案中,任何方法还可以包括在施用后的以下时间段内检测所述荧光部分的荧光:至少1小时、至少2小时、至少3小时、至少4小时、至少5小时、至少6小时、至少7小时或至少8小时。在实施方案中,所述方法还可以包括在施用后检测所述荧光部分的荧光多于1小时、多于2小时、多于3小时、多于4小时、多于5小时、多于6小时、多于7小时或多于8小时的时间段。
在实施方案中,任何方法中的所述荧光缀合物在最初施用后不再向所述对象施用。在任何方法中,检测所述输尿管中所述荧光部分的荧光可以包括检测输尿管中的尿流,并且更特别地,检测输尿管中的蠕动尿流。在任何方法中,所述荧光缀合物可以经静脉内施用。在任何方法中,所述荧光缀合物可以经口施用。在任何方法中,所述荧光缀合物可以在外科操作前施用于对象。
在实施方案中,任何方法中的所述外科操作可以包括妇科、泌尿科、结直肠或心血管外科操作;可以涉及腹部或骨盆;可以对肾脏、膀胱、前列腺、子宫、男性或女性生殖系统、直肠、结肠、小肠或大肠进行;可以为开放式外科操作、腹腔镜外科操作、显微镜操作或内窥镜操作;或者可以为癌症外科操作,并且更特别地为前列腺癌外科操作或结直肠癌操作。
在实施方案中,如本文公开的,任何方法中的所述荧光缀合物包含选自以下的荧光部分:荧光蛋白、荧光肽、荧光染料或以上的组合。
在实施方案中,任何方法包括施用药物组合物中的所述荧光缀合物,所述药物组合物可以包含药学上可接受的赋形剂。
在实施方案中,所述荧光缀合物可允许对象中的神经可视化,以及伴随的(或同时的)神经和输尿管可视化。在实施方案中,所述荧光缀合物可赋予外科操作期间的不同时间对象的神经可视化和输尿管可视化。
附图简述
图1:静脉内施用约2000纳摩尔荧光缀合物(SEQ ID NO:747)后活体野生型小鼠中输尿管的明场和荧光叠加图像。使用定制的荧光检测显微镜在施用后2小时获得图像。左图:白色反射图像。右图:荧光叠加。
详述
本文公开了通过施用包含肽和荧光部分的荧光缀合物(本文中也被称为“缀合物”)进行输尿管可视化的方法,并且更特别地,进行输尿管的荧光可视化的方法。已经发现,某些荧光缀合物(包括包含神经靶向性肽的那些的)代谢和消除支持输尿管中从肾脏通至膀胱期间对荧光的灵敏且延长的检测。有利地,本文中荧光缀合物的使用允许在施用后进行输尿管的早期和后期检测。这些特性强调了此类缀合物的广泛效用,赋予了施用后的较短时间段以及较长时间段内输尿管的可视化。
因此,在实施方案中,方法包括通过检测输尿管的尿流,并且更特别地蠕动输尿管的尿流中的荧光部分,对对象中的输尿管进行可视化。可以经静脉内施用荧光缀合物,并且可以在外科操作前施用于对象。
在实施方案中,荧光缀合物中的肽包含神经靶向性肽,并且更特别地,包含第PCT/US2018/045054号国际专利申请或第PCT/US21/61821号国际专利申请中所公开的神经靶向性肽,二者均整体并入本文中。因此,在实施方案中,本文所公开的荧光缀合物可允许同时检测输尿管和神经。
在实施方案中,荧光缀合物中的肽包含如第WO2019028281A2号国际专利申请中所公开的氨基酸序列QVPWEEPYYVVKKSSGG(具有GG连接子的HNP401-N-2;SEQ ID NO:21)。在实施方案中,荧光缀合物是5FAM-QVPWEEPYYVVKKSSGG-NH2(具有GG连接子的HNP401-N-2;SEQID NO:747)。
通过参考以下描述(包括实例)可以更充分地理解本发明。除非另有定义,否则本文中所使用的所有技术和科学术语具有与本领域普通技术人员通常理解的含义相同的含义。尽管在本发明的实践或测试中可以使用与本文中所描述的方法和材料相似或等效的方法和材料,但本文中描述了合适的方法和材料。另外,材料、方法和实例仅为说明性的,且并非旨在为限制性的。
为了简洁起见,本申请中所引用的所有文件或文件的部分,包括但不限于专利、专利申请、文章、书籍、手册和论文,在此均通过引用整体明确地并入本文中,以用于所有目的。然而,对任何此类出版物的引用不应被解释为承认其为本发明的现有技术。
本说明书各节中标题和副标题的使用仅为组织目的和参考方便,并且不得解释为限制所述主题,其应通过参考说明书作为整体来理解。例如,本领域技术人员将理解根据本文所描述的本发明的精神和范围,适当地组合来自不同标题和章节的各个方面的有用性。
如在阅读本文档后对于本领域普通技术人员将变得显而易见的,所示实施方案及其各种替代方案可以在不局限于所示实例的情况下实现。
I.定义
如本文所用的,术语“一个/种(a/an)”是指“一个/种或多个/种”列举的组分。可替代选择(例如,“或”)的使用应理解为意指可替代选择中的一个、两个或其任意组合。此外,应该理解的是,来源于本文所述结构和取代基的各种组合的单独化合物或化合物组被本申请公开,其程度与就像每种化合物或化合物组被单独阐述相同。因此,特定结构或特定取代基的选择在本公开的范围内。
如本文所用的,术语“约”或“近似”意指包括指定值在内的一系列值,本领域普通技术人员会认为该范围与指定值合理相似。在实施方案中,“约”意指在使用本领域通常可接受的测量值的标准偏差内。在实施方案中,“约”意指扩展到指定值的+/-10%的范围。在实施方案中,“约”意指指定的值。
应理解的是,无论是否明确使用术语“约”,本文所给出的每个量都意指实际给定值和基于本领域普通技术可以合理推断的此类给定值的近似值,包括由于此类给定值的实验和/或测量条件而产生的等效值和近似值。因此,对于其中数值前面为“约”或“近似”的本公开的任何实施方案,本公开包括其中叙述确切值的实施方案。相反,对于其中数值前面不为“约”或“近似”的本公开的任何实施方案,本公开包括其中数值前面为“约”或“近似”开头的实施方案。
术语“包含”和“包括”在本文中以其开放的、非限制性的含义使用。除非另有明确说明,否则本文件中所使用的其他术语和短语及其变型应被解释为开放式的,而不是限制性的。作为上述的实例:术语“实例”被用于提供所讨论项目的示例性例子,而不是其详尽或限制性列表。诸如“常规的”、“正常的”、“已知的”等形容词和具有类似含义的术语不应被解释为将所描述的项目限制在给定的时间段或给定时间的可用项目,而应被理解为包括现在或未来任何时候可能可用或已知的常规或正常技术。同样,在本文件涉及对于本领域普通技术人员将显而易见或已知的技术的情况下,此类技术包括对于技术人员现在或未来任何时间显而易见的或已知的那些技术。
如本文所用的,除非另有说明,否则以下术语具有其所赋予的含义。
术语“多肽”、“肽”和“蛋白质”在本文中可互换地用于指氨基酸残基的聚合物。这些术语适用于天然存在的氨基酸聚合物,以及其中一个或多个氨基酸残基是非天然存在的氨基酸(例如氨基酸类似物)的氨基酸聚合物。这些术语包括任何长度的氨基酸链,包括全长蛋白质(即神经靶向性分子),其中氨基酸残基通过共价肽键连接。如本文所用的,术语“肽”是指长度范围通常为2至约50个残基的氨基酸残基的聚合物。在某些实施方案中,肽的长度范围为约2、3、4、5、7、9、10或11个残基至约50、45、40、45、30、25、20或15个残基。在某些实施方案中,肽的长度范围为约8、9、10、11或12个残基至约15、20或25个残基。在本文提供氨基酸序列的情况下,还考虑了序列的L、D或β氨基酸形式,以及反向(retro)、反转(inversion)和反向-反转异构体。肽还包括其中一个或多个氨基酸残基是相应天然存在的氨基酸的人工化学类似物的氨基酸聚合物,以及天然存在的氨基聚合物。此外,该术语适用于通过肽键合或通过其他修饰的键合连接的氨基酸(例如,其中肽键被α-酯、a/3-酯、硫代酰胺、膦酰胺、氨基甲酸酯、羟基化物等取代(参见例如,Spatola 1983,Chem.Biochem.Amino Acids and Proteins 7:267-357),其中酰胺被饱和胺取代(参见例如,Skiles等人,第4,496,542号美国专利,其通过引用并入本文中,以及Kaltenbronn等人,1990,第969-970页,Proc.1lth American Peptide Symposium,ESCOM SciencePublishers,荷兰等))。
因此,术语“氨基酸”是指天然存在的和合成的氨基酸,以及以类似于天然存在的氨基酸的方式发挥作用的氨基酸类似物和氨基酸模拟物。天然存在的氨基酸是由遗传密码编码的那些氨基酸,以及后来被修饰的那些氨基酸,例如羟脯氨酸、γ-羧基谷氨酸和O-磷酸丝氨酸。氨基酸可以是L-氨基酸或D-氨基酸。氨基酸类似物是指与天然存在的氨基酸具有相同基本化学结构(即与氢、羧基、氨基和R基团结合的碳)的化合物,例如高丝氨酸、正亮氨酸、甲硫氨酸亚砜。此类类似物具有修饰的R基团(例如,正亮氨酸)或修饰的肽主链,但保留与天然存在的氨基酸相同的基本化学结构。氨基酸模拟物是指具有与氨基酸的一般化学结构不同的结构,但以类似于天然存在的氨基酸的方式发挥作用的化合物。
氨基酸在本文中可以通过其通常已知的三字母符号或通过IUP AC-IUB生物化学命名委员会(the IUP AC-IUB Biochemical Nomenclature Commission)推荐的单字母符号来指代。同样,核苷酸也可以通过它们通常接受的单字母代码来指代。
本领域技术人员将认识到,改变、添加或删除编码序列中单个氨基酸或小百分比氨基酸的肽、多肽或蛋白质序列的单个取代、缺失或添加是“保守修饰的变体”,其中该改变导致氨基酸被化学相似的氨基酸取代。提供功能相似氨基酸的保守取代表在本领域是众所周知的。此类保守修饰的变体是多态变体、种间同源物和等位基因的补充,并且不排除多态变体、种间同源物和等位基因。
以下8个组各自包含彼此的保守性取代的氨基酸:1)丙氨酸(A)、甘氨酸(G);2)天冬氨酸(D)、谷氨酸(E);3)天冬酰胺(N)、谷氨酰胺(Q);4)精氨酸(R)、赖氨酸(K);5)异亮氨酸(I)、亮氨酸(L)、蛋氨酸(M)、缬氨酸(V);6)苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W);7)丝氨酸(S)、苏氨酸(T);和8)半胱氨酸(C)、蛋氨酸(M)(参见例如,Creighton,Proteins(1984))。
如本文所使用的“序列同一性”(或“同一性”)是指在比对序列并引入缺口(如有必要)以实现最大序列同一性百分比,并且不考虑任何保守性取代作为序列同一性的一部分之后,单个给定序列中与另一参考多肽序列中的氨基酸残基相同的氨基酸残基的百分比。如本文所用的“序列同源性”(或“同源性”)是指在比对序列并引入缺口(如有必要)以实现最大序列同源性百分比之后,单个给定序列中与另一参考多肽序列中的氨基酸残基相同或具有相似化学性质的氨基酸残基的百分比。因此,与序列同一性相反,序列同源性将任何保守取代(如本文所述的)视为序列比对的一部分。序列同一性或序列同源性可以使用众所周知的方法来确定,包括公开可用的计算机程序,如由Altschul等人,1997,Nucl.AcidsRes.25,3389-3402定义的NCBI BLAST 2.0软件。这些程序任选地使用默认的缺口权重优化比对序列,以便在给定序列和参考序列之间产生最高水平的序列同一性或序列同源性。
如本文所用的,术语“标记”是指促进本文所公开的靶向分子的可视化和/或检测的分子。在实施方案中,标记是荧光部分。
术语“个体”、“患者”或“对象”可互换使用。如本文所用的,它们意指任何哺乳动物(即分类学分类动物界:脊索动物门:脊椎动物亚门:哺乳动物纲内的任何目、科和属的物种)。在实施方案中,哺乳动物是牛、马、绵羊、猪、猫、狗、山羊、小鼠、大鼠、兔、豚鼠、非人灵长类动物或人。在实施方案中,哺乳动物是人类对象,并且更特别地,正在经受外科操作的人类对象。这些术语都不要求或仅限于以医疗保健工作者(例如医生、注册护士、护士从业人员、医生助理、护理员或临终关怀工作者)的监督(例如持续或间歇性的)为特征的情况。
本文中使用的术语“施用(administer/administering/administration)”等是指可用于实现将试剂或组合物递送至所期望生物作用部位的方法。这些方法包括但不限于肠胃外注射(例如,静脉内、皮下、腹膜内、肌内、血管内、鞘内、玻璃体内、输注或局部)。任选地与本文所述的试剂和方法一起采用的施用技术包括例如以下中所讨论的那些:Gennaro:Remington:The Science and Practice of Pharmacy,第21版(Lippincott Williams&Wilkins,2005)和Goodman&Gilman's The Pharmacological Basis of Therapeutics(McGraw-Hill Professional,2005)。在实施方案中,施用是经由全身静脉注射到人类患者中。
术语“有效量”可与“治疗有效量”互换,并且意指足以达到所述目的的量,例如,达到施用的效果,诸如允许在手术中(在手术过程、外科操作、外科方法或操作期间)对输尿管进行荧光可视化。“有效量”的实例是足以有助于治疗、预防或减少由手术或医疗操作引起的不良事件(诸如腹部外科操作期间的医源性输尿管损伤(IUI))的量。所期望的效果可以但不一定通过施用一剂剂量而发生。它也可能发生在一系列剂量的施用之后。因此,可以在一次或多次施用中施用有效量。组合物的治疗有效量的确定在技术人员的能力范围内,特别是根据本文的详细公开内容。例如,可以配制用于人类的剂量,以达到已发现在动物中有效的浓度。可以通过监测本文所公开的试剂或组合物的有效性并向上或向下调节剂量来调节人类中的剂量。基于本文所述的方法和其他方法来调节剂量以在人类中实现最大功效完全在普通技术人员的能力范围内。
本文所用的术语“药学上可接受的”是指不会消除本文所述的试剂和组合物的生物活性或性质,并且相对无毒(即,该物质的毒性显著大于该物质的益处)的物质。在一些情况下,可将药学上可接受的物质施用于个体,而不会引起显著的不期望的生物效应或以有害的方式与含有该物质的组合物的任何组分显著相互作用。
如本文中使用的术语“手术”是指可用于通过物理干预来操纵、改变或引起效果的任何方法或操作。手术方法和操作包括但不限于开放式手术、显微镜手术、内窥镜手术、腹腔镜手术、微创手术、机器人手术。在一些情况下,手术的对象是人类对象或人类患者。外科操作可以包括妇科、泌尿科、结直肠或心血管外科操作。外科操作还可以包括但不限于腹部或骨盆操作。在某些情况下,对肾脏、膀胱、前列腺、子宫、男性或女性生殖系统、直肠、结肠、小肠或大肠进行外科操作。外科操作可以是癌症外科操作,包括例如前列腺癌外科操作或结直肠操作。外科操作还可以包括呈现出输尿管损伤风险的操作,并且在一些情况下,可能也会影响神经,因为本文所述的组合物和方法可以支持手术中神经可视化,包括手术期间对象中同时的神经和输尿管可视化。
II.方法
本公开提供了可视化输尿管的方法,特别是在手术期间,使用荧光缀合物可视化输尿管的方法,所述荧光缀合物包含连接到荧光部分的肽,即标记的肽。在实施方案中,肽包含神经靶向性肽。在实施方案中,本文所述的荧光缀合物(及其组合物)可用作此类方法中的外科辅助物,以降低外科操作期间输尿管损伤,且特别是医源性输尿管损伤(IUI)的可能性。
如本文进一步描述的,已经观察到神经靶向性荧光缀合物可以在通过输尿管期间允许显著和扩展的荧光的条件下通过肾脏排泄清除。因此,可以通过检测通过输尿管的尿流,且更特别地通过输尿管蠕动尿流中的荧光部分来实现输尿管可视化。输尿管可视化可以持续延长的时间段,在施用某些荧光缀合物后持续数小时或更长时间。
因此,在实施方案中,本公开提供了使用本文所述的任何分子和组合物对对象的输尿管进行可视化的方法。在实施方案中,对象正在经受操作,如诊断操作、医疗操作或外科操作。
在一方面,方法包括:(a)向对象施用有效量的荧光缀合物,其中所述荧光缀合物包含肽和荧光部分;以及(b)检测施用后对象输尿管中的荧光部分的荧光。
在另一方面,方法包括:(a)向正经受外科操作的对象施用有效量的荧光缀合物,其中所述荧光缀合物包含肽和荧光部分;以及(b)通过检测输尿管中荧光部分的荧光,对对象中的输尿管进行可视化。
在另一方面,方法包括:(a)在外科操作之前鉴定处于输尿管损伤中的对象;(b)向进行外科操作的对象施用有效量的荧光缀合物,其中所述荧光缀合物包含肽和荧光部分;以及(c)通过检测输尿管中的荧光部分的荧光对输尿管进行可视化。如本文所用的,处于输尿管损伤风险中的对象包括需要本文所述的诊断、医疗或外科操作的对象。
在实施方案中,最初在外科操作之前施用荧光缀合物。在实施方案中,在最初施用后未施用荧光缀合物。在实施方案中,在外科操作其间施用荧光缀合物。在实施方案中,在外科操作之前和期间施用荧光缀合物。
在实施方案中,外科操作包括妇科、泌尿科、结直肠或心血管外科操作。在实施方案中,外科操作包括腹部或骨盆操作。在实施方案中,对肾脏、膀胱、前列腺、子宫、男性或女性生殖系统、直肠、结肠、小肠或大肠进行外科操作。在实施方案中,外科操作为开放式外科操作、腹腔镜外科操作、显微镜操作或内窥镜操作。在实施方案中,外科操作为癌症外科操作,并且更特别地为前列腺癌外科操作。
在这些方法中任一种的实施方案中,如本文所述的,向对象施用荧光缀合物,所述对象包括人类和哺乳动物(例如,小鼠、大鼠、猪、猫、狗和马)。在实施方案中,对象是哺乳动物。在实施方案中,对象是灵长类动物。在实施方案中,对象是人类。在实施方案中,人类对象是儿科对象(21岁及以下)、成人对象(22岁至65岁)或老年对象(65岁及以上)。
可以通过本文进一步描述的任何途径施用荧光缀合物。在实施方案中,经静脉内施用荧光缀合物。在实施方案中,经口施用荧光缀合物。在实施方案中,通过任何途径施用的荧光缀合物可以作为药物组合物施用,如本文所述,所述药物组合物可以包括药学上可接受的赋形剂。
可以通过本领域已知的任何合适的方法检测输尿管中荧光缀合物的荧光部分。例如,可以通过用适当波长的光激发手术场中的荧光团,并使用滤光片、透镜和相机的组合检测产生的荧光(和手术场)来检测荧光部分。
在方法的实施方案中,通过适用于荧光引导手术(FGS)的医疗装置检测输尿管中的荧光部分。此类适配的装置可以包括但不限于在开放式手术中使用的手持或安装的装置;微创装置,如用于腹部和骨盆操作的腹腔镜和内窥镜;前列腺手术中使用的机器人手术系统;以及其他装置,如手术放大镜。装置可以提供来自明场照射和荧光发射的实时同步信息。可以使用一个或多个光源来激发和照射样品或手术场。可以使用根据荧光部分的发射光谱定制的光学滤光片、成像透镜和数码相机(如CCD和CMOS检测器系统)来收集光以产生最终图像。还可以进行实时视频处理以增强荧光检测期间的对比度并提高荧光信号的灵敏度。
在方法的实施方案中,在施用后的以下时间段内检测输尿管中的荧光部分的荧光:至少1小时、至少2小时、至少3小时、至少4小时、至少5小时、至少6小时、至少7小时或至少8小时。
在方法的实施方案中,在施用后检测输尿管中荧光部分的荧光多于1小时、多于2小时、多于3小时、多于4小时、多于5小时、多于6小时、多于7小时或多于8小时的时间段。
在方法的实施方案中,在施用后30分钟后、1小时后、2小时后、3小时后、4小时后、5小时后、6小时后、7小时后或多于8小时后检测输尿管中荧光部分的荧光。
在方法的实施方案中,荧光缀合物可允许同时的神经检测,以及输尿管可视化,包括手术中神经和输尿管可视化。此类神经可以包括人类神经,诸如例如‘054申请中所公开的,如运动神经、感觉神经、交感神经和副交感神经、外周神经和自主神经。
更通常地,本文所述的方法、缀合物和组合物也可以包括开放式外科操作、腹腔镜外科操作、显微镜操作和内窥镜操作。
此外,本文所述的方法、缀合物和组合物也可以被用于外科操作中,其中神经以及输尿管的可视化是可取的。
III.荧光缀合物
用于本方法中的荧光缀合物包括与荧光部分连接的肽(或在其他情况下包含荧光标记的肽),并且更特别地,神经靶向性肽。
肽
在实施方案中,神经靶向性肽是任何肽,其包括任何缺失或连接子变体,如第PCT/US2018/045054号国际专利申请(“‘054申请”,作为WO2019028281A2公开)中所公开的,其整体并入本文中)。因此,此类肽包含表1中列出的以下氨基酸序列(肽序列)(SEQ ID NO:1-17、20-28和96-102)中的任一种或由其组成:
表1
在实施方案中,肽包含SEQ ID NO:1-14、16、20-28和96-102中的任一种或由其组成。
另外,肽可以包含‘054申请中所描述的氨基酸序列的任何变体或由其组成。此类变体可以包括但不限于肽,其包含与表1中(或在其他情况下如‘054申请中所公开)的氨基酸序列共有75%-99%同一性或75%-99%同源性的氨基酸序列或由其组成。
在实施方案中,肽包含与SEQ ID NO:1-14、16、20-28和96-102中的任一种具有至少75%同一性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:1-14、16、20-28和96-102中的任一种具有至少80%同一性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:1-14、16、20-28和96-102中的任一种具有至少85%同一性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:1-14、16、20-28和96-102中的任一种具有至少90%同一性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:1-14、16、20-28和96-102中的任一种具有至少95%同一性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:1-14、16、20-28和96-102中的任一种具有至少97%同一性的氨基酸序列或由其组成。
在实施方案中,肽由与SEQ ID NO:1-14、16、20-28和96-102中的任一种共有至少80%同源性的肽序列组成或包含与SEQ ID NO:1-14、16、20-28和96-102中的任一种共有至少80%同源性的肽序列。在实施方案中,肽由与SEQ ID NO:1-14、16、20-28和96-102中的任一种共有至少80%同源性的肽序列组成或包含与SEQ ID NO:1-14、16、20-28和96-102中的任一种共有至少80%同源性的肽序列。在实施方案中,肽包含与SEQ ID NOS:1-14、16、20-28和96-102中的任一种共有至少85%同源性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:1-14、16、20-28和96-102中的任一种共有至少90%同源性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:1-14、16、20-28和96-102中的任一种共有至少95%同源性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:1-14、16、20-28和96-102中的任一种共有至少99%同源性的氨基酸序列或由其组成。
在实施方案中,肽包含含有核心结合结构域PYYVVKK(SEQ ID NO:40)和QVPWEE(SEQ ID NO:41)的N-末端序列的约13个至约25个氨基酸的氨基酸序列或由其组成。
在实施方案中,肽包含PYY或PYYVV(SEQ ID NO:83)的氨基酸核心结合结构域和QVPWEE(SEQ ID NO:41)的N-末端序列。在实施方案中,肽包含PYY的氨基酸核心结合结构域和QVPWEE(SEQ ID NO:41)的N-末端序列。在实施方案中,肽包含PYYVV(SEQ ID NO:83)的氨基酸核心结合结构域和QVPWEE(SEQ ID NO:41)的N-末端序列。
在实施方案中,肽包含QVPWEEPYYVVKKSSGG(HNP401-N-2,具有GG连接子;SEQ IDNO:21)或由其组成。
在实施方案中,肽包含选自以下的氨基酸序列或由其组成:SGQVPWEEPYYVVKKSS(HNP401;SEQ ID NO:1)、WEYHYVDLNWTSQHPQ(HNP402;SEQ ID NO:2)和DLPDIIWDFNWETA(HNP403;SEQ ID NO:3)。
在实施方案中,肽包含选自以下的氨基酸序列或由其组成:SGQVPWEEPYYVVKKSS(HNP401;SEQ ID NO:1)、Ac-QVPWEEPYYVVKKSSGGC(HNP401-N-2,具有GGC连接子;SEQ IDNO:7)、Ac-SGQVPWEEPYYVVKKGGC(HNP401-C-2,具有GGC连接子;SEQ ID NO:11)、QVPWEEPYYVVKKSS(HNP401-N-2;SEQ ID NO:20)、QVPWEEPYYVVKKSSGG(HNP401-N-2,具有GG连接子;SEQ ID NO:21)和SGQVPWEEPYYVVKK(HNP401-C-2;SEQ ID NO:25)和SGQVPWEEPYYVVKKGG(HNP401-C-2,具有GG连接子;SEQ ID NO:99)。
在实施方案中,肽包含SEQ ID NO:1、4、7-14、20-28和96-102中任一种的氨基序列或由其组成。
在实施方案中,肽包含SEQ ID NO:1、20和22-24中任一种的氨基序列或由其组成。
在实施方案中,肽包含SEQ ID NO:1和25-28中任一种的氨基序列或由其组成。
在实施方案中,肽包含SEQ ID NO:4和7-10中任一种的氨基序列或由其组成。
在实施方案中,肽包含SEQ ID NO:4和11-14中任一种的氨基序列或由其组成。
在实施方案中,肽包含SEQ ID NO:21和100-102中任一种的氨基序列或由其组成。
在实施方案中,肽包含SEQ ID NO:96-99中任一种的氨基序列或由其组成。
在实施方案中,肽是第PCT/US21/61821号PCT申请(“‘821申请”)中所公开的神经靶向性肽,其整体并入本文中。在一些实施方案中,这些肽来源于基于与四种不同的神经靶蛋白之一的选择性结合的噬菌体展示文库筛选:人髓磷脂蛋白零(Human Myelin ProteinZero,MPZ)、髓磷脂碱性蛋白、髓磷脂蛋白脂质蛋白(髓磷脂PLP)和巢蛋白-2。此类肽包含表2中列出的氨基酸序列(SEQ ID NO:18、19、29-82、84-95和103-471)中的任一种或由其组成。在一些实施方案中,这些肽来源于基于与层粘连蛋白三聚体421、521或两者的选择性结合的噬菌体展示筛选。此类肽包含表3中列出的氨基酸序列(SEQ ID NO:472-678)中的任一种或由其组成。在一些实施方案中,这些肽来源于基于与神经元和神经提取物而非肌肉提取物的选择性结合的噬菌体展示筛选。此类肽包含表4中列出的氨基酸序列(SEQ ID NO:679-746)中的任一种或由其组成。
表2
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表3
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表4
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因此,在实施方案中,肽包含选自SEQ ID NO:18、19、29-82、84-95和103-746的氨基酸序列或由其组成。在实施方案中,肽包含选自SEQ ID NO:18、19、29-82、84-95和103-746的氨基酸序列或由其组成。在实施方案中,肽包含选自SEQ ID NO:75-82、84-95和103-746的氨基酸序列或由其组成。在实施方案中,肽包含选自SEQ ID NO:55-74和188-362的氨基酸序列或由其组成。在实施方案中,肽包含选自SEQ ID NO:75-82、84-95和103-187的氨基酸序列或由其组成。在实施方案中,肽包含选自SEQ ID NO:33-54和363-446的氨基酸序列或由其组成。在实施方案中,肽包含选自SEQ ID NO:18、19、29-32和447-471的氨基酸序列或由其组成。在实施方案中,肽包含选自SEQ ID NO:472-678的氨基酸序列或由其组成。在实施方案中,肽包含选自SEQ ID NO:679-746的氨基酸序列或由其组成。
在实施方案中,肽包含第PCT/US21/61821号国际专利申请(“‘821申请”)中描述的氨基酸序列的变体或由其组成。因此,此类变体包括但不限于包含与SEQ ID NO:18、19、29-82、84-95和103-746中的任一种共有75%-99%同一性或75%-99%同源性的氨基酸序列或由其组成的肽。
在实施方案中,肽包含与SEQ ID NO:18、19、29-82、84-95和103-746中的任一种具有至少75%同一性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:18、19、29-82、84-95和103-746中的任一种具有至少80%同一性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:18、19、29-82、84-95和103-746中的任一种具有至少85%同一性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:18、19、29-82、84-95和103-746中的任一种具有至少90%同一性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:18、19、29-82、84-95和103-746中的任一种具有至少95%同一性的氨基酸序列或由其组成。
在实施方案中,肽由与SEQ ID NO:18、19、29-82、84-95和103-746中的任一种共有至少80%同源性的氨基酸序列组成或包含与SEQ ID NO:18、19、29-82、84-95和103-746中的任一种共有至少80%同源性的氨基酸序列。在实施方案中,肽包含与SEQ ID NO:18、19、29-82、84-95和103-746中的任一种共有至少85%同源性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:18、19、29-82、84-95和103-746中的任一种共有至少90%同源性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:18、19、29-82、84-95和103-746中的任一种共有至少95%同源性的氨基酸序列或由其组成。在实施方案中,肽包含与SEQ ID NO:18、19、29-82、84-95和103-746中的任一种共有至少99%同源性的氨基酸序列或由其组成。
本发明的肽是通过本领域技术人员已知的任何合适的方法合成的,包括并入本文中的‘054和‘821申请中所公开的那些方法。例如,本发明的肽可以通过固相肽合成进行化学合成。在实施方案中,本发明的肽在N-末端被乙酰化(“Ac”或“乙酰基”),在C-末端被酰胺化(“CONH2”或“NH2”),或两者。例如,SEQ ID NO:747对应于酰胺化的肽,其以甘氨酰胺终止。
荧光部分
如本文所用的,术语“荧光部分”意指任何荧光分子,其包括荧光蛋白、荧光肽、荧光团(如荧光染料)或任何其他荧光配体或标志物。
本文所述荧光部分的具体实例仅为说明性的,且不意在限制与本文所公开的肽一起使用的荧光部分。
荧光团(或荧光染料)包括在可见光以及近红外(NIR)区域中发挥作用的分子。
常见的荧光团类别包括但不限于氧杂蒽,诸如罗丹明、对甲氨基酚和荧光素,以及它们的衍生物;bimanes;香豆素及其衍生物,诸如伞形酮和氨基甲基香豆素;芳香胺,诸如丹酰;方酸盐(squarate)染料;苯并呋喃;荧光花菁;咔唑;二氰亚甲基吡喃;聚甲炔;氧杂苯并蒽(oxabenzanthrane);吡喃鎓(pyrylium);喹诺酮(carbostyl);苝;吖啶酮;喹吖啶酮;红荧烯;蒽;晕苯;菲(phenanthrecene);芘;丁二烯;芪;卟啉;酞菁(pthalocyanine);镧金属螯合物复合物;稀土金属螯合物复合物;以及以上的衍生物。荧光染料例如在第4,452,720号美国专利;第5,227,487号美国专利;以及第5,543,295号美国专利中有所讨论。
与本文所公开的缀合物一起使用的典型荧光素染料包括但不限于羧基荧光素、5-羧基荧光素、6-羧基荧光素、5(6)-羧基荧光素、荧光素异硫氰酸盐、荧光素-5-异硫氰酸盐、荧光素-6-异硫氰酸盐、5,6-二羧基荧光素、5-(和6)-磺酸基荧光素、砜荧光素、琥珀酰荧光素、5-(和6)-羧基SNARF-1、羧基荧光素磺酸盐、羧基荧光素两性离子、羧基荧光素季铵盐、羧基荧光素膦酸盐、羧基荧光素GABA、羧基荧光素-cys-Cy5和荧光素谷胱甘肽。荧光素染料的实例也可以例如发现于第6,008,379号美国专利、第5,750,409号美国专利、第5,066,580号美国专利和第4,439,356号美国专利中。
在实施方案中,荧光部分包含羧基荧光素分子(FAM),即具有添加的羧基的荧光素分子。因此,术语“FAM”可以包括在5位置(5-FAM)或6位置(6-FAM)中具有羧基的荧光素分子。
在实施方案中,荧光部分可以包括IR800CW、青色荧光蛋白(CFP);EGFP;5-FAM;6-FAM;FAM;荧光素;IAEDANS;EDANS;BODIPY FL;TRITC;Cy5;Cy3;YFP;LC Red 640;AlexaFluor 546;四甲基罗丹明;Dabcyl;QSY 7;QSY 9;QSY 21;以及BBQ-650染料。
在实施方案中,荧光部分包含罗丹明染料,诸如例如5-(和6)-羧基罗丹明110、四甲基罗丹明-6-异硫氰酸盐、5-羧基四甲基罗丹明、5-羧基对甲氨基酚衍生物、四甲基和四乙基罗丹明、二苯基二甲基和二苯基二乙基罗丹明、二萘基罗丹明、罗丹明101磺酰氯(TEXAS RED)和其他罗丹明染料。其他罗丹明染料可以例如发现于第6,080,852号美国专利;第6,025,505号美国专利;第5,936,087号美国专利;第5,750,409号美国专利中。
在实施方案中,荧光部分包括花菁染料,诸如例如Cy2、Cy3、Cy3B、Cy3.5、Cy5、Cy5.5、Cy 7和吲哚菁绿。
在实施方案中,荧光团表现出绿色荧光(例如494nm/519nm或494/524nm)、橙色荧光(例如554nm/570nm)、红色荧光(例如590nm/617nm)或远红荧光(例如651nm/672nm)激发/发射光谱。在实施方案中,荧光团是具有在约350nm至约775nm范围内的激发和发射光谱的荧光团。在实施方案中,激发和发射光谱为约346nm/446nm、约494nm/519nm、约554nm/570nm、约555nm/572nm、约590nm/617nm、约651nm/672nm、约679nm/702nm或约749nm/775nm。
在实施方案中,荧光团的激发和发射光谱在可见光谱区(约380nm至约700nm)内。
在实施方案中,荧光团的激发和发射光谱在近红外(NIR)范围内,包括NIR-I光谱区域(约700nm至约900nm)和NIR-II光谱区域(约1000nm至约1700nm)。参见例如,Zhu等人,2018,Theranostics 8,4141-4151。
在实施方案中,荧光团可以包括但不限于AlexaFluor 3、AlexaFluor 5、AlexaFluor 350、AlexaFluor 405、AlexaFluor 430、AlexaFluor 488、AlexaFluor 500、AlexaFluor 514、AlexaFluor 532、AlexaFluor 546、AlexaFluor 555、AlexaFluor 568、AlexaFluor 594、AlexaFluor 610、AlexaFluor 633、AlexaFluor 647、AlexaFluor 660、AlexaFluor 680、AlexaFluor 700和AlexaFluor 750(分子探针AlexaFluor染料,可从LifeTechnologies,Inc.(USA)获得)。在实施方案中,荧光团可以包括但不限于Cy染料,其包括Cy2、Cy3、Cy3B、Cy3.5、Cy5、Cy5.5和Cy7(可从GE Life Sciences或Lumiprobes获得)。在实施方案中,荧光团可以包括但不限于DyLight 350、DyLight 405、DyLight 488、DyLight550、DyLight 594、DyLight 633、DyLight 650、DyLight 680、DyLight 750和DyLight 800(可从Thermo Scientific(USA)获得)。在实施方案中,荧光团可以包括但不限于FluoProbes 390、FluoProbes 488、FluoProbes 532、FluoProbes 547H、FluoProbes 594、FluoProbes 647H、FluoProbes 682、FluoProbes 752和FluoProbes 782、AMCA、DEAC(7-二乙基氨基香豆素-3-羧酸);7-羟基-4-甲基香豆素-3;7-羟基香豆素-3;MCA(7-甲氧基香豆素-4-乙酸);7-甲氧基香豆素-3;AMF(4'-(氨基甲基)荧光素);5-DTAF(5-(4,6-二氯三嗪基)氨基荧光素);6-DTAF(6-(4,6-二氯三嗪基)氨基荧光素);FAM(羧基荧光素);6-FAM(6-羧基荧光素)、5(6)-FAM尸胺;5-FAM尸胺;5(6)-FAM乙二胺(ethylenediamme);5-FAM乙二胺;5-FITC(FITC异构体I;荧光素-5-异硫氰酸盐);5-FITC尸胺;荧光素-5-马来酰亚胺;5-IAF(5-碘乙酰氨基荧光素);6-JOE(6-羧基-4',5'-二氯-2',7'-二甲氧基荧光素);5-CRll0(5-羧基罗丹明110);6-CRl l0(6-羧基罗丹明110);5-CR6G(5-羧基罗丹明6G);6-CR6G(6-羧基罗丹明6G);5(6)-羧基罗丹明6G尸胺;5(6)-羧基罗丹明6G乙二胺;5-ROX(5-羧基-X-罗丹明);6-ROX(6-羧基-X-罗丹明);5-TAMRA(5-羧基四甲基罗丹明);6-TAMRA(6-羧基四甲基罗丹明);5-TAMRA尸胺;6-TAMRA尸胺;5-TAMRA乙二胺;6-TAMRA乙二胺;5-TMR C6马来酰亚胺;6-TMR C6马来酰亚胺;TR C2马来酰亚胺;TR尸胺;5-TRITC;G异构体(四甲基罗丹明-5-异硫氰酸盐);6-TRITC;R异构体(四甲基罗丹明-6-异硫氰酸盐);丹酰尸胺(5-二甲基氨基萘-l-(N-(5-氨基戊基))磺胺);EDANS C2马来酰亚胺;荧光胺;NBD;以及吡咯亚甲基及其衍生物。
在实施方案中,荧光部分包含环境敏感的荧光染料或荧光团。环境敏感的荧光染料或荧光团的实例包括5,6-羧基-二乙基对甲氨基酚(pH敏感的)、花青(膜电位敏感的)和尼罗红羧酸(脂质敏感的)。
在实施方案中,荧光部分是荧光肽或荧光蛋白。在实施方案中,荧光蛋白是绿色荧光蛋白(GFP)。在实施方案中,荧光部分是GFP的衍生物或变体,包括例如:EGFP、祖母绿(emerald)、超级折叠(superfolder)GFP、azami green mWasabi、TagGFP、TurboGFP、AcGFP、ZsGreen、T-Sapphire、EBFP、EBFP2、Azurite、mTagBFP、ECFP、mECFP、Cerulean、mTurquoise、CyPet、AmCyan1、Midori-Ishi Cyan、TagCFP、mTFP1(Teal)、EYFP、Topaz、Venus、mCitrine、YPet、TagYFP、PhiYFP、ZsYellow1、mBanana、Kusabira Orange、Kusbira Orange2、mOrange、mOrange2、dTomato、dTomato-Tandem、TagRFP、TagRFP-Y、DsRed、DsRed2、DsRed-Express(T1)、DsRed-Monomer、mTangerine、mRuby、mApple、mStrawberry、AsRed2、mRFP1、JRed、mCherry、HcRed1、mRaspberry、dKeima-Tandem、HcRed-Tandem、mPlum、AQ143、mKalamal、YFP和Citrine。
在实施方案中,荧光部分包括荧光分子,如‘054和‘821申请中所公开的,其通过引用整体并入本文中。
在实施方案中,荧光部分与高分子量分子缀合,如水溶性聚合物,包括但不限于葡聚糖、PEG、血清白蛋白或聚(氨基胺)树状聚合物。
本文所公开的荧光部分可以结合到肽的N-末端、C-末端或内部位置(例如,结合到内部氨基酸)。在实施方案中,两种、三种、四种或更多种肽直接或间接结合到荧光部分。在实施方案中,本文所公开的任何肽与两种或更多种荧光部分结合,所述荧光部分可以相同或不同。
在实施方案中,本文所公开的荧光部分直接与本文所公开的任何肽结合。
连接子
在实施方案中,荧光部分例如经由连接子间接结合到肽上。如本文所用的,“连接子”是能够与本文所公开的肽结合(例如共价结合)的任何分子。连接子包括但不限于,直链或支链含碳连接子、杂环含碳的连接子、氨基酸连接子(例如D-氨基酸或L-氨基酸)、亲脂性残基、肽连接子、肽核酸连接子、腙连接子、SPDB二硫化物、磺基-SPDB、马来酰亚胺甲基环己烷-1-羧酸酯(MCC)、氨基己酸连接子,以及聚醚连接子(例如,PEG)。连接子包括例如可从Quanta Biodesign,Powell,OH获得的聚(乙二醇)连接子。这些连接子任选地具有酰胺键合、巯基键合或杂官能键合。连接子还包括本领域中所公开或描述的其他连接子分子,包括并入本文中的‘054和‘821申请中所描述的那些。
在实施方案中,连接子通过共价键合与本文公开的靶向分子结合。连接子可以通过在一个位置与货物(cargo)分子形成共价键合,并在另一位置与肽形成共价键合,来将货物分子(如荧光部分)连接到肽。可以通过连接子上的官能团与肽和货物分子上的官能团之间的反应形成共价键合。在实施方案中,共价键合包括醚键、硫醚键、胺键、酰胺键、碳-碳键、碳-氮键、碳-氧键或碳-硫键。例如,可以通过荧光素的5位置处的羧酸官能团和肽的N-末端处的伯胺之间的缩合反应形成共价键合,如在荧光缀合物5-FAM-QVPWEEPYYVVKKSSGG-NH2(HNP401-N-2,具有GG连接子;SEQ ID NO:747)中。
在实施方案中,连接子是柔性的。在实施方案中,连接子是刚性的。在实施方案中,连接子具有柔性段和刚性段。
在实施方案中,连接子包含线性结构。在实施方案中,连接子包含非线性结构。在实施方案中,连接子包含支链结构。在实施方案中,连接子包含环状结构。
在实施方案中,连接子是烷基。在实施方案中,连接子是杂烷基。
在实施方案中,连接子是亚烷基。在实施方案中,连接子是亚烯基。在实施方案中,连接子是亚炔基。在实施方案中,连接子是杂亚烷基。
“烷基”基团是指脂肪族烃基。烷基部分可以是饱和烷基或不饱和烷基。取决于结构,烷基可以是单自由基或二自由基(即亚烷基)。
“烷基”部分可以具有1至10个碳原子(无论其何时出现在本文中,数字范围如“1至10”指给定范围内的每个整数;例如,“1至10个碳原子”意指烷基可以由1个碳原子、2个碳原子、3个碳原子等,多达且包括10个碳原子组成,尽管本定义也涵盖术语“烷基”的出现,其中没有指定数值范围)。烷基也可以是具有1至6个碳原子的“低级烷基”。本文所述化合物的烷基可以被指定为“Ci-C4烷基”或类似的指定。仅通过实例的方式,“C1-C4烷基”表示烷基链中有一至四个碳原子,即烷基链选自:甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。典型的烷基包括但绝不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、乙烯基、丙烯基、丁烯基等。
在实施方案中,连接子包含环结构(例如芳基)。如本文所用的,术语“环”是指任何共价闭合的结构。环包括例如碳环(例如,芳基和环烷基)、杂环(例如,杂芳基和非芳族杂环)、芳族化合物(例如芳基和杂芳基)和非芳族化合物(例如,环烷基和非芳族杂环)。环可以任选地被取代。环可以是单环或多环的。
如本文所用的,术语“芳基”是指芳环,其中形成环的每个原子都是碳原子。芳基环可以由五个、六个、七个、八个、九个或多于九个碳原子形成。芳基可以任选地被取代。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。取决于结构,芳基可以是单自由基或二自由基(即亚芳基)。
术语“环烷基”是指单环或多环非芳族基团,其中形成环的每个原子(即骨架原子)都是碳原子。环烷基可以是饱和的或部分不饱和的。环烷基包括具有3至10个环原子的基团。环烷基包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
在实施方案中,环是环烷烃。在实施方案中,环是环烯烃。
在实施方案中,环是芳香环。术语“芳香族”是指具有离域π-电子系统的平面环,该系统含有4n+2π个电子,其中n是整数。芳环可以由五个、六个、七个、八个、九个或多于九个原子形成。芳族化合物可以任选地被取代。术语“芳族的”包括碳环芳基(如苯基)和杂环芳基(或“杂芳基”或“杂芳族化合物”)基团(例如,吡啶)。该术语包括单环或稠环多环(即共享相邻碳原子对的环)基团。
在实施方案中,环是杂环。术语“杂环”是指含有1至4个杂原子的杂芳族和杂脂环族基团,每个杂原子选自O、S和N,其中每个杂环基团在其环系统中具有4至10个原子,并且条件是所述基团的环不包含两个相邻的O或S原子。非芳族杂环基团包括在其环系统中仅具有3个原子的基团,但芳族杂环基团在其环系统中必须具有至少5个原子。杂环基团包括苯并-稠环系统。3元杂环基团的实例是氮丙啶基。4元杂环基团的实例是氮杂环丁烷基(来源于氮杂环丁烷)。5元杂环基团的实例是噻唑基。6元杂环基团的实例是吡啶基,并且10元杂环基团的实例是喹啉基。非芳族杂环基团的实例为吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢硫代吡喃基、哌啶基、吗啉基、硫代吗啉基、噻吨基(thioxanyl)、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁基(thietanyl)、高哌啶基、氧杂环庚基(oxepanyl)、硫杂环庚基(thiepanyl)、氧氮杂卓基(oxazepinyl)、二氮杂基(diazepinyl)、硫氮杂基(thiazepinyl)、1,2,3,6-四氢吡啶、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二恶烷基、1,3-二氧戊环基、吡唑啉基、二噻烷基、二硫戊环基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂双环[3.1.0]己基、3-氮杂环[4.1.0]庚基、3H-吲哚基和喹嗪基。芳族杂环基团的实例为吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基(cinnolinyl)、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、恶二唑基、噻二唑基、呋咱基(furazanyl)、苯并呋咱基、苯并硫苯基、苯并噻唑基、苯并恶唑基、喹唑啉基、喹喔啉基、萘啶基和呋喃吡啶基(fαropyridinyl)。在可能的情况下,上述基团可以是C-附接的或N-附接的。例如,来源于吡咯的基团可以是吡咯-1-基(N-附接的)或吡咯-3-基(C-附接的)。此外,来源于咪唑的基团可以是咪唑-1-基或咪唑-3-基(均为N-附接的)或咪唑-2-基、咪唑-4-基或咪唑-5-基(均为C-附接的)。杂环基团包括苯并稠环系统和被一个或两个氧代(=0)部分取代的环系统,如吡咯烷-2-酮。取决于结构,杂环基团可以是单自由基或二自由基(即,杂环烯基团)。
在实施方案中,环是稠合的。术语“稠合”是指其中两个或更多个环共有一个或多个键的结构。在实施方案中,环是二聚体。在实施方案中,环是三聚体。在实施方案中,环是被取代的。
术语“碳环的”或“碳环”是指其中形成环的每个原子都是碳原子的环。碳环包括芳基和环烷基。因此,该术语将碳环与杂环(“杂环的”)区分开来,其中杂环的环主链包含至少一个不同于碳的原子(即杂原子)。杂环包括杂芳基和杂环烷基。碳环和杂环可以任选地被取代。
在实施方案中,连接子被取代。术语“任选取代的”或“取代的”意指所提及的基团可以被一个或多个单独且独立地选自以下的另外基团取代:Ci-Ce烷基、C3-Cg环烷基、芳基、杂芳基、C2-C6杂脂环、羟基、Ci-C6烷氧基、芳氧基、Ci-C6烷基硫、芳基硫、Ci-C6烷基亚砜、芳基亚砜、Ci-C6烷基砜、芳基砜、氰基、卤代、C2-C8酰基、C2-C8酰基氧、硝基、Ci-C6卤代烷基、Ci-C6氟代烷基和氨基,包括Ci-C6烷基氨基,以及以上的受保护的衍生物。通过实例的方式,任选的取代基可以是LSRS,其中每个L独立地选自键、-O-、-C(=O)-、-S-、-S(=O)-、-S(O)2-、-NH-、-NHC(O)-、-C(O)NH-、S(O)2NH-、-NHS(O)2-、-OC(O)NH-、-NHC(O)O-、-(CpC6烷基)-或-(C2-C6烯基)-;并且每个R独立地选自H、(Ci-C4烷基)、(C3-C8环烷基)、杂芳基、芳基和Ci-C6杂烷基。任选取代的非芳族基团可以被一个或多个氧代(=0)取代。可以形成上述取代基的保护性衍生物的保护基团是本领域技术人员已知的。
在实施方案中,具有与一个分子(例如,靶向分子)上的基团反应的一个官能团和在其他分子(例如,荧光部分或药物)上反应的另一基团的双功能连接子被用于形成所期望的缀合物。可选地,进行衍生化以提供官能团。因此,例如,在肽上产生游离巯基的操作也是已知的(参见第4,659,839号美国专利)。连接子可替代地包含杂双官能交联剂,其包含形成能够与靶向分子相互作用的杂环环的两个或更多个不同的反应性基团。例如,杂双功能交联剂(如半胱氨酸)可包含胺反应性基团,并且硫醇反应性基团可与衍生的靶向分子上的醛相互作用。适用于杂双功能交联剂的反应性基团的另外的组合包括例如,胺和巯基反应性基团;羰基和巯基反应性基团;胺和光反应性基团;巯基和光反应性基团;羰基和光反应性基团;羧酸盐和光反应性基团;以及精氨酸和光反应性基团。杂双功能交联剂的实例包括N-琥珀酰亚胺4-(2-吡啶基二硫代)丁酸酯(SPDB)和马来酰亚胺甲基环己烷-1-甲酸酯(MCC)。
在实施方案中,连接子是可切割的。在实施方案中,连接子是不可切割的。连接子可以对细胞外环境化学稳定(例如在血流中化学稳定),以及/或者可以包括不稳定的键合。连接子可以包括被设计为在细胞内特异性地或非特异性地切割和/或牺牲(immolate)或以其他方式断裂的键合。可切割的连接子可以对特定位点处的酶(如细胞外蛋白酶)敏感。
可切割连接子可以包括缬氨酸-瓜氨酸肽、缬氨酸-丙氨酸肽、苯丙氨酸-赖氨酸或其他肽(如形成蛋白酶识别和切割位点的肽)。此类含肽的连接子可以包含五氟苯基基团。含肽的连接子可以包括丁二酰亚胺或马来酰亚胺基团。含肽的连接子可以包括对氨基苯甲酸(PABA)基团。含肽的连接子可以包括氨基苄氧羰基(PABC)基团。含肽的连接子可以包括PABA或PABC基团和五氟苯基基团。含肽的连接子可以包括PABA或PABC基团和琥珀酰亚胺基团。含肽的连接子可以包括PABA或PABC基团和马来酰亚胺基团。
不可切割的连接子通常对蛋白酶不敏感,且对细胞内过程不敏感。不可切割的连接子可以包括马来酰亚胺基团。不可切割的连接子可以包括琥珀酰亚胺基团。不可切割的连接子可以是马来酰亚胺-烷基-C(O)-连接子。不可切割的连接子可以是马来酰亚氨基己酰基连接子。马来酰亚氨基己酰基连接子可以是N-马来酰亚胺甲基环己烷-1-羧酸酯。马来酰亚氨基己酰基连接子可以包括琥珀酰亚胺基团。马来酰亚氨基己酰基连接子可以包括五氟苯基基团。
在实施方案中,由一个或多个氨基酸组成的肽连接子被用于连接靶向分子和荧光部分或药物。通常,肽连接子除了连接分子或保持它们之间的一些最小距离或其他空间关系之外将不具有特定的生物活性。然而,可以选择连接子的组成氨基酸来影响分子的一些性质,如折叠、净电荷或疏水性。在实施方案中,肽连接子相对较短,通常少于约10个氨基酸,优选少于约8个氨基酸,且更优选少于5个氨基酸。非限制性示例性实例包括可添加到肽的C-末端的甘氨酸和甘氨酸-丝氨酸连接子。在实施方案中,肽连接子包含半胱氨酸残基或非天然氨基酸残基(例如硒代半胱氨酸(Sec)、对乙酰苯丙氨酸(pAcF)、对叠氮甲基-L-苯丙氨酸(pAMF)和叠氮-赖氨酸(AzK)),以用于位点特异性缀合。在实施方案中,肽连接子是甘氨酸-甘氨酸-甘氨酸-半胱氨酸(GGGC)(SEQ ID NO:15)连接子、甘氨酸-甘氨酸-半胱氨酸(GGC)连接子、甘氨酸-甘氨酸(GG)连接子或半胱氨酸(C)连接子。在实施方案中,将GGGC(SEQ ID NO:15)、GGC、GG或C连接子添加到肽的N-末端或C-末端。
在实施方案中,本发明的荧光缀合物可以任选地与增加其结合的多价性和亲合力的高分子量分子缀合。在实施方案中,高分子量分子是水溶性聚合物。合适的水溶性聚合物的实例包括但不限于肽、糖、聚(乙烯基)、聚(醚)、聚(胺)、聚(羧酸)等。在实施方案中,水溶性聚合物是葡聚糖、聚乙二醇(PEG)、聚氧化亚烷基、聚唾液酸、淀粉或羟乙基淀粉。使用任何合适的方法将肽缀合到水溶性聚合物(参见Hermanson G.,Bioconjugate Techniques第2版,Academic Press,Inc.2008)。
在实施方案中,可以对本发明的荧光缀合物进行修饰以增加溶解性。增加溶解性的肽修饰包括添加亲水性氨基酸、PEG部分或两者。在实施方案中,PEG部分是8-氨基-3,6-二氧杂辛酸(AEEA);12-氨基-4,7,10-三氧杂十二酸;或者15-氨基-4,7,10,13-四氧杂五-癸酸。在实施方案中,可以将大约一至十个(例如,一个、两个、三个、四个、五个、六个、七个、八个、九个或十个)亲水性氨基酸添加到肽的N-末端、C-末端、内部位置或以上的任意组合,以增加溶解性。亲水性氨基酸包括D、E、H、K、N、Q、R、S、T和G。在实施方案中,肽在N-末端或C-末端包含K、KK、G或GG。
在实施方案中,荧光缀合物包含5-FAM-QVPWEEPYYVVKKSSGG-NH2(HNP401-N-2,具有GG连接子;SEQ ID NO:747),并且可以被用于本文所述的任何方法中。
在实施方案中,荧光缀合物包含与具有GCC连接子的HNP401(Ac-SGQVPWEEPYYVVKKSSGGC-CONH2;SEQ ID NO:748)的C-末端半胱氨酸连接的FAM。
IV.药物组合物
在某些实施方案中,本文公开了包含本文所公开的荧光缀合物的药物组合物。本文的药物组合物是使用一种或多种生理上可接受的载体(包括赋形剂和助剂)配制的,所述载体有助于将活性剂加工成药学上使用的制剂。适当的制剂取决于所选择的施用途径。此类组合物可以用本领域已知的方法和赋形剂制备,如例如发现于Gennaro:Remington:TheScience and Practice of Pharmacy,第21版(Lippincott Williams&Wilkins,2005);Allen:Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems,第11版(Wolters Kluwer,2018);Brunton等人:Goodman&Gilman's The Pharmacological Basisof Therapeutics(McGraw-Hill Professional,2005);以及Rowe:Handbook ofPharmaceutical Excipients(Pharmaceutical Press,2005)中。
在药物组合物的实施方案中,荧光缀合物中的肽可以由包括本文所述的所有变体和组合的任何氨基酸序列组成或包含包括本文所述的所有变体和组合的任何氨基酸序列。在实施方案中,肽由如本文所述的表1中列出的任何氨基酸序列或其任何变体组成或包含如本文所述的表1中列出的任何氨基酸序列或其任何变体。在实施方案中,肽包含SEQ IDNO:1-14、16、20-28和96-102中的任一种或由其组成。在实施方案中,肽由表2-4中列出的任何氨基酸序列或其任何变体组成或包含表2-4中列出的任何氨基酸序列或其任何变体。在实施方案中,肽包含选自SEQ NO:75-82 84-95和103-187的氨基酸序列。在实施方案中,肽包含选自SEQ NO:55-74和188-362的氨基酸序列。在实施方案中,肽包含选自SEQ NO:33-54和363-446的氨基酸序列。在实施方案中,肽包含选自SEQ NO:18、19和29-32和447-471的氨基酸序列。在实施方案中,肽包含选自SEQ ID NO:472-678的氨基酸序列。在实施方案中,肽包含选自SEQ ID NO:679-746的氨基酸序列。在实施方案中,肽由SEQ ID NO:21的氨基酸序列组成或包含SEQ ID NO:21的氨基酸序列。
在实施方案中,药物组合物中的荧光缀合物包含SEQ ID NO:747。
在实施方案中,本文所公开的药物组合物还包含药学上可接受的稀释剂、赋形剂、载体或溶剂。合适的水性和非水性载体、稀释剂、溶剂或媒介物的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油、聚氧乙烯氢化蓖麻油(cremophor)等)、以上的合适的混合物、植物油(如橄榄油)和可注射有机酯(如油酸乙酯)。通常用于制造药学上可接受的固体、液体或其他剂型的其他常用的表面活性剂(如吐温类(Tweens)、司盘类(Spans)和其他乳化剂)或生物利用度增强剂也可用于配制目的。生物利用度增强剂可以包括穿透或渗透增强剂。参见例如,Muheem等人,2016,Saudi Pharm.J.24,413-428;Brayden等人,2020,Adv.DrugDeliv.Rev.2020年5月29日:S0169-409X(20)30040-5;Ibrahim等人2020,J.Pham.Sci.28,403-416。在一些制剂中,可以保持适当的流动性,例如,通过使用诸如卵磷脂的包衣,在分散剂的情况下通过保持所需的粒径,以及通过使用表面活性剂。
在实施方案中,药物组合物包括其他药物或药物试剂、载体、佐剂,诸如保存剂、稳定剂、润湿剂或乳化剂、溶液促进剂、用于调节渗透压的盐和/或缓冲剂。另外,药物组合物还含有其他有治疗价值的物质。
在实施方案中,本文所公开的肽缀合物经由药物递送媒介物或载体递送至对象。在实施方案中,递送媒介物由天然材料或合成材料或两者制成。在实施方案中,递送媒介物是纳米粒子、微粒、聚合物胶束、纳米胶囊、树状聚合物、大PEG、纳米凝胶、脂质体、富勒烯、纳米结构脂质载体、纳米壳、量子点、基于蛋白质的纳米载体(例如,白蛋白、弹性蛋白、醇溶蛋白、豆球蛋白、玉米醇蛋白、大豆蛋白、牛奶蛋白、基于乳清的纳米载体)、有机纳米载体(例如,明胶、葡聚糖、瓜尔胶、壳聚糖、胶原)、多糖基载体(例如,葡聚糖、壳聚糖、果胶)、脂质乳液或以上的组合。
在实施方案中,本文所公开的药物组合物通过任何合适的施用途径施用于对象,包括但不限于局部、经口、直肠内、阴道内、鼻内、吸入、肠胃外(静脉内、动脉内、皮下、腹膜内、肌内、血管内、鞘内、玻璃体内、输注)施用。在某些实施方案中,将本文所公开的药物组合物施用于对象是局部或全身施用。在实施方案中,本文所公开的药物组合物经静脉内施用。
适用于肌内、皮下或静脉注射的制剂包括生理上可接受的无菌水性溶液或非水性溶液、分散剂、混悬剂或乳剂,以及用于重构为无菌注射溶液或分散剂的无菌粉末。适用于皮下注射的制剂还含有任选的添加剂,如本领域已知的防腐剂、润湿剂、乳化剂和分散剂。在实施方案中,适用于静脉内注射的制剂可在水性溶液(如生理盐水缓冲剂和本领域已知的其他生理相容性缓冲剂)中制备。对于静脉内注射,任选在水溶液中,优选在生理相容性缓冲剂(如Hank溶液、Ringer溶液或生理盐水缓冲剂)中配制活性剂。
肠胃外注射任选地涉及团注或连续输注。注射用制剂任选地以单位计量形式存在(例如,在安瓿或多剂量容器中),其中添加有防腐剂。在实施方案中,本文所述的药物组合物的形式适合作为在油性或水性媒介物中的无菌混悬剂、溶液或乳剂进行肠胃外注射,并且含有制剂(如混悬剂、稳定剂和/或分散剂)。用于肠胃外施用的药物制剂包括水溶性形式的活性剂的水性溶液。另外,混悬剂可任选地制备为合适的油性注射混悬剂。
在实施方案中,经口施用本文的药物组合物。适合经口施用的剂量形式可以是固体或液体,并且可以包括例如药丸、胶囊、锭剂、片剂、囊片(caplet)、凝胶囊片(凝胶帽)、糖浆、水性混悬剂或溶液、可咀嚼形式、可吞咽形式、可溶解形式、泡腾剂、颗粒状形式和口服液体溶液。在具体实施方案中,剂型是固体剂型,并且更具体地,包括片剂或胶囊,或者通过本文公开的媒介物或载体经口施用。
在实施方案中,本文所述的药物组合物为适用于精确剂量的单次施用的单位剂量形式。在单位剂量形式中,制剂被分为含有适当量的本文公开的活性剂的单位剂量。在实施方案中,单位剂量是包含离散量制剂的包装形式。非限制性实例是包装的片剂或胶囊,以及小瓶或安瓿中的粉末。在实施方案中,将水性悬浮剂组合物包装在单剂量不可再封闭的容器中。可选地,使用多剂量可重新封闭的容器,在这种情况下,通常在组合物中包括防腐剂。仅通过实例的方式,用于肠胃外注射的制剂以单位剂型呈现,其包括但不限于安瓿,或者以添加防腐剂的多剂量容器呈现。
在实施方案中,药物组合物经由全身静脉内施用对象,特别是人类患者,且更特别是正在经受手术的人类患者。
在实施方案中,药物组合物经口施用于对象,特别是人类患者,且更特别是正在经受手术的人类患者。
实施例1
神经靶向性荧光缀合物在输尿管可视化中的使用
引言
先前进行了噬菌体展示筛选以鉴定与人神经匀浆或分离的人神经蛋白结合的肽。参见‘054和‘821申请。此类肽可以连接或标记到用于各种应用的货物分子上。如果用荧光部分标记,例如,此类缀合物可能用于荧光辅助手术期间神经的体内标记,并且如果连接到活性剂,例如,此类缀合物潜在地可用作靶向治疗。
将示例性肽与荧光染料缀合以产生荧光缀合物(这里也被称为缀合物),并在啮齿动物模型中进行评估,其中它们在静脉内施用后显示出灵敏的神经检测。这些缀合物包括FAM NP41,其包含荧光染料羧基荧光素(FAM),其经由赖氨酰胺键合与乙酰化NP41(Ac-SHSNTQTLAKAPEHTGK;SEQ ID NO:749)的C-末端赖氨酸连接,以及FAM-HNP401,其包含与具有GCC连接子的乙酰化HNP401(Ac-SGQVPWEEPYYVVKKSSGGC-CONH2;SEQ ID NO:748)的C-末端半胱氨酸缀合的FAM。参见‘054申请;Hingorani等人2018,Theranostics 8,4226-4237;Whitney等人2011,Nat.Biotechnol.29,352-356。
进一步的研究显示了局部施用FAM-NP41、FAM-HNP401和对应于SEQ ID NOS:20、22-24和25-28的包括HNP401的N-末端和C-末端缺失变体的其他缀合物后,人类(和啮齿动物)切除的神经组织的荧光标记。Whitney等人,2011,Nat.Biotechnol.29,352-356;Wu等人,2011,Laryngoscope 121,805-810;Hussain等人,2015,PloS One 10,e0119600;Hingorani等人,2018,Theranostics 8,4226-4237。
然而,这些研究尚未揭示缀合物的特性(如活性、代谢和清除率)-尤其是在施用后的后期阶段。例如,在啮齿动物模型中,NP41的血清半衰期(如通过血清荧光测量的)约为10分钟,表明缀合物从血液中快速清除。在血液中观察到FAM-HNP401的类似的短半衰期(15分钟)。相反,NP41的神经荧光具有约50分钟的半衰期,并且可以在组织中以低水平持续数小时。类似地,在静脉内施用数小时后,在大鼠坐骨神经和前列腺神经中观察到FAM-HNP401的荧光。参见例如,Whitney等人,2011,Nat.Biotechnol.29,352-356;Hingorani等人,2018,Theranostics 8,4226-4237。
关于结合到神经(或其他组织)的缀合物的清除和随后的活性的细节尚不清楚,并且不知道这些性质是否可能支持缀合物在荧光引导手术中的其他用途。这里描述的研究揭示出,神经靶向性缀合物可以连同肾脏排泄一起,赋予对输尿管灵敏和延长的荧光可视化(照亮)。结果支持了此类缀合物作为外科辅助物的扩展应用。通过突出神经,它们可以作为手术(如头颈部外科操作)中的引导剂,其中它们可能有助于防止神经损伤。正如这里描述的,通过突出输尿管,它们可用于其他手术中,如存在输尿管损伤风险的许多腹部和骨盆外科操作。
结果
啮齿动物模型用于评估静脉内施用后5-FAM-QVPWEEPYYVVKKSSGG-NH2(HNP401-N-2,具有GG连接子;SEQ ID NO:747)的荧光可视化的动力学。缀合物以宽范围的量施用,并使用定制的显微镜检测荧光。例如,如图1所示,在小鼠模型中,经静脉内施用约2000纳摩尔(~200mg/kg)后2小时,输尿管很容易被照亮。探索了对应于~10mg/kg至~200mg/kg剂量的100纳摩尔至2000纳摩尔的量范围的另外的研究也揭示了在小鼠模型中,经静脉内施用荧光缀合物SEQ ID NO:747后的输尿管照亮。在大鼠模型中观察到了类似的发现。然而,此类荧光可视化不能反映输尿管的特异性或直接标记。相反,它反映了从肾脏到膀胱的输尿管下方尿流的荧光。此外,术中实时成像揭示了输尿管搏动,其使尿液集中,并可以增强输尿管的荧光可视化。进一步的研究揭示出,在施用这种缀合物后,输尿管照亮的时间过程延长。例如,在缀合物施用后,在少于1小时以及多达至少6小时内观察到输尿管的荧光可视化。
啮齿动物模型中的其他研究已经证明,在施用包含另外的肽和荧光部分的其他缀合物后,输尿管照亮延长。这些包括由与FAM缀合的相关HNP401肽组成的分子,以及由与其他荧光部分缀合的有关HNP401肽组成的分子。另外,这里呈现的研究允许连同输尿管一起同时对神经进行可视化。
讨论:
这些观察结果支持本文所述的神经靶向性荧光缀合物在输尿管照亮中的一般适用性。因此,本文所公开的缀合物可以被用于帮助外科医生在外科操作期间,在物理接触并因此潜在地损伤输尿管之前,对其进行可视化。此外,在外科操作期间发生意外损伤(即医源性损伤)的情况下,此类可视化允许更快速地识别损伤并更早地进行治疗和干预。
另外,已经观察到,本文所述的荧光缀合物的施用可以在施用后提供延长的输尿管可视化时间段。不受特定机制的限制,这种延长时间段的可视化据信反映了荧光缀合物在神经元或神经(如在外周神经系统)或其他组织中的逐渐积累,随后它们逐渐释放、代谢和被泌尿系统排泄。因此,与单独全身施用荧光染料或直接注射荧光染料相反,施用肽-荧光缀合物可以通过不破坏手术的方便施用而有利地延长输尿管照亮的时间段,提供早期和更长期照射。另外,施用此类缀合物可以提供对神经或输尿管的伴随或暂时不同的检测。
此类荧光介导的辅助在外科操作期间呈现输尿管损伤,尤其是医源性输尿管损伤(IUI)的重大风险的外科操作期间尤其重要。由于输尿管从腹部延伸到骨盆,这种风险可能适用于广泛的外科操作。可能受益于输尿管照亮的适用操作包括复杂的腹部和骨盆手术,如妇科、泌尿科和结直肠外科操作,以及心血管外科操作。它们还包括对输尿管附近的器官和系统(如肾脏、膀胱、前列腺、子宫、男性或女性生殖系统、直肠、结肠、小肠或大肠)进行的外科操作。它们还可以包括癌症外科操作(如前列腺癌外科操作或结直肠癌操作),或者其中增强的输尿管以及神经可视化是可取的操作。
实施例2
手术患者尿液中荧光缀合物的生物分析
在经静脉内施用500mg母体测试药物(对应于荧光缀合肽,SEQ ID NO:747)前30分钟、在头颈部手术前输注后30分钟以及22小时后采集尿液样本。使用合格的生物分析方法,通过液相色谱串联质谱法(LC-MS/MS)测定完整母体测试药物的浓度。还评估了代谢物M3-M8(最初从体外研究中鉴定)的存在,其对应于与荧光部分缀合的母体肽的缩短形式。结果如表5所示。
表5
*BQL:低于定量限(10ng/ml)
在30分钟的时间点,在评估的五名对象中的四名中检测到可定量水平的测试药物(或荧光代谢物M4、M6和M7)。在22小时的时间点,在评估的两名对象中均检测到荧光代谢物M4和M6。正如预期的那样,在任何预剂量样品中都没有检测到测试药物和荧光代谢物。
这些数据与啮齿类动物模型中的剂量和输尿管成像实验一致,表明单次施用测试药物可导致荧光分子在尿液中立即(例如30分钟)和长期积累(例如22小时)。反过来,这可以在外科操作的早期和后期阶段赋予延伸的输尿管可视化,以及支持在外科操作或其他应用中对神经和输尿管同时或不同地进行可视化。
实施例3
手术期间的输尿管和神经照射
本公开的荧光缀合物对输尿管(和神经)进行成像的能力可以使用适当设计的临床研究来评估,如以下针对经受胃肠道/泌尿生殖道(GI/GU)手术的患者所述的那些
在该预见性实例(prophetic example)中,临床试验包括一项开放标记的多中心研究,其评估了80名经受GI/GU手术的对象的测试药物(对应于荧光缀合肽,SEQ ID NO:747)的施用。入选该研究的纳入标准包括要求对象在神经(和输尿管)可能有损伤风险的GI/GU区域中经受手术。例如,此类操作可以包括结直肠或前列腺手术。
入选对象在手术前2至5小时通过静脉内输注接受单剂量的测试药物(500mg)。通过腹腔镜,通过实时白光反射(WLR)和荧光(FL)成像来评估测试药物的荧光。
使用多个终点来评估主要和次要功效目标。
关于神经检测,终点包括可视化评分系统,以测量测试药物在单独使用WLR相对于成对使用(WLR与FL重叠)改善对比度增强、分支描绘和神经长度中的功效。它们还包括计算神经(和邻近的非神经)组织的多个区域的信号与背景比,以测量测试药物在使用WLR相对于FL改善神经可视化中的功效。
关于输尿管检测,终点包括可视化评分系统,以测量测试药物在单独使用WLR相对于使用WLR与FL重叠改善输尿管的对比度增强中的功效。它们还包括计算输尿管(和邻近的非输尿管)组织的多个区域的信号与背景比,以测量测试药物在使用WLR相对于FL改善输尿管可视化中的功效。
以多个终点显示利用测试药物的神经和输尿管检测功效的显著改善。在外科操作中的早期和晚期时间观察到改善。因此,本公开的荧光缀合物可用于荧光引导的GI/GU外科操作,包括在增强的神经、输尿管或两者的可视化中。此类增强的可视化的益处可以包括外科医生在外科操作中识别输尿管和神经的信心的显著提高,以及这种外科操作的持续时间的显著减少。
提供以上陈述的实例是为本领域普通技术人员给出关于如何制备和使用本公开的组合物和方法的实施方案的完整公开和描述,并且不旨在限制发明人认为是其公开内容的范围。对本领域技术人员显而易见的用于执行本公开内容的上述模式的修改旨在落入以下权利要求的范围内。说明书中提到的所有专利和出版物都指示了本公开所属领域的技术人员的技能水平。本公开中引用的所有参考文献均通过引用被并入本文中,其程度与就像每篇参考文献单独通过引用整体并入本文中相同。
在不脱离本申请的精神和范围的情况下,可以对本申请进行许多修改和变化,这对本领域技术人员来说是显而易见的。本文所述的具体实施方案和实例仅通过实例的方式提供,并且本申请仅受所附权利要求的条款,以及权利要求有权获得的等价物的完整范围限制。
此外,尽管提供了本公开中的某些细节以传达对所附权利要求所限定的本发明的彻底理解,但对本领域技术人员显而易见的是,可以在没有这些细节的情况下实践某些实施方案。此外,在某些情况下,没有描述公知的方法、操作或其他具体细节,以避免不必要地混淆由所附权利要求限定的本发明的方面。
本申请要求于2021年1月14日提交的第63/137,621号美国临时申请的优先权,该申请在此通过引用整体并入本文中。
序列表
<110> 阿鲁莫生物科学公司(Alume Biosciences, Inc.)
<120> 用于外科操作中输尿管可视化的方法和组合物
<130> 110267.405WO
<150> US 63/137621
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Ser Met Trp Ser Gln Phe Arg
1 5
<210> 36
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 36
Asn Pro Asn Trp Arg Thr Ile
1 5
<210> 37
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 37
Phe Lys Met Pro Ile Pro Thr
1 5
<210> 38
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 38
Tyr Pro Lys Leu Trp Thr Tyr
1 5
<210> 39
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 39
Asn Pro Ser His His Pro Arg
1 5
<210> 40
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 核心结合结构域
<400> 40
Pro Tyr Tyr Val Val Lys Lys
1 5
<210> 41
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> N-末端序列
<400> 41
Gln Val Pro Trp Glu Glu
1 5
<210> 42
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 42
Leu Thr His His Phe Ala Pro
1 5
<210> 43
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 43
Arg His Asn Val Glu Phe Ser
1 5
<210> 44
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 44
Phe Pro Val Val Thr Arg Asn
1 5
<210> 45
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 45
Leu Arg Phe Gln Ile Pro Pro
1 5
<210> 46
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 46
Leu Ala Leu Tyr Ala Arg Met
1 5
<210> 47
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 47
Gly Pro Phe Leu Phe Thr Val
1 5
<210> 48
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 48
Tyr Thr Pro Met Gly Thr Gly
1 5
<210> 49
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 49
Arg Phe Glu Leu Pro Ala Pro
1 5
<210> 50
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 50
His Gln Gly Ser Arg Thr Tyr
1 5
<210> 51
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 51
Thr Asn Pro Trp Lys Pro His
1 5
<210> 52
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 52
Met Thr Pro His Thr Ser Cys
1 5
<210> 53
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 53
Gly Leu Ile Arg His Tyr Thr
1 5
<210> 54
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 54
Ala Thr Leu Lys Pro Tyr Arg
1 5
<210> 55
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 55
His Arg Leu Pro Trp His His
1 5
<210> 56
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 56
Asp Gly Lys Asn Thr Ser Asn
1 5
<210> 57
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 57
Ala Gly Phe Pro Pro Asn Thr
1 5
<210> 58
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 58
Gln Asn Thr Gly Leu Lys Trp
1 5
<210> 59
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 59
Gln Ile Gly Val Leu Pro Ser
1 5
<210> 60
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 60
Asp Pro Trp Val Met Leu Arg
1 5
<210> 61
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 61
Ser Pro Asp Arg Thr Ser Leu
1 5
<210> 62
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 62
Met Gln Thr Gln Gly Arg Val
1 5
<210> 63
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 63
Leu Arg Pro Ile Ser His Glu
1 5
<210> 64
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 64
Ala Trp Ser Thr Ser Ser Val
1 5
<210> 65
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 65
Ala Gly Gln Leu Met Arg Cys Ala Asn Cys
1 5 10
<210> 66
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 66
Trp Thr Met Lys Pro Asn Tyr
1 5
<210> 67
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 67
Ile Leu Leu Pro Ser Leu Asn
1 5
<210> 68
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 68
Ser Lys Ser Asp Ala Trp Arg
1 5
<210> 69
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 69
Ala Ile Thr Ser Arg Asn Ala
1 5
<210> 70
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 70
Ser Val Leu Arg Met Leu Asn
1 5
<210> 71
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 71
Leu Pro Met Arg Ile Leu Thr
1 5
<210> 72
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 72
Glu His Gly Tyr Tyr Lys Val
1 5
<210> 73
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 73
His Pro Ser Thr Trp His Lys
1 5
<210> 74
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 74
Asn Asp Thr Lys Thr Pro Ser
1 5
<210> 75
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 75
Gly Asp Glu Arg Ile Val Arg Thr Leu Ser His Asn
1 5 10
<210> 76
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 76
Gly Leu Thr Pro Lys Leu Phe
1 5
<210> 77
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 77
Arg Val Pro His Ser Arg Thr
1 5
<210> 78
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 78
Thr Glu Ser Leu Phe Pro His
1 5
<210> 79
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 79
Gly Pro Leu Arg Met Ala Thr
1 5
<210> 80
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 80
Asp Arg Asn Ser Val Phe Trp
1 5
<210> 81
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 81
Ser Ala His Ala Lys His His
1 5
<210> 82
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 82
Lys Met Ala Gly His Thr Val
1 5
<210> 83
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 核心结合结构域
<400> 83
Pro Tyr Tyr Val Val
1 5
<210> 84
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 84
Thr Met Ala Ser Pro Ala Lys
1 5
<210> 85
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 85
Val Leu Thr Lys Pro Met Pro
1 5
<210> 86
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 86
Leu Ser Ser Pro Leu Ser Leu
1 5
<210> 87
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 87
Trp Pro Ser Ile Ser Arg Pro
1 5
<210> 88
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 88
Ser His Ser Pro Gly Asn Lys
1 5
<210> 89
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 89
Glu Thr Thr Arg Asn Tyr Gly
1 5
<210> 90
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 90
Ile Lys Pro Pro Tyr Thr His
1 5
<210> 91
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 91
Val Leu Lys Asn Asn Pro Thr
1 5
<210> 92
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 92
Asp Pro Ile Thr Arg Leu Lys
1 5
<210> 93
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 93
Ser His Leu Ala Ser Arg Pro
1 5
<210> 94
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 94
Thr Ser Pro Trp Glu Leu Arg
1 5
<210> 95
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 95
Ala Leu Pro Leu Ser Ala Ser
1 5
<210> 96
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HNP401-C-8 (具有GG连接子)
<400> 96
Ser Gly Gln Val Pro Trp Glu Glu Pro Gly Gly
1 5 10
<210> 97
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HNP401-C-6 (具有GG连接子)
<400> 97
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Gly Gly
1 5 10
<210> 98
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HNP401-C-4 (具有GG连接子)
<400> 98
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Gly Gly
1 5 10 15
<210> 99
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HNP401-C-2 (具有GG连接子)
<400> 99
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Gly
1 5 10 15
Gly
<210> 100
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HNP401-N-8 (具有GG连接子)
<400> 100
Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly Gly
1 5 10
<210> 101
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HNP401-N-6 (具有GG连接子)
<400> 101
Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly Gly
1 5 10
<210> 102
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HNP401-N-4 (具有GG连接子)
<400> 102
Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly Gly
1 5 10 15
<210> 103
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 103
Cys Leu Lys Gln Gln Thr Gly Asp Cys
1 5
<210> 104
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 104
Glu Gly His Val Trp Ser Glu Tyr Thr Trp Gly Thr
1 5 10
<210> 105
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 105
Phe Met Ser Asp Val Asp His
1 5
<210> 106
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 106
Ile Ser Ser Val Thr Val Val
1 5
<210> 107
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 107
Lys Gln Pro Ala Met Phe Asn
1 5
<210> 108
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 108
Leu Ile Ser Pro Thr Ala Arg
1 5
<210> 109
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 109
Leu Val Leu Gln Thr Thr Pro
1 5
<210> 110
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 110
Asn Pro Thr Ser Glu Gly Ala
1 5
<210> 111
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 111
Thr His Ser Thr Asp Leu Ser
1 5
<210> 112
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 112
Thr Thr Asn Val Thr Glu Ile Glu Arg Glu Ser Tyr
1 5 10
<210> 113
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 113
Tyr Ala Pro Trp Arg Val Phe
1 5
<210> 114
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 114
Tyr Gly Gln Ser Ile Thr Glu
1 5
<210> 115
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 115
Cys Asp Ile Lys Asp Ala Asn Ser Cys
1 5
<210> 116
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 116
Cys Ile Lys Gly Glu Asp Asn Gln Cys
1 5
<210> 117
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 117
His Asn Gln Leu Leu Tyr Thr
1 5
<210> 118
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 118
Ile Glu Gln Val Gly Trp Arg
1 5
<210> 119
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 119
Lys Thr Pro Ile Leu Ala Ser
1 5
<210> 120
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 120
Leu Trp Ala Lys Arg Asp Ala
1 5
<210> 121
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 121
Asn Pro Ile Ser Pro Arg Asn
1 5
<210> 122
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 122
Asn Thr Ala Ser Met Thr Thr
1 5
<210> 123
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 123
Ser Ala His Ser Val Val Glu
1 5
<210> 124
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 124
Tyr Ser Ser Leu Thr Ser Asn
1 5
<210> 125
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 125
Ala Trp Thr Met Arg Ala Ser
1 5
<210> 126
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 126
Cys Glu Arg Ile Gly Pro Arg Glu Cys
1 5
<210> 127
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 127
Cys Gln Lys Trp Phe Thr Phe Ala Cys
1 5
<210> 128
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 128
Cys Ser Asn Ala Leu Asn Lys Ala Cys
1 5
<210> 129
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 129
Phe Ser Pro Arg Asp Val Ser
1 5
<210> 130
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 130
Phe Ser Thr Thr Gly Arg Gly
1 5
<210> 131
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 131
His His Pro Leu Phe Ile Asp
1 5
<210> 132
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 132
Leu Val Asn Pro Phe Pro Glu
1 5
<210> 133
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 133
Tyr Glu Gly Glu Arg Gly Ala
1 5
<210> 134
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 134
Cys Glu Asp Arg Gln Arg Ser Met Cys
1 5
<210> 135
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 135
Cys Gly Glu Lys Ile Met Ser Leu Cys
1 5
<210> 136
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 136
Asp Arg Tyr Leu Leu Asn Gln
1 5
<210> 137
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 137
Phe Pro Ser Tyr Thr Ile Ser
1 5
<210> 138
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 138
Gly Gly Ser Lys Val Trp Gly
1 5
<210> 139
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 139
Gly Leu Trp Arg His Thr Met
1 5
<210> 140
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 140
Lys Arg Asn Leu Trp Asp Ile
1 5
<210> 141
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 141
Ser Pro Asn Thr Asn Ser His
1 5
<210> 142
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 142
Thr Leu Leu His Tyr Ser Ala
1 5
<210> 143
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 143
Val Pro Leu Ala Tyr Leu Arg
1 5
<210> 144
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 144
Val Val Pro Leu Lys Trp Ile
1 5
<210> 145
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 145
Cys Arg Val Gly Val Thr Ser Ala Cys
1 5
<210> 146
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 146
Phe Ala Leu Pro Ala Gly Leu
1 5
<210> 147
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 147
Phe Arg Val Thr Gln Thr Ala
1 5
<210> 148
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 148
His Pro Leu Met Val Pro Ser
1 5
<210> 149
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 149
Leu Pro Asn Ala Asn Asn Leu
1 5
<210> 150
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 150
Met Ile His Thr Arg Gln Thr
1 5
<210> 151
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 151
Ser Glu Thr Glu Ser Tyr Met
1 5
<210> 152
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 152
Ser Asn Ala Leu Ser Tyr Phe
1 5
<210> 153
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 153
Ser Tyr Leu Pro Pro Phe Ile
1 5
<210> 154
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 154
Val His Thr Pro Tyr Arg Ser
1 5
<210> 155
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 155
Trp Pro Arg Pro Ile Gln Ile
1 5
<210> 156
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 156
Trp Thr Ser Val Ala Thr Ala
1 5
<210> 157
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 157
Ala Leu Pro Ile Ser Tyr Leu
1 5
<210> 158
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 158
Phe Glu His Met Ala Val Thr
1 5
<210> 159
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 159
Asn Ala Ser Val Pro Pro Lys
1 5
<210> 160
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 160
Ser Gly His Gly Ala Phe Arg
1 5
<210> 161
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 161
Thr Thr Leu Val Val Thr Ala
1 5
<210> 162
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 162
Cys Pro Asp Ala Ala Arg Asn Ser Cys
1 5
<210> 163
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 163
Cys Tyr Ser Ser Val Ala Asp Met Cys
1 5
<210> 164
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 164
Leu Ser Pro Pro Arg Ile Met
1 5
<210> 165
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 165
Trp Met Thr Asn Leu Asp Pro
1 5
<210> 166
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 166
Lys Leu Pro Thr Leu Ser Val
1 5
<210> 167
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 167
Ala Met Ser Asn Leu Ser Tyr
1 5
<210> 168
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 168
His Pro Phe Pro Arg Phe Asp
1 5
<210> 169
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 169
Leu Pro Ala Glu Ser His Trp
1 5
<210> 170
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 170
Ser Thr His Glu Trp Arg Thr
1 5
<210> 171
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 171
Thr Thr Trp Pro Asn Thr Ala
1 5
<210> 172
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 172
Tyr Met Lys His Ser Pro Gly
1 5
<210> 173
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 173
Ala Tyr Leu Glu Asp Trp Arg Ser Met Ser Thr Arg
1 5 10
<210> 174
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 174
Gly Pro Val Val Ser Gly Met
1 5
<210> 175
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 175
His Leu Asp Ser Arg Arg His
1 5
<210> 176
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 176
Leu Val Leu Ser Asn Pro Arg
1 5
<210> 177
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 177
Asn Met Ser His Ser Asn Arg
1 5
<210> 178
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 178
Ser Val Ala Tyr Val Pro Val
1 5
<210> 179
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 179
Tyr Pro Gln Ala Arg Thr Ser
1 5
<210> 180
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 180
Met Tyr His Asp Ser Val Ser
1 5
<210> 181
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 181
Ala Asp Asn Val Leu Arg Arg Ala Leu Glu Asn Ile
1 5 10
<210> 182
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 182
Gln Ile Ala His Leu Glu Tyr
1 5
<210> 183
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 183
Gly Met Val Ser Pro His His Ser Val Tyr Arg His
1 5 10
<210> 184
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 184
Gly Ser Trp Ser Ser Gly Phe
1 5
<210> 185
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 185
Asn Gly Ala Tyr Ser Leu Ala Ile Arg Tyr Thr Ser
1 5 10
<210> 186
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 186
Tyr Thr Pro Asn Trp His Phe Arg Trp Met Pro Ala
1 5 10
<210> 187
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3人MPZ
<400> 187
Gly Glu Trp Arg Ala Arg Ile Asp Gln Asp Val Ser
1 5 10
<210> 188
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 188
Ala Gly Ser Leu Leu Ser Leu
1 5
<210> 189
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 189
Ala Ile Pro Pro Arg Lys Leu
1 5
<210> 190
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 190
Ala Ile Ser Trp Lys Gly Phe
1 5
<210> 191
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 191
Ala Lys Phe Thr Met Trp Val
1 5
<210> 192
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 192
Ala Leu Arg Asp Thr Arg Val
1 5
<210> 193
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 193
Ala Leu Tyr Asn Gln Met Thr
1 5
<210> 194
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 194
Ala Gln Phe Leu Thr Ile Tyr
1 5
<210> 195
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 195
Ala Gln Leu Gly Ala Phe Arg
1 5
<210> 196
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 196
Ala Arg Val Pro Asn Pro Leu
1 5
<210> 197
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 197
Cys Thr Met Thr Asn Gln Tyr Asp Cys
1 5
<210> 198
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 198
Asp Ser Gln Glu Lys Ser Val
1 5
<210> 199
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 199
Asp Val Arg Ile Trp Thr Leu
1 5
<210> 200
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 200
Glu Leu Lys Ser Leu Arg Phe
1 5
<210> 201
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 201
Glu Ser Lys Ser Pro Arg Glu
1 5
<210> 202
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 202
Glu Thr His Tyr Lys Ile Ala
1 5
<210> 203
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 203
Phe Asp Leu Leu Ala Arg Lys
1 5
<210> 204
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 204
Phe Gln Leu Ser Tyr Glu Thr
1 5
<210> 205
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 205
Gly Glu Pro Ala Leu Val Thr
1 5
<210> 206
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 206
Gly Pro Arg Val Thr Pro His
1 5
<210> 207
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 207
Gly Gln Trp Trp Lys Met Leu
1 5
<210> 208
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 208
Gly Arg His Thr Asp Val Val
1 5
<210> 209
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 209
Gly Ser Pro Tyr Gly Trp Gly
1 5
<210> 210
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 210
Gly Val Ala Glu Val Gly Leu
1 5
<210> 211
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 211
His Ala His Trp Ala Arg Leu
1 5
<210> 212
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 212
His Phe Thr Phe Phe Pro Ile
1 5
<210> 213
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 213
His Pro Trp Ser His Pro Asn
1 5
<210> 214
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 214
His Gln Met Arg Thr Met Leu
1 5
<210> 215
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 215
His Gln Pro Leu Phe Pro Arg
1 5
<210> 216
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 216
His Arg Thr His Leu His Gln
1 5
<210> 217
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 217
His Ser Gly Pro Leu Leu Pro
1 5
<210> 218
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 218
His Ser Ser Ala Thr Met Ser
1 5
<210> 219
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 219
Ile Gly Thr Arg Trp His Gln
1 5
<210> 220
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 220
Ile Asn Phe Pro Phe Ala Val
1 5
<210> 221
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 221
Ile Pro Ile Pro Tyr Arg Thr
1 5
<210> 222
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 222
Ile Pro Tyr Ser Gln Met Pro
1 5
<210> 223
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 223
Lys Ile Ile Thr Thr Lys Ser
1 5
<210> 224
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 224
Lys Met Ser Leu Ala Pro Pro
1 5
<210> 225
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 225
Lys Val His His Leu Ala Arg
1 5
<210> 226
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 226
Leu Glu Leu His Gln Asn Val
1 5
<210> 227
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 227
Leu Ile Thr His Pro Gln Leu
1 5
<210> 228
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 228
Leu Met Leu Pro Gln Leu Glu
1 5
<210> 229
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 229
Leu Val Pro Pro Val Asn His
1 5
<210> 230
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 230
Met Asn Ser Pro Leu Ala Gln
1 5
<210> 231
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 231
Met Gln Arg Leu Gly Ala Asp
1 5
<210> 232
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 232
Asn Gly Pro Asn Ser Leu Gln
1 5
<210> 233
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 233
Asn Gly Val Ser Ser Ser Leu
1 5
<210> 234
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 234
Asn Leu Thr Tyr Leu Arg Phe
1 5
<210> 235
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 235
Gln Gly Ala Tyr Val Arg Pro
1 5
<210> 236
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 236
Gln Lys Ala Leu Pro Gln Thr
1 5
<210> 237
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 237
Gln Thr Ser Ile Met Ser Gly
1 5
<210> 238
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 238
Gln Tyr Trp Asp Ile Leu Gly
1 5
<210> 239
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 239
Arg Gly His Pro Ser Gln Leu
1 5
<210> 240
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 240
Arg Ser Arg Lys His Arg Pro
1 5
<210> 241
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 241
Arg Thr Thr Asp Trp Trp Thr
1 5
<210> 242
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 242
Arg Val Ile Pro Ser Thr Thr
1 5
<210> 243
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 243
Ser Ala Val Leu Met Pro Pro
1 5
<210> 244
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 244
Ser Glu Gly Leu Thr Leu Leu
1 5
<210> 245
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 245
Ser Gly Pro Phe Pro Leu Val
1 5
<210> 246
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 246
Ser Ile Gln Thr Ser Ala Met
1 5
<210> 247
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 247
Ser Lys Leu Ala Gly Phe Pro
1 5
<210> 248
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 248
Ser Lys Pro His Ala Ser His
1 5
<210> 249
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 249
Ser Leu Asp His Leu Arg Leu
1 5
<210> 250
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 250
Ser Leu Lys Thr Thr Asn Pro
1 5
<210> 251
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 251
Ser Leu Trp Gln Thr Leu Arg
1 5
<210> 252
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 252
Ser Leu Trp Thr His Arg Thr
1 5
<210> 253
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 253
Ser Asn Ala His Thr Leu Pro
1 5
<210> 254
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 254
Ser Pro Lys Pro Asp Ile Pro
1 5
<210> 255
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 255
Ser Arg His Leu Pro Pro Leu
1 5
<210> 256
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 256
Ser Ser Phe Tyr Val Ala Tyr
1 5
<210> 257
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 257
Ser Ser Met Arg Tyr Asn Ser
1 5
<210> 258
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 258
Ser Val Gly Leu Pro Thr Lys
1 5
<210> 259
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 259
Ser Tyr Arg Ser Met Ala Pro
1 5
<210> 260
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 260
Ser Tyr Val Thr Val Phe Arg
1 5
<210> 261
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 261
Thr Gly Pro Ser Ser Ala Val
1 5
<210> 262
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 262
Thr Gly Ser Val Ser Lys Gln
1 5
<210> 263
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 263
Thr His Lys His Met Met Thr
1 5
<210> 264
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 264
Thr Ile Arg Val Ala His Thr
1 5
<210> 265
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 265
Thr Pro Gly Arg Ala Thr Leu
1 5
<210> 266
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 266
Thr Pro Val Leu Trp Leu Pro
1 5
<210> 267
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 267
Thr Pro Val Arg Leu Asn Thr
1 5
<210> 268
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 268
Thr Arg Ile Pro Ile Leu Leu
1 5
<210> 269
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 269
Thr Thr Thr Gln Gly His Pro
1 5
<210> 270
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 270
Val Gly Thr Phe Trp Thr Arg
1 5
<210> 271
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 271
Val Ile Arg Thr Ala Ala Met
1 5
<210> 272
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 272
Val Leu Ser Pro Tyr His Asn
1 5
<210> 273
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 273
Val Arg Gly Thr Pro Asn His
1 5
<210> 274
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 274
Trp Asp Leu Pro Gln Asn Arg
1 5
<210> 275
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 275
Trp Asp Leu Arg His Ser Lys
1 5
<210> 276
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 276
Trp Thr Tyr His Pro Thr Thr
1 5
<210> 277
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 277
Trp Val Pro Asp Arg Ser Leu
1 5
<210> 278
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 278
Tyr Pro Thr Tyr Leu Ser Tyr
1 5
<210> 279
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 279
Tyr Pro Tyr Val Pro Ile Tyr
1 5
<210> 280
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 280
Tyr Ser Ser Arg Leu Asn Asp
1 5
<210> 281
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 281
Tyr Thr Ala Ser Pro Arg Trp
1 5
<210> 282
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 282
Tyr Val Asn Arg Val Lys Gln
1 5
<210> 283
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 283
Ala Ala Gly Gln Arg Ser Phe
1 5
<210> 284
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 284
Ala Ile Leu Thr Arg Pro Pro
1 5
<210> 285
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 285
Ala Leu Gly Thr Arg Pro Leu
1 5
<210> 286
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 286
Ala Ser Asn Thr Ser Lys Gly
1 5
<210> 287
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 287
Ala Val Arg Gln Thr Thr Met
1 5
<210> 288
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 288
Cys Glu Asp Ser Asp Lys Ser Val Cys
1 5
<210> 289
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 289
Cys Asn Arg Val Pro Phe Lys Gln Cys
1 5
<210> 290
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 290
Cys Pro Arg Met Asn Asn Pro Leu Cys
1 5
<210> 291
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 291
Asp Val Val Lys Asp Val Ile
1 5
<210> 292
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 292
Glu Ser Pro Tyr Pro His Ser
1 5
<210> 293
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 293
Phe Lys Leu Pro Trp Ala Ser
1 5
<210> 294
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 294
Phe Leu Asn Gln Ala Pro Thr
1 5
<210> 295
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 295
Phe Ser Ala Gly Val Gly Lys
1 5
<210> 296
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 296
Gly His Ser His Tyr Ile Leu Gly Lys Pro Thr Ala
1 5 10
<210> 297
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 297
Gly Pro Ile Thr His Ala Ile
1 5
<210> 298
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 298
His Phe Leu Arg Pro Ser Asp
1 5
<210> 299
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 299
His Leu Leu Lys Thr His Ser
1 5
<210> 300
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 300
His Met Ala Gly Val Asn Gln
1 5
<210> 301
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 301
His Pro Asp Thr Leu Pro Gln
1 5
<210> 302
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 302
His Pro Thr Gly Thr Pro Thr
1 5
<210> 303
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 303
His Thr Gly Leu Arg Ser Leu
1 5
<210> 304
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 304
Lys Gly Gln Pro Leu Phe Arg
1 5
<210> 305
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 305
Lys Tyr Arg His Gly Ala Glu
1 5
<210> 306
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 306
Leu Phe Arg Arg Val Thr Glu
1 5
<210> 307
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 307
Leu Thr Lys Ser Leu Asn His
1 5
<210> 308
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 308
Met Pro Leu Leu Glu Leu Pro
1 5
<210> 309
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 309
Met Thr Asn His Gly Asn Ala
1 5
<210> 310
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 310
Asn Leu Lys Leu Trp Thr Arg
1 5
<210> 311
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 311
Asn Leu Leu Gln Gly Val Met
1 5
<210> 312
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 312
Asn Met Tyr Pro Arg Val Thr
1 5
<210> 313
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 313
Asn Ser Ser Pro His Gln Ile
1 5
<210> 314
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 314
Gln Gly Thr Leu Phe Asp Thr
1 5
<210> 315
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 315
Gln Pro Ile Asp Ser Thr Ser
1 5
<210> 316
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 316
Ser Glu Pro Gly Thr Val Arg
1 5
<210> 317
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 317
Ser Gly Asn Leu Lys Lys Ala
1 5
<210> 318
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 318
Ser Ile Ala Glu Val Leu Gly Leu Trp Arg Asn Val
1 5 10
<210> 319
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 319
Ser Ile Arg Met Thr Glu Ile
1 5
<210> 320
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 320
Ser Ile Ser Lys Ile Arg Thr
1 5
<210> 321
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 321
Ser Leu Arg Ser Val Gly Ala
1 5
<210> 322
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 322
Ser Ser Gly Met Leu Ser Lys
1 5
<210> 323
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 323
Ser Tyr Thr Leu Ser Arg Ser
1 5
<210> 324
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 324
Thr Leu Leu Thr Ala Leu Thr
1 5
<210> 325
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 325
Thr Pro Leu Tyr Leu Ser Ser
1 5
<210> 326
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 326
Val Ser Phe Thr Leu Glu Pro
1 5
<210> 327
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 327
Val Val Asp Met Ser Thr Tyr
1 5
<210> 328
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 328
Trp Pro Asp Leu Arg Ile Leu
1 5
<210> 329
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 329
Trp Ser Leu Pro Leu Leu Ser
1 5
<210> 330
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 330
Trp Ser Pro Arg Trp Pro Ser
1 5
<210> 331
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 331
Tyr Leu Pro Pro Pro Leu Pro
1 5
<210> 332
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 332
Asp Ser Tyr Leu Leu Ser Ala
1 5
<210> 333
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 333
Phe Val Leu Pro Asn Lys Asn
1 5
<210> 334
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 334
Ile Ile Leu Pro Ser Ala Gln
1 5
<210> 335
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 335
Lys Asn Ser Ile Ala Pro Arg
1 5
<210> 336
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 336
Leu Pro Pro Gln Ile Ser Arg
1 5
<210> 337
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 337
Met Pro Ser Leu Lys His Gln
1 5
<210> 338
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 338
Asn Pro Thr Asp Thr Asn Lys
1 5
<210> 339
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 339
Asn Thr Ser Leu Ser Phe Lys
1 5
<210> 340
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 340
Gln Asn Ser Tyr Leu Ser Asn
1 5
<210> 341
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 341
Gln Gln Ala His Leu Gln Ser
1 5
<210> 342
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 342
Ser Pro Pro Arg Phe Ile Pro
1 5
<210> 343
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 343
Ser Trp Phe Glu Ser His Asn
1 5
<210> 344
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 344
Thr Pro Gln Val Met Leu Lys
1 5
<210> 345
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 345
Thr Ser Pro Pro Leu Ala His
1 5
<210> 346
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 346
Thr Ser Arg Leu Val Ser Thr
1 5
<210> 347
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 347
Val Ala His Gln Arg Val Ser
1 5
<210> 348
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 348
Val Pro Thr Leu Arg Ile Pro
1 5
<210> 349
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 349
Tyr Ala Thr Ala Thr Pro Ser
1 5
<210> 350
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 350
Ala Asn Leu Ser Arg Ser Val
1 5
<210> 351
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 351
Phe Ser Ala Arg Thr Asn Thr
1 5
<210> 352
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 352
His Phe Tyr Gly Pro Gly Pro
1 5
<210> 353
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 353
His Pro Trp Leu Gly Asn Arg
1 5
<210> 354
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 354
His Tyr Ser Pro Asn Val Met
1 5
<210> 355
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 355
Asn Phe Ala Gln His Met Gln
1 5
<210> 356
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 356
Ser Asn Ala Glu Arg Trp Arg
1 5
<210> 357
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 357
Ser Arg Pro Thr Arg Val Pro
1 5
<210> 358
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 358
Ser Val Glu Tyr Gly Gln Leu
1 5
<210> 359
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 359
Thr Gly Asn Leu Arg Leu Tyr
1 5
<210> 360
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 360
Met Asp Leu Ser Leu Lys Pro
1 5
<210> 361
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 361
Asn Thr Pro Lys Val Leu Ala
1 5
<210> 362
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂碱性蛋白
<400> 362
Thr Gln Met Thr Met Asp Ser
1 5
<210> 363
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 363
Ala Ser Leu Thr Leu Ala Leu
1 5
<210> 364
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 364
Asp Arg His Glu Gly His Arg
1 5
<210> 365
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 365
Phe Arg Ile Asp Lys Ser Met
1 5
<210> 366
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 366
Gly His Leu Gln Ser Leu Phe
1 5
<210> 367
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 367
Gly Leu Trp Gly Pro Ser Leu
1 5
<210> 368
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 368
Lys Pro Ser Ala Ser Ile Tyr
1 5
<210> 369
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 369
Leu Pro Ser His Ala Ser Ile
1 5
<210> 370
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 370
Leu Pro Val Lys Asn Leu Leu
1 5
<210> 371
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 371
Met Lys Ile Met Pro Met Asp
1 5
<210> 372
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 372
Ser Ala Gln Ser Arg Ser Phe
1 5
<210> 373
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 373
Ser Leu Pro Ser Leu Leu Pro
1 5
<210> 374
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 374
Ser Val Val Tyr Gln Asn Ser
1 5
<210> 375
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 375
Thr Thr Thr Ile Ala Asp Met
1 5
<210> 376
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 376
Val Thr Gly Pro Gly Thr Pro
1 5
<210> 377
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 377
Val Thr Pro Asn Lys Ala Arg
1 5
<210> 378
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 378
Trp His Tyr Thr Pro Ser Met
1 5
<210> 379
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 379
Trp Ser Arg Ile Ser Val Asp
1 5
<210> 380
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 380
Ala Leu Phe Gln Glu Arg Lys
1 5
<210> 381
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 381
Ala Gln Ala Ser Ser Ala Arg
1 5
<210> 382
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 382
Glu Val Leu Tyr Pro Asn Asn
1 5
<210> 383
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 383
His Leu His Thr Arg Pro Thr
1 5
<210> 384
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 384
Ile Arg Pro Thr His Asn Gly
1 5
<210> 385
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 385
Lys Gly Val Ile Pro Ala Thr
1 5
<210> 386
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 386
Leu His Gln Thr Tyr Arg Pro
1 5
<210> 387
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 387
Leu Pro His Arg Leu Asn Pro
1 5
<210> 388
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 388
Thr Gly Ile Ser Ser Thr Pro
1 5
<210> 389
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 389
Thr Met Pro Ile Lys Ala Met
1 5
<210> 390
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 390
Val Pro Gly His Ile Ser Gly
1 5
<210> 391
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 391
Val Ser Ala Ser Trp Met Pro
1 5
<210> 392
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 392
Trp Ser Pro His Gly Tyr Lys
1 5
<210> 393
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 393
Tyr Ser Gln Ala Ile Ser Ala
1 5
<210> 394
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 394
Ala Val Val Ala Met Asn Lys
1 5
<210> 395
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 395
Gly Ile Pro Ser Ser Lys Asn
1 5
<210> 396
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 396
Asn Asp Ala Ser Thr Val Ser
1 5
<210> 397
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 397
Gln Leu Pro Arg Asn Asn Leu
1 5
<210> 398
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 398
Ser Leu Asn Arg Gly Gly Ala
1 5
<210> 399
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 399
Ser Leu Pro Gly Tyr Arg His
1 5
<210> 400
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 400
Ser Val Leu Pro Asp Lys Leu
1 5
<210> 401
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 401
Thr Leu Trp Ala Gln Lys Thr
1 5
<210> 402
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 402
Thr Gln Pro Arg Tyr Pro Ser
1 5
<210> 403
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 403
Val Phe Pro Glu Arg Arg Val
1 5
<210> 404
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 404
Val Gly Tyr Arg Ser Ala Ser
1 5
<210> 405
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 405
Val Arg Thr Ser Met Asn His
1 5
<210> 406
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 406
Tyr Thr Trp Thr Pro Ser Arg
1 5
<210> 407
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 407
Phe Ser Leu Asp Arg Asp Gly
1 5
<210> 408
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 408
Phe Ser Thr Pro Thr Asn Val
1 5
<210> 409
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 409
Gly Pro Ala Ala Val Ile Ile
1 5
<210> 410
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 410
Gly Trp Ser Thr Ala Ile Arg
1 5
<210> 411
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 411
His Lys Ala Pro Leu Gly Thr
1 5
<210> 412
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 412
Ile Asp Arg Val Arg Gly Leu
1 5
<210> 413
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 413
Leu Met Gln Lys Pro Ser Ile
1 5
<210> 414
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 414
Ser Val Met Trp Met Thr Pro
1 5
<210> 415
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 415
Thr Lys Ile Thr Pro His Arg
1 5
<210> 416
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 416
Tyr Ser Ser Arg Leu Thr Ala
1 5
<210> 417
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 417
Ala Arg Phe Val Pro Leu Thr
1 5
<210> 418
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 418
Asp Gly Ser Arg Asp Leu Val
1 5
<210> 419
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 419
Glu Lys Ser Thr Thr Val Ala
1 5
<210> 420
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 420
Tyr Ser Asp Thr Tyr Lys His
1 5
<210> 421
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 421
Glu Pro Ser Ser Phe Thr Phe
1 5
<210> 422
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 422
Gly Lys Ser Tyr Ser Gln Ile
1 5
<210> 423
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 423
Gly Asn Val Phe Gln Thr Ser
1 5
<210> 424
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 424
Ile Ile Pro Pro Thr Ser Val
1 5
<210> 425
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 425
Leu Pro Leu Arg Leu His Ala
1 5
<210> 426
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 426
Asn Val Phe Ser Ala Thr Pro
1 5
<210> 427
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 427
Gln Arg Arg Ser Val Ile Leu
1 5
<210> 428
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 428
Ser Gly Val Ala Thr Tyr Thr
1 5
<210> 429
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 429
Ser Trp Asp Val Leu Glu Leu
1 5
<210> 430
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 430
Thr Phe Pro Glu Arg Leu Arg
1 5
<210> 431
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 431
Trp Ser Pro His Arg Ser Phe
1 5
<210> 432
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 432
Ile His His Leu Glu Ser Ser
1 5
<210> 433
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 433
Leu Asn Gly Ile Ser Ala Leu
1 5
<210> 434
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 434
Ser Ala Leu Ile Ser Thr Arg
1 5
<210> 435
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 435
Ser Gly Leu His Tyr Ala Leu
1 5
<210> 436
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 436
Thr Arg Ala Ser Tyr Pro Gln
1 5
<210> 437
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 437
Asn Ile Pro Ser Ser Ile Leu
1 5
<210> 438
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 438
Gln Pro Asn Met Leu Lys Pro
1 5
<210> 439
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 439
Arg Leu Gln Pro Glu Pro Thr
1 5
<210> 440
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 440
Ser Val Glu Lys Tyr Ser Lys
1 5
<210> 441
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 441
Val Ser Ser Gln Glu Gln Ala
1 5
<210> 442
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 442
Trp Asn Thr Ala Asp Arg Leu
1 5
<210> 443
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 443
Met Pro His Ala Pro Val Gln
1 5
<210> 444
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 444
Thr Asp Val Glu Met Val Pro
1 5
<210> 445
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 445
Ala His Gln Ser Ser Val Thr
1 5
<210> 446
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3髓磷脂PLP
<400> 446
Gly Ser Ala Trp Lys Lys His
1 5
<210> 447
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 447
Cys Ile His His Lys Gly Val Leu Cys
1 5
<210> 448
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 448
Cys Lys Asp Gly His Ile Arg His Cys
1 5
<210> 449
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 449
Cys Asn Leu Ala Thr Ser Leu Gln Cys
1 5
<210> 450
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 450
Cys Arg Ser Pro His Glu Pro Met Cys
1 5
<210> 451
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 451
Cys Val Asp Lys Met Ala Ser Val Cys
1 5
<210> 452
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 452
Cys Tyr Ser Ala Pro Thr Lys Ser Cys
1 5
<210> 453
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 453
Glu Ala Met Met His Arg Asn
1 5
<210> 454
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 454
Leu His Ile Thr Pro Glu Val
1 5
<210> 455
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 455
Leu Ser Ile Arg Gly Leu Thr
1 5
<210> 456
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 456
Asn Ile Leu Ser Gln Val Asn
1 5
<210> 457
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 457
Gln Leu Leu Glu Ser Arg Thr
1 5
<210> 458
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 458
Gln Met Asp Ala Lys His Met
1 5
<210> 459
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 459
Gln Thr Leu Arg Pro Lys Gln
1 5
<210> 460
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 460
Thr Ile Ala Ser Leu Leu Val
1 5
<210> 461
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 461
Trp Leu Ala Ala Gly Ser Gln
1 5
<210> 462
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 462
Ala Leu Tyr Leu Pro Gly Arg
1 5
<210> 463
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 463
Ala Arg Met Ala Phe Ser Leu
1 5
<210> 464
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 464
Ala Thr Tyr Asn Met Ser Gln
1 5
<210> 465
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 465
Gly Leu Arg Thr Met Glu Pro
1 5
<210> 466
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 466
Thr Pro Trp Leu Pro Thr Ile
1 5
<210> 467
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 467
Tyr Asn His Thr Met Met Tyr
1 5
<210> 468
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 468
Cys Ser Phe Lys Met Asn Gln Lys Cys
1 5
<210> 469
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 469
Leu Val His Pro Phe His Gly
1 5
<210> 470
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 470
Cys Ser Ser Ser Ala Pro Arg Ile Cys
1 5
<210> 471
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> R3巢蛋白-2
<400> 471
His Ser Arg Leu Pro Thr Pro
1 5
<210> 472
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 472
Cys Lys Ser Pro Ile Lys Gly Thr Cys
1 5
<210> 473
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 473
Cys Leu Gln Lys Asn His Lys Phe Cys
1 5
<210> 474
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 474
Cys Val Leu Lys Cys Glu Asp Gln Lys Tyr Arg Gly
1 5 10
<210> 475
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 475
Asp Gly Ala Asn Met Phe Asn Ile Ala Pro Ala Asn
1 5 10
<210> 476
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 476
Asp Arg Met Tyr Ser Thr Val Pro Ala Glu Gly Leu
1 5 10
<210> 477
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 477
Glu Ala Val Ser Thr Gln Ile
1 5
<210> 478
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 478
Gly Ile Asn Leu Arg Ala Leu Asp Leu His Ala Asn
1 5 10
<210> 479
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 479
His Gln Ser Val Thr Gly Val Arg Ser His Phe His
1 5 10
<210> 480
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 480
Ser Val Val Gly Trp Ala Ala Pro Arg Thr Ala Gln
1 5 10
<210> 481
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 481
Thr Ile Leu Lys Pro Ala Ala Gln Gly Phe Ala Asp
1 5 10
<210> 482
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 482
Thr Ser Ala Val Ser Leu Arg
1 5
<210> 483
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 483
Thr Thr Leu Trp Leu Asp Arg Asp Glu Ala Leu Lys
1 5 10
<210> 484
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 484
Val Ile Ala Asp Gln Ser Lys Ser Ala Val Ala Val
1 5 10
<210> 485
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 485
Ala Gln Asn Leu Arg Val His Ala Trp Ala Ser Leu
1 5 10
<210> 486
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 486
Cys Pro Met His Gln Ser Lys Thr Cys
1 5
<210> 487
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 487
Cys Thr Asp Gly Arg Asn Phe Val Cys
1 5
<210> 488
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 488
Cys Thr Gly Glu Thr Leu Leu Thr Cys
1 5
<210> 489
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 489
Cys Thr Ser Ser Ser His Gln Thr Cys
1 5
<210> 490
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 490
Glu Thr Gly Gly Leu Ala Tyr Gly Ser Gly Gln Lys
1 5 10
<210> 491
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 491
Gly Ile Val Pro Ser Arg His Thr Thr Gly Leu Gly
1 5 10
<210> 492
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 492
Gly Trp Thr Ser Asp Leu Ser Arg Asn Val Arg Gly
1 5 10
<210> 493
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 493
His Thr Gln Ile His Arg Leu
1 5
<210> 494
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 494
Lys Phe Ala Asp Thr Lys Leu Thr Ser Leu Arg Tyr
1 5 10
<210> 495
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 495
Gln Leu Gln His Val His Leu
1 5
<210> 496
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 496
Gln Pro Thr Pro Ser Gln Ile Lys Phe Thr Arg Thr
1 5 10
<210> 497
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 497
Arg Ala Leu Asp Arg Tyr Leu Pro Trp Ser Pro His
1 5 10
<210> 498
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 498
Ser Leu Pro Tyr Ala Ala Ser Leu Asn Ser Val Glu
1 5 10
<210> 499
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 499
Ser Thr Asn Val Gln Arg Ala
1 5
<210> 500
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 500
Ser Val Leu Ser Thr Gly Thr Ala Asn Gln Arg His
1 5 10
<210> 501
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 501
Ser Val Gln Thr Pro Met Trp Arg Ser Leu Val Gly
1 5 10
<210> 502
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 502
Ser Trp His Phe Thr Gly Thr Pro Phe Met Asn Arg
1 5 10
<210> 503
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 503
Ser Tyr Thr Ala Thr Trp Ser Glu Met Ser Arg Ser
1 5 10
<210> 504
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 504
Thr Ala Leu Ser His Arg His Glu Ala Met Arg Trp
1 5 10
<210> 505
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 505
Thr Lys Gly Ile Ala Pro Lys
1 5
<210> 506
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 506
Thr Val Ala Arg Ser Thr Ala Gln Glu Arg Ser Ile
1 5 10
<210> 507
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 507
Ala Val Arg Pro Leu Gly Leu Pro Asp Asn His Arg
1 5 10
<210> 508
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 508
Cys Ile Gly Gly Pro His Arg Asn Cys
1 5
<210> 509
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 509
Cys Lys Ser Pro Ala Ile Lys Gly Cys
1 5
<210> 510
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 510
Cys Asn Ser Trp Lys Ala Ala Lys Cys
1 5
<210> 511
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 511
Asp Ser Leu Tyr Arg Gly Met His Gln Pro Arg Ile
1 5 10
<210> 512
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 512
Glu Asp Arg Met Met Thr Tyr Arg Tyr Thr Ser Thr
1 5 10
<210> 513
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 513
Glu Val Glu Arg Ile Leu Thr Pro His Val Asn Asn
1 5 10
<210> 514
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 514
Phe Asn Ser Asp Ser Arg Ser Thr His Gln Glu Asp
1 5 10
<210> 515
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 515
His Pro Ala Trp Ala Asp Phe Phe Thr Met Ser Ser
1 5 10
<210> 516
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 516
Ile Asp Leu Ser Leu Arg Ser
1 5
<210> 517
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 517
Ile Asp Gln Ser Gly Leu Gln Lys Ser Gly Met Lys
1 5 10
<210> 518
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 518
Leu Gly Ser Ser Arg Ser Pro Ser Ser Phe Leu Gly
1 5 10
<210> 519
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 519
Asn Gly His Glu Val Gln Ser Arg Ala Ala Asn Arg
1 5 10
<210> 520
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 520
Gln Gly Trp Lys Asp Arg Leu Pro Ile Trp Arg Tyr
1 5 10
<210> 521
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 521
Ser His Asp Val Ala Asn Gly Thr Ser Val Arg Thr
1 5 10
<210> 522
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 522
Ser Pro Asp Arg Thr Asn Trp Gly Trp Gln Thr Asn
1 5 10
<210> 523
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 523
Ser Val Glu Ser Asn Ser Lys Leu Thr Met Pro Arg
1 5 10
<210> 524
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 524
Trp Pro Met Met Gln Thr Arg
1 5
<210> 525
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 525
Cys Lys Ser Glu Arg Gly Pro Glu Cys
1 5
<210> 526
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 526
Cys Gln Gly Trp Pro Arg Pro Met Cys
1 5
<210> 527
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 527
Cys Ser Arg Ala Gly Leu Ser Ala Cys
1 5
<210> 528
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 528
Cys Thr Trp Lys His Arg Asp Asn Cys
1 5
<210> 529
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 529
Gly Leu Leu Asp Trp Gly Ser Leu Gln Gly Gly Asn
1 5 10
<210> 530
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 530
Gly Pro Leu Leu Phe Arg Gly
1 5
<210> 531
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 531
Gly Ser Pro Glu Lys Arg Thr
1 5
<210> 532
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 532
Lys Ala Ser Ile Ala Tyr Asp
1 5
<210> 533
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 533
Leu Gly Tyr Gly Gln Gly Thr Pro His Arg Ser Asn
1 5 10
<210> 534
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 534
Gln Gly Trp Glu Phe Gln Val Pro Ala Arg His Ser
1 5 10
<210> 535
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 535
Gln Thr Phe Gly Tyr Ser Met Phe Asn Val Arg Thr
1 5 10
<210> 536
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 536
Arg Asn Leu His Tyr Pro Leu Asn His Pro Phe Met
1 5 10
<210> 537
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 537
Thr Ala Pro Arg Trp Thr Gln
1 5
<210> 538
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 538
Val Pro Ser Tyr Ile Leu Arg
1 5
<210> 539
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 539
Trp Arg Ser Pro Leu Thr Thr
1 5
<210> 540
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 540
Cys Gln Thr Ser Gly His His Gln Cys
1 5
<210> 541
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 541
Cys Ser Ser Gln Ala Lys Arg Ser Cys
1 5
<210> 542
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 542
Cys Thr Ala Trp Thr Arg Gln Glu Cys
1 5
<210> 543
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 543
Glu Tyr Val Lys Phe Ser His Ser Pro Arg Thr Tyr
1 5 10
<210> 544
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 544
Gly Gly Trp Gln Ser Leu Trp Asp Lys Pro Glu His
1 5 10
<210> 545
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 545
Gly Pro Met Leu Lys Asn Leu Ser Asp Ala Val Thr
1 5 10
<210> 546
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 546
Asn His Asp Gln Gly Ser Leu Thr Arg Trp Arg Ser
1 5 10
<210> 547
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 547
Ser Leu Leu Ser Val Val Asn Thr Ser Ser Lys Ser
1 5 10
<210> 548
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 548
Val Val Pro Ser Trp Pro Ser Val His Arg Pro Pro
1 5 10
<210> 549
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 549
Trp Gly Trp Asn Gly Ala Asn Met Ser Pro Arg Gly
1 5 10
<210> 550
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 550
Cys His Asn Ala Asp Asn Asn Gly Cys
1 5
<210> 551
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 551
Leu Pro Met Leu Arg His Ser
1 5
<210> 552
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 552
Asn Asp Thr Gly Arg His Ala Ser Gly Ile Ser Lys
1 5 10
<210> 553
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 553
Gln Ala Leu Arg Thr Asn Tyr Ser Pro Leu Asn Ser
1 5 10
<210> 554
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 554
Thr Leu Lys Ala Gly Thr Arg Ala Asn Asp Gly Val
1 5 10
<210> 555
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 555
Cys Gly Glu Thr Thr Ala Gly Lys Cys
1 5
<210> 556
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 556
His Ser Thr Tyr Ala Pro Gly
1 5
<210> 557
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 557
Gln Ile Asn Trp Lys Gln Ala Asp Lys Asn Ala Asp
1 5 10
<210> 558
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 558
Ala Leu Pro Trp Gln Ser Gly Val His Gly Thr Lys
1 5 10
<210> 559
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 559
Thr Phe Gly Ser Gly Arg Ser Met Pro Ile Gln Tyr
1 5 10
<210> 560
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 560
Val Tyr Arg Asn Gly Gly Gly Leu Pro Leu Thr Ala
1 5 10
<210> 561
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 561
Ala Leu Lys Ile Gly Pro Glu Thr Thr Ile Tyr Met
1 5 10
<210> 562
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 562
Asp Trp Thr Gln Val Arg Val Thr Asn Trp Phe Leu
1 5 10
<210> 563
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 563
Leu Gly His Gln Asn Gly Gly Arg Ala Asp Met Trp
1 5 10
<210> 564
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 564
Met Thr Asn Ser Gly Ala Lys
1 5
<210> 565
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 565
Trp Ala Tyr Thr Asp Tyr Met
1 5
<210> 566
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 566
Ala His Ala Ala Gly Arg Asp Met Arg Gln Gly Thr
1 5 10
<210> 567
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 567
Asp Val Ile His Ser Ser Arg Gly Ala Tyr Phe Glu
1 5 10
<210> 568
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 568
Asn Trp Thr His Leu Gly Val Ala Arg Leu Gln Pro
1 5 10
<210> 569
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 569
Ser Tyr Asp Gly Thr Met Leu Lys Gln Val Arg Leu
1 5 10
<210> 570
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 570
Trp Gln Trp Arg Ser Thr Glu Leu Gly Tyr Arg Tyr
1 5 10
<210> 571
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 571
Trp Ser Pro Ala Asn Gly Trp Arg His Gln Thr Ile
1 5 10
<210> 572
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 572
Cys Leu His Asn Gly Gln Arg Ser Cys
1 5
<210> 573
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 573
Cys Thr Pro Arg Ser Ala Thr Leu Cys
1 5
<210> 574
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 574
Asp Ile Met Lys Ser Pro Arg Ser Asn Leu Arg Ser
1 5 10
<210> 575
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 575
Gln Thr Phe His Glu Tyr Leu Asn Pro Ala Arg Gly
1 5 10
<210> 576
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 576
Ser Leu Asn Thr Thr Trp Val Ser Pro Met Met Lys
1 5 10
<210> 577
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 577
Ala Gln Arg Met Asn Gln Ala
1 5
<210> 578
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 578
Gly Asp Ala Gln Ile Leu Met
1 5
<210> 579
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 579
Gly His Arg Thr Leu Val Thr Ser Glu Arg Tyr Leu
1 5 10
<210> 580
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 580
Leu Gly Pro Ser Thr Gln Gly Ala Gly Gln Thr Arg
1 5 10
<210> 581
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 581
Thr Phe Ala Ala Ala Gln Ala Glu Leu Ile Met Val
1 5 10
<210> 582
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 582
Trp Glu Glu His Arg Val Glu Ile Leu Pro Asp Val
1 5 10
<210> 583
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 583
Ala Gly Ala Tyr Thr Ser Arg His Ala Phe Asp Glu
1 5 10
<210> 584
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 584
Cys Gly Leu Ala Thr Asn Lys Ser Cys
1 5
<210> 585
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 585
Gly Asp Val Ile Thr Ala Tyr Ile Asn Pro Trp Pro
1 5 10
<210> 586
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 586
Gly Tyr Asp Leu Ser Arg Leu Trp Gly Met Ala Ser
1 5 10
<210> 587
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 587
Ala Asn Arg Tyr Leu Ala Ser
1 5
<210> 588
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 588
Cys Lys Trp Thr Gln Leu Trp Gly Cys
1 5
<210> 589
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 589
Cys Leu Lys Asp Thr His Leu Asn Cys
1 5
<210> 590
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 590
Gly Gln Pro Arg Asn Ile His Leu Pro Gly Thr His
1 5 10
<210> 591
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 591
Gly Ser Thr Thr His Pro His Phe Gly Leu Pro Gly
1 5 10
<210> 592
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 592
Gly Trp Ile Gln Asp Thr Phe Val Leu Gly Arg Ser
1 5 10
<210> 593
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 593
Gln Gly His Pro Phe Ile Tyr
1 5
<210> 594
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 594
Ser Asn Pro Lys His Val Ser Ser Leu Gly Gln Met
1 5 10
<210> 595
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 595
Trp Gly Ala Asn Thr Thr Gly Arg Thr His Gly Gly
1 5 10
<210> 596
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 596
Ala Gln Gly Val Trp Trp Ser Glu Trp Phe Ala Pro
1 5 10
<210> 597
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 597
Cys Phe Gln Pro Lys Met Asn Ser Cys
1 5
<210> 598
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 598
Cys Trp Ser Gly Asn Ser Arg Ser Cys
1 5
<210> 599
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 599
Phe Pro Leu Lys Ile Arg Thr
1 5
<210> 600
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 600
Leu Ala Arg Ser Ser Ile Met Ala Ala Asn Asn Val
1 5 10
<210> 601
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 601
Ala Lys Thr Gln Ala Pro Ser Asn Trp Ser Gly Val
1 5 10
<210> 602
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 602
Cys Ser Val Trp Asn Ser Gly Asn Cys
1 5
<210> 603
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 603
Cys Thr Gly Arg Ile Ser Lys His Cys
1 5
<210> 604
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 604
Gly Ala Met Met Asn Ser Asn Asn Leu Val Ala Arg
1 5 10
<210> 605
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 605
Gly Gly Gly Tyr His Ile Phe Gly Pro Leu Val Thr
1 5 10
<210> 606
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 606
His Ser Phe Leu Gly Ala Arg
1 5
<210> 607
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 607
Leu Leu Ala Gly Pro Phe Arg
1 5
<210> 608
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 608
Gln Thr Leu Gln Thr Arg His
1 5
<210> 609
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 609
Ala Leu Gly Gly Glu Pro Arg Lys Ala Tyr Gln Arg
1 5 10
<210> 610
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 610
Cys Asn His Leu Thr Gln Lys Leu Cys
1 5
<210> 611
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 611
Cys Thr Ser Lys Leu Ala Arg His Cys
1 5
<210> 612
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 612
Ala Val Tyr Pro Leu Asp Leu Gly Ala Gly Met Arg
1 5 10
<210> 613
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 613
Cys His Arg Thr Tyr Asn Ser Thr Cys
1 5
<210> 614
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 614
Leu Asp Arg Asn Ala Asp Ser Val Arg Ala Val Leu
1 5 10
<210> 615
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 615
Thr Thr Asn Gly Val Pro Gly His Asp Arg Ser Pro
1 5 10
<210> 616
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 616
Ala Asp Met Pro Gln Met Thr Leu Lys Tyr Gly Val
1 5 10
<210> 617
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 617
Ala Trp Asn Gly Asn Arg Ser
1 5
<210> 618
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 618
Gly Asp Leu Leu Leu Lys Arg
1 5
<210> 619
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 619
Val Pro Gln Ile Arg Ile Lys
1 5
<210> 620
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 620
Ser Trp Gln Met Arg Ser Tyr
1 5
<210> 621
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 621
Tyr His Leu Gly Pro Asn Gln Lys Met Arg Thr Ser
1 5 10
<210> 622
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 622
Ala Ser His Ser Arg Pro Leu Met Asn Tyr Ala Pro
1 5 10
<210> 623
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 623
Gln Thr Arg Trp Asp Asp Gly Ser Tyr Gln Ile Ser
1 5 10
<210> 624
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 624
Ser Leu Ala Val Ala Asn Thr Arg Phe Met Ile Arg
1 5 10
<210> 625
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 625
Glu Gly His Val Trp Ser Glu Tyr Thr Trp Gly Thr
1 5 10
<210> 626
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 626
Glu Thr Tyr Lys Val Thr Arg Val Ile Ser Pro Trp
1 5 10
<210> 627
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 627
Gly His Pro Trp Thr Glu Ile Asp Phe Met Ser Ser
1 5 10
<210> 628
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 628
Lys Gln Glu Leu Ser Asp Asn Leu Ala Ser His Arg
1 5 10
<210> 629
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 629
Ser Phe Arg Asn Leu Glu Lys Leu Ser Leu Trp Ser
1 5 10
<210> 630
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 630
Gly Asp Leu Trp Asn Val Pro
1 5
<210> 631
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 631
Gly Pro Lys Asn His His Gln
1 5
<210> 632
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 632
Gly Ser Gly Phe Arg Asn Glu Glu His Ser Ala His
1 5 10
<210> 633
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 633
Asn Asn Asn Ala Ala Met Gln Asn His Gly Val Arg
1 5 10
<210> 634
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 634
Arg Ala Gln Ala His Gln Val
1 5
<210> 635
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 635
Cys Ser Leu Ala Asn Pro Ala Thr Cys
1 5
<210> 636
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 636
Gly Glu Pro Leu Thr Arg Phe Pro Asn Ser Asp Ser
1 5 10
<210> 637
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 637
Lys Pro Ile Leu Trp Asn Arg Ser Leu Asn Ala Leu
1 5 10
<210> 638
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 638
Gly Phe Ala Asp Val Ile His Arg Lys Trp Ser Ser
1 5 10
<210> 639
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 639
His Gln Ser Leu Ala Gly Val Pro Trp Ser Arg His
1 5 10
<210> 640
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 640
Val Pro Val Phe Leu Asp Gln Ala Arg Val Met Lys
1 5 10
<210> 641
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 641
Asp Asp Leu Leu Thr Ala Pro Arg Leu Gly Val Trp
1 5 10
<210> 642
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 642
Ser Asp Arg Gly Lys Thr Val Leu His Gly Gln Ile
1 5 10
<210> 643
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 643
Cys Gly Ile Thr Gln Thr Thr Thr Cys
1 5
<210> 644
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 644
Cys His Gln Arg Gln Gln Thr Tyr Cys
1 5
<210> 645
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 645
Glu Tyr Trp His Gln Arg Gly Ser Trp Phe His Arg
1 5 10
<210> 646
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 646
Tyr Thr Pro Arg Asn Gln Leu
1 5
<210> 647
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 647
Cys Thr Lys Ser Pro Ser Asn Ser Cys
1 5
<210> 648
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 648
Trp Ala Phe Lys Ala Pro Gln
1 5
<210> 649
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 649
Gly Ser Leu Asp Met Gly Asn Asn Lys Gln Pro Val
1 5 10
<210> 650
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 650
Ala Val Val Ser Gln Asn Gln Met Ser Gln Gln Lys
1 5 10
<210> 651
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 651
Cys Leu Asn Gln Lys Trp Glu Ala Cys
1 5
<210> 652
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 652
Trp Pro Val Arg Asn Leu Leu
1 5
<210> 653
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 653
Gly Tyr Arg Ser Phe Ile His Glu Asn Trp Ser Ile
1 5 10
<210> 654
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 654
Ser Gly Trp Glu Gly Lys Thr His Gln Gly Val Arg
1 5 10
<210> 655
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 655
Leu Gln Ser Asn Ala Ala Asp His His Gln Gly Met
1 5 10
<210> 656
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 656
Ala Thr Ser Lys Tyr Pro Asn Ser Trp Ala Gln Thr
1 5 10
<210> 657
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 657
Asp Arg Leu Thr Pro Ile Thr Trp Asp Trp Ser Arg
1 5 10
<210> 658
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 658
Trp Thr Lys His Asn Thr Pro Ala His His Leu Ser
1 5 10
<210> 659
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 659
Trp Asn Ala Asn Tyr Gly Thr Met Thr Arg His Ala
1 5 10
<210> 660
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 660
His Ala Ser Asn Gln Arg Val
1 5
<210> 661
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 661
Gly Arg Thr Ile His Ser Met
1 5
<210> 662
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 662
Arg Leu Val Thr Ala Ser Met Val Ser Pro Ser Phe
1 5 10
<210> 663
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 663
Asp Gly Gln Val Ser Asp His Ser Tyr Val Gln Trp
1 5 10
<210> 664
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 664
Lys Ile Ser Met Asn Arg Leu His Ala Asn Phe Thr
1 5 10
<210> 665
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 665
Trp Asp Leu Pro Thr Leu Arg Lys Thr Lys Gln Ala
1 5 10
<210> 666
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 666
Trp Val Ala Ala Glu Arg Arg
1 5
<210> 667
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 667
Met Thr His Ser Ala His Asn Ser Gln Lys Thr Asn
1 5 10
<210> 668
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 668
Trp Gly Leu Lys Leu Pro His
1 5
<210> 669
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 669
Gln Gly Trp Phe Arg His Ser
1 5
<210> 670
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 670
Ile Pro Val Gly Glu Arg Lys
1 5
<210> 671
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 671
Cys Met Asn Lys Ile Gln Arg Asp Cys
1 5
<210> 672
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 672
Lys Ala Leu Gly Tyr Ser Leu Val Gly Gly Glu Trp
1 5 10
<210> 673
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 673
Ala Pro Lys Val Thr Asn Ala Arg Pro Thr Gln Leu
1 5 10
<210> 674
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 674
Ala Trp Val Glu Ala Gln Asn Ala Ser Asn Pro Ser
1 5 10
<210> 675
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 675
Cys Ser Lys His Asn His Ser Arg Cys
1 5
<210> 676
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 676
Gly Lys Pro Asp His Arg Leu Val Ser Leu Trp Arg
1 5 10
<210> 677
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 677
Cys Ser His His Lys Leu Lys Gln Cys
1 5
<210> 678
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 层粘连蛋白421/521
<400> 678
Gly Gly Tyr Asp Leu Pro Trp Ala Asn Trp Gln Asn
1 5 10
<210> 679
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 679
Gly Trp Gln Met Phe Pro Pro Met Gln Asn Thr Arg
1 5 10
<210> 680
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 680
Ser Ser Leu Tyr Met Asn Gly Trp Ser Arg Asp Gln
1 5 10
<210> 681
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 681
Tyr Ala Gly Gln Asn Gly Trp Met Arg Ser Asp Leu
1 5 10
<210> 682
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 682
Val Glu Arg Leu Asn Trp Pro Lys Arg Met Gln Ser
1 5 10
<210> 683
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 683
Trp Asp Val Ala Trp Leu Glu Arg Arg Ala Leu His
1 5 10
<210> 684
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 684
Val Arg Leu Pro Met Leu Ala Ser Met Gly His Gln
1 5 10
<210> 685
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 685
Asp Arg Gly Leu Thr Ile Leu Thr Asp Asp Leu Arg
1 5 10
<210> 686
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 686
Gly Trp Asn Glu Ala Thr Asn Ser Ala Arg His Thr
1 5 10
<210> 687
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 687
Glu Phe Ala Arg Phe Arg Val Phe Gly Val Ala Glu
1 5 10
<210> 688
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 688
Asn Arg Ile Gly His Gly Thr Ala Thr Gly Thr Leu
1 5 10
<210> 689
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 689
Val Thr Asp Met Leu Gly Ile Pro Lys Leu His Ala
1 5 10
<210> 690
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 690
Asp Glu Leu Val Gly Gly Ala Pro Trp Tyr Lys Ser
1 5 10
<210> 691
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 691
Gly Leu Leu Arg Glu Pro Asp Glu Leu Met Phe Leu
1 5 10
<210> 692
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 692
Gln Asn Ile Val Glu Asn Phe Ile Asp Asn Glu Arg
1 5 10
<210> 693
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 693
Ser Gly Glu Tyr Asn Leu Ile Lys Pro Asn Leu Leu
1 5 10
<210> 694
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 694
Glu Glu Ser Asn Ala Lys Leu Glu Leu Leu Ser Arg
1 5 10
<210> 695
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 695
Gly Trp Ala Asn Ser Ile Thr Tyr Arg Asn Leu Tyr
1 5 10
<210> 696
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 696
Asn Tyr Ala Val Gly Asp Arg Ile Thr Lys Asn Ile
1 5 10
<210> 697
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 697
His Gly Ile Val Phe Ser Lys Arg Pro Phe Ser Asn
1 5 10
<210> 698
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 698
Phe Asp Pro Leu Ser Arg Asn Val Pro His Lys Thr
1 5 10
<210> 699
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 699
Asn Ala Val His Arg Pro Asp Leu Asn Leu Leu Ala
1 5 10
<210> 700
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 700
Gly Met Arg Thr Gly Asp Asp Ser Pro Lys Tyr Pro
1 5 10
<210> 701
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 701
Ile Pro Gly Gln Thr Pro Arg Met Pro His Ser Lys
1 5 10
<210> 702
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 702
Lys Thr Thr Ser Met Thr Ala Leu Thr Met Gly Leu
1 5 10
<210> 703
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 703
Val Asn Tyr Gln Thr Pro Trp Asn Lys His Trp Tyr
1 5 10
<210> 704
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 704
Val Glu Ser Gly His Ala Tyr Ser Val Ser Ser Trp
1 5 10
<210> 705
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 705
Val Arg Ser Asp Met Val Ser Gly Gly Leu Gln Lys
1 5 10
<210> 706
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 706
Tyr Ala Asn Gly Ile Glu Ala Lys Asp Ser Ser Arg
1 5 10
<210> 707
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 707
Tyr Ala Trp Asp Thr Val Ala Ser Arg Asn Tyr Lys
1 5 10
<210> 708
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 708
Leu Gln Thr His Ser Ile Thr Tyr Arg His Glu Arg
1 5 10
<210> 709
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 709
Ser Leu Gly Ser Ser Phe Val Gln Gly Gly Glu Leu
1 5 10
<210> 710
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 710
Trp Glu Lys His Thr Gly Pro Leu Ser Arg Tyr Leu
1 5 10
<210> 711
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 711
Ala Phe Arg Phe Glu Phe Gln Val Pro Asp Ser His
1 5 10
<210> 712
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 712
Gly His Ala His Ser Leu Thr Gln Asn Pro Leu Phe
1 5 10
<210> 713
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 713
Gly Leu Thr Ile Met Ser Ser Arg His Ser Leu Gln
1 5 10
<210> 714
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 714
Asn Gly Met Asn Trp Leu Gln Val His Gln Leu Ser
1 5 10
<210> 715
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 715
Trp Ser Gly Gly Met Glu Asp Asn Ser Asn Arg Leu
1 5 10
<210> 716
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 716
Ala Ile Met Ser Tyr Asn Ser Pro Trp Ile Gln Gly
1 5 10
<210> 717
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 717
Asp Val Met Gln Met Phe His Gln Val His Phe Tyr
1 5 10
<210> 718
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 718
Gln Ala Asn Leu Tyr Tyr Trp Asp Pro Ser Asp Leu
1 5 10
<210> 719
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 719
Gln Arg Ala Thr Asn Asp Ile Leu Ile Arg Gly Trp
1 5 10
<210> 720
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 720
Ser Pro Met Ala Asn Val Trp Phe Asn Arg Leu Ser
1 5 10
<210> 721
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 721
Tyr Ser Ala Asn Ser Asn Pro Lys Lys Ser Leu Met
1 5 10
<210> 722
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 722
Ala Leu Asn His Asn Gly Pro Val Lys Thr Gly Leu
1 5 10
<210> 723
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 723
Asp Ala Ser Gln Tyr Pro Leu Val Ser Gly Leu Trp
1 5 10
<210> 724
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 724
Glu Pro Trp Gln Ser Arg Asp Lys Val Ile Glu Glu
1 5 10
<210> 725
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 725
Gly Leu Trp Asp Gly Lys Gly Arg Ile Val Glu Val
1 5 10
<210> 726
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 726
Gly Thr Val Ser Tyr Met Val Lys Met Asp Asn Asn
1 5 10
<210> 727
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 727
Ser Leu Gln Leu Trp Asn Ser Glu Lys Val Thr Thr
1 5 10
<210> 728
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 728
Trp Val Gly Pro Asp Ile Ile Ala Gln Met Arg Ile
1 5 10
<210> 729
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 729
Glu Ile Ile Val Met Ser Gly Ser Asn Val Thr Asn
1 5 10
<210> 730
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 730
His Ser Gly Ala Tyr Thr Ile Gln Ala Ser Tyr Lys
1 5 10
<210> 731
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 731
Met Leu Lys Met Glu Arg Pro Gly Arg Met Ala Tyr
1 5 10
<210> 732
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 732
Ser Asp His Thr Phe Lys Arg Val Met Phe Arg Trp
1 5 10
<210> 733
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 733
Glu Met Val Pro Met Lys Phe Leu Met Met Ala Lys
1 5 10
<210> 734
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 734
Asn Thr Glu Tyr Ser Arg Tyr Thr Ser Ile Trp Lys
1 5 10
<210> 735
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 735
Thr Asp Asn Gly Ser Phe Leu Gly Lys Leu Thr Ser
1 5 10
<210> 736
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 736
Thr Glu Trp Met Val Arg Ala Ser Ser Ile Gly Glu
1 5 10
<210> 737
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 737
Val Pro Val Pro Lys Lys Met Ser Leu Asp Pro Thr
1 5 10
<210> 738
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 738
Trp Pro Leu Lys Arg Phe Glu Gln Leu Pro Leu Lys
1 5 10
<210> 739
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 739
Met Leu Arg His Val Asp Leu Thr Glu Pro Asn Ala
1 5 10
<210> 740
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 740
Gln Ser Thr Leu Gly Val His Met Leu Arg Val Ser
1 5 10
<210> 741
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 741
Arg Thr Val Ile Thr Asn Glu Met Leu Leu Leu Val
1 5 10
<210> 742
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 742
Ser Glu Pro Ile Glu Lys Gly Ser Arg Thr Ile Val
1 5 10
<210> 743
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 743
Thr Leu Asn Ala Arg Asp Gln Leu Ser Ile Asn Gly
1 5 10
<210> 744
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 744
Gly Thr Ala Leu Asn Leu Gln Lys Asp Ile Asn Lys
1 5 10
<210> 745
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 745
Ser Gly Trp His Leu Val Met Ser Met Ser Ile Gly
1 5 10
<210> 746
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 神经结合肽
<400> 746
Thr Ser Ala His His Asp Arg Thr Leu Ala Gly Ser
1 5 10
<210> 747
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 具有GG连接子的HNP401-N-2
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 5FAM
<220>
<221> MOD_RES
<222> (17)..(17)
<223> NH2
<400> 747
Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser Ser Gly
1 5 10 15
Gly
<210> 748
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 具有GCC连接子的HNP401
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<220>
<221> MOD_RES
<222> (20)..(20)
<223> CONH2
<400> 748
Ser Gly Gln Val Pro Trp Glu Glu Pro Tyr Tyr Val Val Lys Lys Ser
1 5 10 15
Ser Gly Gly Cys
20
<210> 749
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> NP41
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ac
<400> 749
Ser His Ser Asn Thr Gln Thr Leu Ala Lys Ala Pro Glu His Thr Gly
1 5 10 15
Lys
Claims (63)
1.对对象的输尿管进行可视化的方法,所述方法包括:
(a)向所述对象施用有效量的荧光缀合物,其中所述荧光缀合物包含肽和荧光部分;以及
(b)检测施用后所述输尿管中所述荧光部分的荧光;
其中所述荧光缀合物的肽包含选自以下的氨基酸序列:SEQ ID NO:1-14、16、18-82和84-748。
2.如权利要求1所述的方法,其中所述对象正经受外科操作。
3.如权利要求2所述的方法,其中所述荧光缀合物最初在所述外科操作之前施用。
4.如权利要求3所述的方法,其中所述荧光缀合物在最初施用之后不再向所述对象施用。
5.如权利要求2至4中任一项所述的方法,其中所述外科操作包括妇科、泌尿科、结直肠或心血管外科操作。
6.如权利要求2至4中任一项所述的方法,其中所述外科操作包括腹部或骨盆操作。
7.如权利要求2至4中任一项所述的方法,其中对肾脏、膀胱、前列腺、子宫、男性或女性生殖系统、直肠、结肠、小肠或大肠进行所述外科操作。
8.如权利要求2至4中任一项所述的方法,其中所述外科操作为开放式外科操作、腹腔镜外科操作、显微镜操作或内窥镜操作。
9.如权利要求2至4中任一项所述的方法,其中所述外科操作为癌症外科操作,并且更特别地为前列腺癌外科操作或结直肠癌外科操作。
10.方法,其包括:
(a)向正经受外科操作的对象施用有效量的荧光缀合物,其中所述荧光缀合物包含肽和荧光部分;以及
(b)通过检测输尿管中所述荧光部分的荧光,使所述对象的输尿管可视化;
其中所述荧光缀合物的肽包含选自以下的氨基酸序列:SEQ ID NO:1-14、16、18-82和84-748。
11.如权利要求10所述的方法,其中所述荧光缀合物最初在所述外科操作之前施用。
12.如权利要求11所述的方法,其中所述荧光缀合物在最初施用之后不再向所述对象施用。
13.如权利要求10至12中的一项所述的方法,其中所述外科操作包括妇科、泌尿科、结直肠或心血管外科操作。
14.如权利要求10至12中的一项所述的方法,其中所述外科操作包括腹部或骨盆操作。
15.如权利要求10至12中的一项所述的方法,其中对肾脏、膀胱、前列腺、子宫、男性或女性生殖系统、直肠、结肠、小肠或大肠进行所述外科操作。
16.如权利要求10至12中的一项所述的方法,其中所述外科操作为开放式外科操作、腹腔镜外科操作、显微镜操作或内窥镜操作。
17.如权利要求10至12中的一项所述的方法,其中所述外科操作为癌症外科操作,并且更特别地为前列腺癌外科操作或结直肠癌外科操作。
18.减少输尿管损伤的方法,所述方法包括:
(a)在外科操作之前鉴定处于输尿管损伤风险中的对象;
(b)向正经受所述外科操作的对象施用有效量的荧光缀合物,其中所述荧光缀合物包含肽和荧光部分;以及
(c)通过检测所述输尿管中所述荧光部分的荧光,使所述输尿管可视化;
其中所述荧光缀合物的肽包含选自以下的氨基酸序列:SEQ ID NO:1-14、16、18-82和84-748。
19.如权利要求18所述的方法,其中所述荧光缀合物最初在所述外科操作之前施用。
20.如权利要求19所述的方法,其中所述荧光缀合物在最初施用之后不再向所述对象施用。
21.如权利要求18至20中任一项所述的方法,其中所述输尿管损伤由结扎、成角、横断、撕裂、挤压、局部缺血或切除术引起。
22.如权利要求18至21中任一项所述的方法,其中所述外科操作包括妇科、泌尿科、结直肠或心血管外科操作。
23.如权利要求18至21中任一项所述的方法,其中所述外科操作包括腹部或骨盆操作。
24.如权利要求18至21中任一项所述的方法,其中对肾脏、膀胱、前列腺、子宫、男性或女性生殖系统、直肠、结肠、小肠或大肠进行所述外科操作。
25.如权利要求18至21中任一项所述的方法,其中所述外科操作为开放式外科操作、腹腔镜外科操作、显微镜操作或内窥镜操作。
26.如权利要求18至21中任一项所述的方法,其中所述外科操作为癌症外科操作,并且更特别地为前列腺癌外科操作或结直肠癌外科操作。
27.如权利要求1至26中任一项所述的方法,其中所述肽是神经靶向性肽。
28.如权利要求1至27中任一项所述的方法,其中所述荧光部分缀合至所述肽的N-末端、C-末端或N-末端和C-末端两者。
29.如权利要求1至28中任一项所述的方法,其还包括在施用后的以下时间段内检测所述荧光部分的荧光:至少1小时、至少2小时、至少3小时、至少4小时、至少5小时、至少6小时、至少7小时或至少8小时。
30.如权利要求1至29中任一项所述的方法,其还包括在施用后多于1小时、多于2小时、多于3小时、多于4小时、多于5小时、多于6小时、多于7小时或多于8小时的时间段内;或者在施用后30分钟、1小时、2小时、3小时、4小时、5小时、6小时、7小时之后或多于8小时之后检测所述荧光部分的荧光。
31.如权利要求1至30中任一项所述的方法,其中检测所述输尿管中所述荧光部分的荧光包括检测所述输尿管中尿流的荧光部分,并且更特别地,检测所述输尿管中蠕动尿流的荧光部分。
32.如权利要求1至31中任一项所述的方法,其中所述肽包含选自以下的氨基酸序列:SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3。
33.如权利要求1至31中任一项所述的方法,其中所述肽包含选自以下的氨基酸序列:SEQ ID NO:1-14、16、20-28和96-102。
34.如权利要求1至31中任一项所述的方法,其中所述肽包含选自以下的氨基酸序列:SEQ ID NO:1、4、7-14、20-28和96-102。
35.如权利要求1至31中任一项所述的方法,其中所述肽包含选自以下的氨基酸序列:SEQ ID NO:18、19、29-82、84-95和103-746。
36.如权利要求1至31中任一项所述的方法,其中所述肽包含选自以下的氨基酸序列:SEQ ID NO:75-82、84-95和103-187。
37.如权利要求1至31中任一项所述的方法,其中所述肽包含选自以下的氨基酸序列:SEQ ID NO:55-74和188-362。
38.如权利要求1至31中任一项所述的方法,其中所述肽包含选自以下的氨基酸序列:SEQ ID NO:33-54和363-446。
39.如权利要求1至31中任一项所述的方法,其中所述肽包含选自以下的氨基酸序列:SEQ ID NO:18、19、29-32和447-471。
40.如权利要求1至31中任一项所述的方法,其中所述肽包含选自以下的氨基酸序列:SEQ ID NO:472-678。
41.如权利要求1至31中任一项所述的方法,其中所述肽包含选自以下的氨基酸序列:SEQ ID NO:679-746。
42.如权利要求1至31中任一项所述的方法,其中所述肽包含选自以下的氨基酸序列:SEQ ID NO:1、SEQ ID NO:7、SEQ ID NO:11、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:25和SEQ ID NO:99。
43.如权利要求42所述的方法,其中所述肽包含SEQ ID NO:21的氨基酸序列。
44.如权利要求42所述的方法,其中所述肽包含SEQ ID NO:1的氨基酸序列或其从N-末端或C-末端缺失2-8个氨基酸的变体。
45.如权利要求44所述的方法,其中所述肽包含以下的氨基酸序列:SEQ ID NO:1、SEQID NO:20、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQID NO:27或SEQ ID NO:28。
46.如权利要求45所述的方法,其中所述氨基酸序列在C-末端还包含GC、GG或GGC氨基酸序列。
47.如权利要求46所述的方法,其中所述氨基酸序列选自:SEQ ID NO:4、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:21、SEQ ID NO:102、SEQ ID NO:101、SEQ ID NO:100、SEQ IDNO:99、SEQ ID NO:98、SEQ ID NO:97和SEQ ID NO:96。
48.如权利要求1至47中任一项所述的方法,其中所述荧光部分选自:荧光蛋白、荧光肽、荧光染料和以上的组合。
49.如权利要求1至48中任一项所述的方法,其中所述荧光部分包含:氧杂蒽;bimane;香豆素;芳香胺;苯并呋喃;荧光花菁;咔唑;二氰亚甲基吡喃;聚甲炔;氧杂苯并蒽;吡喃鎓;喹诺酮;苝;吖啶酮;喹吖啶酮;红荧烯;蒽;晕苯;菲;芘;丁二烯;芪;卟啉;酞菁;镧金属螯合物复合物;稀土金属螯合物复合物;或者以上的衍生物。
50.如权利要求1至48中任一项所述的方法,其中所述荧光部分包含羧基荧光素、5-羧基荧光素、6-羧基荧光素、5(6)-羧基荧光素、荧光素异硫氰酸盐、荧光素-5-异硫氰酸盐、荧光素-6-异硫氰酸盐、5,6-二羧基荧光素、5-磺酸基荧光素、6-磺酸基荧光素、砜荧光素、琥珀酰荧光素、5-羧基SNARF-1、6-羧基SNARF-1、羧基荧光素磺酸盐、羧基荧光素两性离子、羧基荧光素季铵盐、羧基荧光素膦酸盐、羧基荧光素GABA、羧基荧光素-cys-Cy5或荧光素谷胱甘肽。
51.如权利要求1至48中任一项所述的方法,其中所述荧光部分包含羧基荧光素(FAM)。
52.如权利要求1至48中任一项所述的方法,其中所述荧光部分包含:
5-羧基罗丹明110、6-羧基罗丹明110、四甲基罗丹明-6-异硫氰酸盐、5-羧基四甲基罗丹明、5-羧基对甲氨基酚衍生物、四甲基和四乙基罗丹明、二苯基二甲基和二苯基二乙基罗丹明、二萘基罗丹明、罗丹明101磺酰氯或其他罗丹明染料。
53.如权利要求1至48中任一项所述的方法,其中所述荧光部分包含Cy2、Cy3、Cy3B、Cy3.5、Cy5、Cy5.5、Cy 7或吲哚菁绿。
54.如权利要求1至48中任一项所述的方法,其中所述荧光部分包含IR800CW、青色荧光蛋白(CFP)、EGFP、5-FAM、6-FAM、FAM、荧光素、IAEDANS、EDANS、BODIPY FL、TRITC、Cy5、Cy3、YFP、LC Red 640、Alexa Fluor 546、四甲基罗丹明、Dabcyl、QSY 7、QSY 9、QSY 21或BBQ-650染料。
55.如权利要求1至31中任一项所述的方法,其中所述荧光缀合物包含SEQ ID NO:747。
56.如权利要求1至31中任一项所述的方法,其中所述肽包含SEQ ID NO:20,并且所述荧光部分包含FAM。
57.如权利要求1至31中任一项所述的方法,其中所述肽包含SEQ ID NO:21,并且所述荧光部分包含FAM。
58.如权利要求1至57中任一项所述的方法,其中所述荧光缀合物经静脉内施用。
59.如权利要求1-57中任一项所述的方法,其中所述荧光缀合物经口施用。
60.如前述权利要求中任一项所述的方法,其还包括施用包含药学上可接受的赋形剂的药物组合物中的所述荧光缀合物。
61.如前述权利要求中任一项所述的方法,其还包括通过所述荧光缀合物的荧光检测对所述对象的神经进行可视化。
62.如权利要求61所述的方法,其中在手术期间同时检测所述对象的所述神经和所述输尿管的可视化。
63.如权利要求61所述的方法,其中在手术期间的不同时间检测所述对象的所述神经和所述输尿管的可视化。
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US4452720A (en) | 1980-06-04 | 1984-06-05 | Teijin Limited | Fluorescent composition having the ability to change wavelengths of light, shaped article of said composition as a light wavelength converting element and device for converting optical energy to electrical energy using said element |
US4439356A (en) | 1981-03-03 | 1984-03-27 | Syva Company | Unsymmetrical fluorescein derivatives |
US4496542A (en) | 1981-03-30 | 1985-01-29 | Usv Pharmaceutical Corporation | N-substituted-amido-amino acids |
US4659839A (en) | 1984-10-10 | 1987-04-21 | Mallinckrodt, Inc. | Coupling agents for radiolabeled antibody fragments |
US5330900A (en) | 1987-12-31 | 1994-07-19 | Tropix, Inc. | Chemiluminescent 3-(substituted adamant-2'-ylidene) 1,2-dioxetanes |
US5066580A (en) | 1988-08-31 | 1991-11-19 | Becton Dickinson And Company | Xanthene dyes that emit to the red of fluorescein |
US5227487A (en) | 1990-04-16 | 1993-07-13 | Molecular Probes, Inc. | Certain tricyclic and pentacyclic-hetero nitrogen rhodol dyes |
US5750409A (en) | 1991-11-18 | 1998-05-12 | Boehringer Mannheim Gmbh | Pentacyclic compounds and their use as absorption or fluorescent dyes |
US5847162A (en) | 1996-06-27 | 1998-12-08 | The Perkin Elmer Corporation | 4, 7-Dichlororhodamine dyes |
US6080852A (en) | 1996-06-27 | 2000-06-27 | The Perkin-Elmer Corporation | 4,7-dichlororhodamine dyes |
US6008379A (en) | 1997-10-01 | 1999-12-28 | The Perkin-Elmer Corporation | Aromatic-substituted xanthene dyes |
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