CN100424509C - 从患有类风湿性关节炎的患者中检测自身抗体的方法、肽和检测试剂盒 - Google Patents
从患有类风湿性关节炎的患者中检测自身抗体的方法、肽和检测试剂盒 Download PDFInfo
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- CN100424509C CN100424509C CNB028246470A CN02824647A CN100424509C CN 100424509 C CN100424509 C CN 100424509C CN B028246470 A CNB028246470 A CN B028246470A CN 02824647 A CN02824647 A CN 02824647A CN 100424509 C CN100424509 C CN 100424509C
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- peptide
- citrulline
- arg
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Abstract
本发明涉及一种从患有类风湿性关节炎的患者中检测自身抗体的方法。为此,根据本发明,使用了至少两种肽单元,其中至少一种肽单元包括非来源于丝聚蛋白(原),纤维蛋白,纤维蛋白原,波形纤维蛋白,细胞角蛋白1和细胞角蛋白9的部分,并且所述肽单元包括XG基序,以及一种肽单元包括XnonG基序,其中X为瓜氨酸或其类似物,而nonG为除甘氨酸之外的氨基酸。
Description
技术领域
本发明涉及一种通过使用包含瓜氨酸残基或其类似物的肽来从患有类风湿性关节炎的患者中检测自身抗体的方法。
背景技术
该方法由国际专利申请PCT/NL97/00624已知。该文献中描述了来源于丝聚蛋白的,包含瓜氨酸或其类似物的肽用于从患有类风湿性关节炎的患者中检测自身抗体的应用。因此,所用的肽适于诊断应用,并且与当时采用的方法相比,使更可靠的检测成为可能。更特别的,该方法能降低假阳性率,也就是具有更高的特异性。此外,其敏感性也相对较高。一种被称为cfc1的肽,被36%的来自患有类风湿性关节炎的患者的血清识别。该肽的环状变异体表现出被更好地识别(63%)。
前言所述的方法还由国际专利申请PCT/FR00/01857已知。该文献中描述了来源于纤维蛋白或纤维蛋白原的,包含瓜氨酸或其类似物的肽用于从患有类风湿性关节炎的患者中检测自身抗体的应用。
PCT/EP98/07714中描述了来源于丝聚蛋白(原)的合成肽在诊断类风湿性关节炎中的应用。该申请中还记载了来源于人波形纤维蛋白,细胞角蛋白1,细胞角蛋白9以及其他中间纤丝蛋白的合成肽。
然而,上述提到的方法仍只能从全部类风湿性关节炎患者中检测出有限数目的患者。因此,强烈需要一种可实现敏感性增加而同时保持实质上相等或甚至提高的特异性的方法。
发明内容
为了达到该目的,本发明提供了一种如前言所述的方法,该方法的特征在于所述的自身抗体与含有XG基序的肽单元和含有XnonG基序的肽单元接触,其中X为瓜氨酸残基或其类似物,G为甘氨酸,而nonG为除甘氨酸以外的氨基酸。
下述实验显示,获自患有类风湿性关节炎的患者的血清中含有两种不同的抗体群。其中一群抗体与诸如上文提到的已出版文献中公开的XG肽单元反应。该群抗体可通过已公开的XG肽单元部分地检测到,当采用本发明所述的肽单元时,则能检测到更大部分的该群抗体。另一群抗体与XnonG肽单元反应。直到目前为止,在已出版的文献中还没有观察到这群抗体。如下文更详细的记载,来自于患有类风湿性关节炎患者的大多数血清都含有这两群抗体。因此,这些血清可以通过包括XG或XnonG肽单元的诊断测试来检测。然而看来似乎相当大一部分患有类风湿性关节炎的患者的血清只含有两群抗体中的一种。因此,采用上述已出版公开的文献中描述的诊断测试,无法检测或仅能检测极小一部分的仅含有对XnonG肽单元的抗体的血清。如今,如果诊断测试中包括XnonG肽单元,则可以检测大部分的这类血清。因而本发明所述的改进诊断方法包括至少一种XG和一种XnonG肽。因此与已出版公开文献中记载的测试相比,本发明所述的诊断测试可达到20%更为敏感。
当所述的具有XnonG基序的肽单元包括一非来源于天然蛋白如人类丝聚蛋白(原),纤维蛋白,或纤维蛋白原,以及相关的蛋白波形纤维蛋白,及细胞角蛋白1和细胞角蛋白9,或其他相关的中间纤丝蛋白的部分时,可以获得特别好的结果。
令人惊奇的是,结果显示,当将该非来源于天然蛋白的XnonG肽与本发明所述的XG肽组合时,可得到一更加改进的诊断方法。更特别的,这种肽单元组合在本发明所述的方法中的应用提供了一种敏感性非常高,且保持优异的特异性的诊断方法。由于上述提到的公开文献仍然是基于下述观念,即来自于RA患者的自身抗体与来源于天然存在的蛋白,例如丝聚蛋白(原),纤维蛋白,纤维蛋白原,波形纤维蛋白,细胞角蛋白1或细胞角蛋白9的肽特别好地发生反应,因此这就更让人惊讶了。例如,PCT/EP98/07714中记载了一种丝聚蛋白来源的XnonG肽(IPG1249)。它与3.3%的SLE患者血清交叉反应,且与丝聚蛋白有82%的同源性。
当所述的具有XnonG基序的肽单元包含一种三肽时,则可获得较好的结果,其中三肽的中间氨基酸为瓜氨酸或其类似物,其优选选自XXK,XXY,KXI,MXR,RXY,WXK,MXH,VXK,NXR,WXS,RXW,YXM,IXX,XXF,RXH,TXV,PXH,AXF,FXR,YXF,LXM,LXY,YXP,HXS和PXW。
优选的,nonG为选自H,I,W,S,R,K,Y,M,F,V,P,Cit或其类似物的氨基酸。如下述实验所示,这类XnonG肽单元非常有效。
包括XG基序的肽单元,可来源于或不来源于丝聚蛋白(原),纤维蛋白,纤维蛋白原,波形纤维蛋白,细胞角蛋白1或细胞角蛋白9,并且有效地是由PCT/NL97/00624中已知的cfc1。
在本文的上下文中,术语氨基酸包括天然的和非天然的氨基酸,和具有D-构型或L-构型的氨基酸。
在本申请中,非天然氨基酸应理解为该类的氨基酸存在于反-倒位肽,反向肽,其中侧链位于肽骨架的酰胺氮原子上的肽,和其中肽骨架上的CO被2,3或优选单一-CH2-基团所替代的肽(假肽)中。
氨基酸还可被修饰。例如,羧酸基团可以被酯化或可被转化为酰胺,同时氨基基团可被烷基化,例如,甲基化。可选的,肽上的功能基团可以提供有保护基团或标记(例如荧光或放射性标记)。肽中的氨基基团和羧酸基团可以以通过使用酸或碱而形成的盐的形式存在。如果采用合成肽,则很容易制备可以使用的本发明范围内的所有种类的变异体。例如,芳族侧链基团,如来源于苯丙氨酸和酪氨酸,可被一个或多个卤素原子卤化。肽模拟(peptidomimetic)和有机模拟(organomimetic)的实施方案也落在本发明的范围内,及其在本发明所述方法中的应用。还可采用其类似物来代替Cit残基,例如那些在图1中列出的氨基酸形式的类似物。这种类似物及其制备方法为本领域的普通技术人员所公知。例如,Sonke et al.在StereoselectiveBiocatalysis(2000),pp.23-58中有记载,以及在Greene:Protectivegroups in Organic synthesis(Wiley,New York 1999)中。
依照有利的实施方案,所述的瓜氨酸类似物的侧链具有如下通式(I):
其中
Q=NH2,CH3,NHCH3或N(CH3)2;
Y=O,NH,或NCH3;
Z=O,NH或CH2;和
n=2,3或4;
条件是如果Q=NH2和Z=NH,则Y不为NH。
在本文上下文中,肽单元应理解为长度至少7个氨基酸的肽。肽单元可以具有一个或多个侧链。同时,肽单元或肽单元的末端可以彼此相互独立地被乙酰化,糖基化,烷基化,或磷酸化。
本文上下文中所述的肽单元是指非来源于丝聚蛋白(原),纤维蛋白,纤维蛋白原,波形纤维蛋白,细胞角蛋白1或细胞角蛋白9,和其他中间纤丝蛋白,如果与这些蛋白的同源性(氨基酸序列的相似性)低于80%,更优选的低于75%,如低于70%或65%,最优选的低于60%,例如低于55%或50%。所述的肽单元列于表5中,其非来源于丝聚蛋白(原),纤维蛋白,纤维蛋白原,波形纤维蛋白,细胞角蛋白1和细胞角蛋白9,且同源性介于15-45%。关于同源性检查,精氨酸、瓜氨酸和瓜氨酸类似物被认为是等同的(同一的)。
包括XG和XnonG的肽单元可以是或不是相同分子的一部分。随后将对此进行叙述。为了进行检测试验,所述的肽单元可以与一载体相连,并可选地提供有标记。得到的复合物可以通过本领域普通技术人员公知的任何方式检测。所述的复合物可以间接检测,例如在竞争试验的情况下,其中复合物本身不标记。与两个肽单元的反应可以同时或相继地并在相同容器(例如微量滴定板的孔)或不同容器中发生。
本申请不旨在作为教导如何成为本领域普通技术人员的教育出版物。因此,本申请仅限于提供了使本领域普通技术人员能够理解发明,实施发明和理解本发明要求保护的范围的充分信息。
优选的,所述的肽单元被确认患有RA的患者的100份随机血清中的至少2份所识别。很明显,优选采用能被显著更高百分比的,优选至少30%的血清识别的肽单元。本发明所述方法中的肽单元的数目优选为2或大于2。
优选的,本发明涉及上述的一种方法,其中具有XG基序的肽单元和具有XnonG基序的肽单元被至少10%的患者系列血清同时识别。毫无疑问,优选那些导致更高敏感性的肽单元组合。采用本文所述的一些肽单元组合,诊断测试可以获得40,60,70,80或甚至85和高于90%的敏感性。
已显示,如果其中的至少一种肽单元为环状肽单元,则检测的敏感性可以进一步提高。
具有XG基序的肽单元和具有XnonG的肽单元优选为多肽(multipeptide)的一部分。根据本发明的上下文,多肽为包括至少2个抗原性肽单元的分子,也就是,可以或可以不通过共价键连接的肽单元的组合。这种多肽可以由线性的,分枝状的,环状的肽单元或这些的组合来组成。多肽既可以由具有相同氨基酸序列的肽单元组成,也可由具有不同氨基酸序列的肽单元组成。根据本发明所述的多肽包括至少7个,优选至少10个氨基酸,也就是所述的肽单元可以重叠。理所当然的,XG和XnonG基序不能重叠。
本发明还涉及对于本发明所述方法非常有用的XnonG肽单元,其包括具有如下通式(II)的序列:
(A1-A2-A3-A4-A5)-Cit-(A6)-(A7-A8-A9-A10-A11)(II)
其中,A1-A2-A3-A4-A5为选自下述的氨基酸序列
-RHGRQ
-IRCitYK
-HGRQCit
-GRQCitCit
-FQMCitH
-CitWRGM
-ARFQM
-QCitYKW
-KPYTV
-RNLRL
-RRRCitY
-RFKSN
-RGKSN
-RWVSQ
-MKPRY
-KSFVW
-YSFVW
-FQMRH
-RNMNR
-RMGRP
及其同源序列;
A7为除甘氨酸之外的氨基酸;
A7-A8-A9-A10-A11为选自下述的氨基酸序列
-KYIIY
-TNRKF
-KWCitKI
-CitRAVI
-RCitGHS
-CitGRSR
-CitYIIY
-CitRLIR
-IERKR
-FMRKP
-FMRRP
-ERNHA
-AVITA
-TPNRW
-TYNRW
-RTPTR
-RIVVV
-HARPR
-RGMCitR
-IRFPV
及其同源序列;
以及具有通式(II)的肽的功能类似物。
本发明还涉及一种XnonG肽单元,其对本发明所述方法十分有用,其包括具有通式(III)的序列:
(B1-B2-B3-B4-B5-B6)-Cit-(B7)-(B8-B9-B10-B11)(III)
其中B1-B2-B3-B4-B5-B6为选自下述的氨基酸序列
-INCitRAS
-ICitKRLY
-KCitCitYNI
-RLYFICit
-IRQGAR
-CitERCitVQ
-CitHQRIT
-RICitRVCit
-GRNQRY
-RCitRQHP
-CitCitRCitVA
-RPKQHV
-RKCitGCitR
-RCitCitRNT
-RCitQCitFT
-QLVYLQ
-QYNRFK
-CitLRHIR
-PRCitCitCitK
-RCitQVRY
-GRCitHAH
-ARHVIR
-RCitGHMF
-GRNIRV
-QIFYLCit
-RQGPIA
-GVYLVR
-NCitCitRRV
-KCitRLCitY
-GRRCitCitL
-RMPHCitH
及其同源序列;
B7为除甘氨酸之外的氨基酸;
B8-B9-B10-B11为选自下述的氨基酸序列
-CitHRR
-CitIRR
-FRRN
-AQTT
-GYPK
-RPPQ
-GCitRK
-PIPR
-YTIH
-RIKA
-CitRVR
-TRRP
-TIRP
-IKCitR
-RNVV
-CitRRY
-CitRPR
-TRCitCit
-CitCitGR
-LCitRCit
-RVRCit
-VPRT
-YCitFR
-ARCitCit
-RQCitR
-HIRR
-CitMMR
-CitRICit
-VRKS
-PCitCitR
-CitRRK
及其同源序列;
以及具有通式(III)的肽的功能类似物。
如联系在A1-A2-A3-A4-A5,A7-A8-A9-A10-A11,B1-B2-B3-B4-B5-B6和B8-B9-B10-B11中的应用,术语“同源序列”是指每一氨基酸序列的至多两个氨基酸可以被许多其他氨基酸置换(包括瓜氨酸和/或其类似物),至多两个氨基酸(including or an analoguethereof)可以被引入,以及至多两个氨基酸可以缺失。
联系在具有通式(II)或(III)的肽中的应用,术语“类似物”是指,可选地
-一个或多个氨基酸可具有D-构型,
-肽的一个或多个侧链(除了瓜氨酸或其类似物的侧链)或末端可以相互独立地被乙酰化,糖基化,烷基化,或磷酸化;以及
-一个或多个氨基酸可被非天然氨基酸所置换。
A6和B7(相互独立)优选选自Cit,H,I,K,R,S,W,Y,M,F,V和P。
用于本发明所述方法的特别优选的肽特征在于其包括至少一个选自下列的肽序列
R H G R Q Cit Cit K Y I I Y
I R Cit Y K Cit I T N R K F
R H G R Q Cit Cit Cit Y I I Y
A R F Q M Cit H Cit R L I R
Q Cit Y K W Cit K I E R K R
K P Y T V Cit K F M R K P
K P Y T V Cit K F M R R P
R N L R L Cit R E R N H A
R R R Cit Y Cit R A V I T A
R F K S N Cit R T P N R W
R G K S N Cit R T Y N R W
R F K S N Cit R T Y N R W
R G K S N Cit R T P N R W
R W V S Q Cit R R T P T R
M K P R Y Cit R R I V V V
K S F V W Cit S H A R P R
Y S F V W Cit S H A R P R
R N M N R Cit W R G M Cit R,和
R M G R P Cit W I R F P V
以及
I N Cit R A S Cit K Cit H R R
I Cit K R L Y Cit M Cit I R R
K Cit Cit Y N I Cit Cit F R R N
R L Y F I Cit Cit R A Q T T
I R Q G A R Cit R G Y P K
Cit E R Cit V Q Cit R R P P Q
Cit H Q R I T Cit V G Cit R K
R I Cit R V Cit Cit T P I P R
G R N Q R Y Cit L Y T I H
R Cit R Q H P Cit H R I K A
Cit Cit R Cit V A Cit F Cit R V R
R P K Q H V Cit H T R R P
R K Cit G Cit R Cit Cit T I R P
R Cit Cit R N T Cit H I K Cit R
R Cit Q Cit F T Cit Cit R N V V
Q L V Y L Q Cit Cit Cit R R Y
Q Y N R F K Cit Cit Cit R P R
Cit L R H I R Cit Q T R Cit Cit
P R Cit Cit Cit K Cit R Cit Cit G R
R Cit Q V R Y Cit Cit L Cit R Cit
G R Cit H A H Cit P R V R Cit
A R H V I R Cit Cit V P R T
R Cit G H M F Cit V Y Cit F R
G R N I R V Cit Cit A R Cit Cit
Q I F Y L Cit Cit H R Q Cit R
R Q G P I A Cit L H I R R
G V Y L V R Cit L Cit M M R
N Cit Cit R R V Cit M Cit R I Cit
K Cit R L Cit Y Cit P V R K S
G R R Cit Cit L Cit R P Cit Cit R
R M P H Cit H Cit S Cit R R K
或其类似物。
本发明所述方法中使用的合适的XG肽优选包括具有通式(IV)的序列
(C1-C2)-(C3-C4-C5)-X-G-C6-(C7-C8-C9-C10) (IV)
其中
C1-C2为HQ,GF,EG或GV;
C3-C4-C5代表3个氨基酸,其中至少1个氨基酸,优选2个氨基酸相互独立地为碱性的,芳族的,或V;
C6等于一个碱性或芳族氨基酸,或等于A,G,E,P,V,S或Cit或其类似物;和
C7-C8-C9-C10为SRAA,SCitAA,RPLD,RVVE或PGLD;
以及具有通式(IV)的肽的类似物。
联系在具有通式(IV)的肽中的应用,术语“类似物”是指,可选地
--一个或多个氨基酸可具有D-构型,
-肽的一个或多个侧链(除了瓜氨酸或其类似物的侧链)或末端相互独立地可以被乙酰化,糖基化,烷基化,或磷酸化;以及
-一个或多个氨基酸可被非天然氨基酸所置换。
适于本发明所述方法使用的XG肽的特定例子包括选自下列的序列
H Q R K W Cit G A S R A A
H Q H W R Cit G A S R A A
H Q F R F Cit G Cit S R A A
H Q E R R Cit G E S R A A
H Q K W R Cit G F S R A A
H Q R W K Cit G G S R A A
H Q R R T Cit G G S R A A
H Q R R G Cit G G S R A A
H Q Cit F R Cit G H S R A A
G F F S A Cit G H R P L D
H Q E R G Cit G K S R A A
H Q E K R Cit G K S R A A
H Q R W L Cit G K S R A A
H Q K R N Cit G K S R A A
E G G G V Cit G P R V V E
H Q W R H Cit G R S Cit A A
H Q K W N Cit G R S R A A
H Q K F W Cit G R S R A A
H Q K Cit K Cit G R S R A A
H Q K W R Cit G R S Cit A A
H Q A W R Cit G R S Cit A A
H Q N Q W Cit G R S R A A
H Q N S K Cit G R S R A A
H Q K R R Cit G R S R A A
H Q K R F Cit G R S R A A
H Q K R Y Cit G R S R A A
H Q K R H Cit G R S R A A
H Q E R A Cit G S S R A A
H Q E K M Cit G V S R A A
H Q K R G Cit G W S R A A
H Q R R V Cit G W S R A A
H Q W N R Cit G W S R A A
H Q Q R M Cit G W S R A A
H Q S H R Cit G W S R A A
H Q F R F Cit G W S R A A
H Q K R R Cit G W S R A A
G V K G H Cit G Y P G L D
或其类似物。
本发明所述的肽优选为环状肽,其中的环包括至少10个氨基酸,更优选至少11个氨基酸。本领域普通技术人员通晓制备环状肽的各种方法,因此无需进一步的解释。
根据本发明的一个最优选的方法,XG肽与至少一个XnonG肽联合使用,其中XG肽选自如下组:
0002-27 H Q K R G Cit G W S R A A
0002-29 H Q R R V Cit G W S R A A
0002-31 H Q R R T Cit G G S R A A
0002-32 H Q R K W Cit G A S R A A
0002-36 H Q F R F Cit G Cit S R A A
0002-37 H Q K W R Cit G R S Cit A A
0002-63 H Q F R F Cit G W S R A A
且XnonG肽选自如下组:
0107-32 K P Y T V Cit K F M R R P
0107-35 A R F Q M Cit H Cit R L I R
0107-45 Y S F V W Cit S H A R P R
0113-30 A R F Q M R H Cit R L I R
0218-36 R N L R L Cit R E R N H A
根据诊断测试期望达到的特异性和敏感性,以及待检测的类风湿性关节炎血清的个别群,优选的XG和XnonG肽单元的组合选自如下组:
0002-27and0107-32;0002-27和0107-35;0002-27和0107-45;
0002-27和0113-30;0002-27和0218-36;0002-29和0107-32;
0002-29和0107-35;0002-29和0107-45;0002-29和0113-30;
0002-29和0218-36;0002-31和0107-32;0002-31和0107-35;
0002-31和0107-45;0002-31和0113-30;0002-31和0218-36;
0002-32和0107-32;0002-32和0107-35;0002-32和0107-45;
0002-32和0113-30;0002-32和0218-36;0002-36和0107-32;
0002-36和0107-35;0002-36和0107-45;0002-36和0113-30;
0002-36和0218-36;0002-37和0107-32;0002-37和0107-35;
0002-37和0107-45;0002-37和0113-30;0002-37和0218-36;
0002-63和0107-32;0002-63和0107-35;0002-63和0107-45;
0002-63 0113-30;0002-63和0218-36.
上述提到的组合显示出产生敏感性平均增加6%,将XG和XnonG肽的这种组合测试的总敏感性升高到75-78%。
下述实施例中描述的结果进一步显示各种不同的肽单元还检测出不同的血清类群。通过加入第3个肽单元或甚至是第4个或更多肽单元,可以实现额外的敏感性增加。取决于选自上述组的肽单元组合,本发明所述的诊断测试的敏感性可达88-92%。
本发明还涉及一种多肽,特征在于其为线性的或分枝状的多肽,包括至少两个相互独立地选自如下的线性的或环状的肽序列:
-选自具有通式(II)和(III)的肽单元及其类似物的肽单元;
-具有通式(IV)的肽单元及其类似物。
这种多肽很适于在本发明所述的方法中使用。由于肽以相同的已知比例使用,并且避免了测定期间或预备工作期间的额外操作(例如,用多肽包被微量滴定板),因此这类多肽使得更简便和更可靠地实施该方法成为可能。
本发明进一步涉及一种从患有类风湿性关节炎的患者中测定自身抗体的存在的诊断试剂盒,其中所述的诊断试剂盒包括根据权利要求5到13任意一项所述的肽,或根据权利要求1 4所述的多肽,或其混合物,以及至少一种另外的试剂。
本发明还涉及如上文所述的肽或免疫毒素分子的抗体,或其组合物,用作药物组合物。
本发明进一步涉及如上文所述的肽或免疫毒素分子的抗体或其组合物用于制备用于类风湿性关节炎的药物组合物或诊断试剂。
本发明还涉及如上文所述的肽或其组合物在制备用于治疗自身免疫性疾病的药物组合物中的应用,其通过增加抗原免疫复合物的大小,从而改善对所形成的免疫复合物的净化来实现。
本发明因此还涉及一种通过向需要这种治疗的患者体内引入至少一种本发明所述的肽,来治疗类风湿性关节炎的方法。
本发明进一步涉及一种用于选择适于诊断RA的肽的方法,其中用从患有RA的患者获得的抗体来筛选肽文库,且其中所述的肽文库选自如下组:
文库(1):H Q E X X Cit X X S R A A
其中X=除了半胱氨酸和色氨酸之外的任何氨基酸
文库(2):H Q X X X Cit G X S R/Cit A A
其中X=除了半胱氨酸之外的任何氨基酸,但包括瓜氨酸
文库(3):H Q E X X Cit X X S R/Cit A A
其中X=除了半胱氨酸之外的任何氨基酸,但包括瓜氨酸
Lib(4):X X X X X X Cit X X X X X
其中X=除了半胱氨酸之外的任何氨基酸,但包括瓜氨酸
或其等同物。
最后,本发明涉及一种可借助于上文提到的方法获得的用于诊断测试中的肽。
术语“用于治疗的药物组合物”或“用于治疗的药物”或“蛋白质在制备用于治疗的药物中的应用”涉及如上所述用于治疗疾病的包含如上文所述的肽或与该肽特异性结合的抗体以及药学上可接受的载体或赋形剂(这两个术语是可互换的)的组合物。本领域普通技术人员熟知的合适的载体或赋形剂为:盐,Ringer′s溶液,葡萄糖溶液,Hank′s溶液,油脂类,油酸乙酯,5%葡萄糖盐水,提高等渗性和化学稳定性的物质,缓冲液和防腐剂。其他适合的载体包括其自身不诱导产生对接受所述组合物的个体有害的抗体的任何载体,如,蛋白质,多糖,聚乳酸,聚乙醇酸,聚合氨基酸和氨基酸聚合物。所述“药物”可以采用本领域普通技术人员已知的任何方式给药。
本发明所述的肽可以被标记(如本领域公知的,放射性,荧光或其他标记方式)或可与载体一起提供。以这种形式存在的这类肽也属于本发明保护范围之内。例如,肽可与载体蛋白偶联,所述的载体蛋白诸如匙孔血蓝蛋白或牛血清白蛋白。同时,本发明所述的肽可以非共价或共价地与固相载体偶联,所述的固相载体诸如微球体(金,聚苯乙烯等),载玻片,芯片,或反应容器壁或微量滴定板上的孔。所述的肽可以用直接或间接的标记进行标记。实例包括生物素,荧光素和酶,例如辣根过氧化物酶。所有这些都是本领域普通技术人员公知的,因此不需要进一步的解释。
附图说明
图1例示可以用于本发明的瓜氨酸类似物。
具体实施方式
实施例
实施例1:肽合成
如De Koster H.S.等人(J.Immunol.Methods,187,pp.177-188,(1995))所述来合成瓜氨酸化(citrullinated)的肽。采用肽分子通过酰胺键结合其上的微粒珠(bead),从而当除去保护基团后,肽分子仍然结合在微粒珠上。为了合成肽,使用了一种自动化多肽合成仪(Abimed AMS422,Abimed,Langenfeld,Germany)。掺入的氨基酸和肽连接物6-氨基己酸用Fmoc-基团保护,并且为了促进偶联,采用PyBOP和N-甲基吗啉活化受保护的氨基酸。必要时,侧链也采用保护对酸敏感的侧链的基团来保护。所采用的微粒珠的直径为约100μm,同时每个微粒珠包含大约100pmol的肽。据估计,该量中的大约0.5%与外部结合,并且在原则上可与抗体接近。
为了更大量合成,采用了具有酸敏感性连接物的微粒珠。肽合成的化学过程与上文中已经描述的过程大致相当。采用三氟乙酸将肽裂解下来,并通过乙醚沉淀的方法分离,所有都依照本领域公知的方法,对此本领域技术人员不需要进一步的解释。当然也可以从商业来源获取具有期望序列的肽。各肽的纯度和身份通过分析RP-HPLC和飞行时间质谱法(MALDI-TOF)来检验。
借助于上述方法,构建了4个肽文库,每一个都包括了大量的(8×106)瓜氨酸化肽。如下通式显示了每一文库中的肽的氨基酸序列:
文库(1):H Q E X X Cit X X S R A A
其中X=除半胱氨酸和色氨酸以外的任何氨基酸
文库(2):H Q X X X Cit G X S R/Cit A A
其中X=除半胱氨酸以外但包括瓜氨酸的任何氨基酸
文库(3):H Q E X X Cit X X S R/Cit A A
其中X=除半胱氨酸以外但包括瓜氨酸的任何氨基酸
文库(4):X X X X X X Cit X X X X X
其中X=除半胱氨酸以外但包括瓜氨酸的任何氨基酸
对这些文库根据下文中描述的方法采用患有类风湿性关节炎的患者的血清来进行筛选。
实施例2:微粒珠偶联的肽与来自于患有类风湿性关节炎(RA)
患者的血清的反应
借助于蛋白A-琼脂糖凝胶,从临床诊断患有RA的患者的血清中分离IgG。将微粒珠与下述溶液一起温育,所述溶液包括i)来自患者的全血清,或ii)与报道酶基团(碱性磷酸酶标记试剂盒;Roche/Boehringer,Mannheim,Germany)缀合的患者的IgG。对于血清(i),将其与碱性磷酸酶缀合的抗-人IgG抗体(Dako D0336;DakoImmunoglobulins,Glostrup,Denmark)一起进行第二次温育。每次温育后,都采用pH 8.9的Tris-HCl缓冲液(50 mM Tris pH 8.9,150 mMNaCl,0.5%Tween20)充分彻底漂洗微粒珠。
借助显微镜,选择肽已结合了最多人IgG的微粒珠(经碱性磷酸酶底物染色后,所述底物转变为不溶的有色产物,从而这些微粒珠成为最强着色的微粒珠)。
实施例3:ELISA
以稍大量合成最感兴趣的肽,以形成线性和环状变异体,在大多数情况下为瓜氨酸和精氨酸(=对照)变异体。
测试这些肽与来自于RA患者的一系列血清的反应性。将所述肽包被于ELISA板并与来自RA患者的血清一起温育。每份血清测试一式两份。来自健康者的血清用作阴性对照。
实施例4:XG肽家族
通过采用与cfc1(参见PCT/NL97/00624,其以参考文献方式包括于此)呈阳性反应的血清,发现具有在相对于瓜氨酸残基的+1位(即C-末端)的甘氨酸的肽。置换+1位置上的G,如采用A(丙氨酸),则降低反应性65%。在某些肽中,-3位置上的E(谷氨酸)优选不被A置换(活性丧失47%)。类似的,-4位置上的Q(谷氨酰胺),-5位置上的H(组氨酸),和+3位置上的S(丝氨酸)常表现出是有利的。
因此,选择出多种具有-XG-组合的肽序列,它们全部都与RA血清反应。优选的该XG家族成员的特定例子为
表1:XG肽家族:
H Q R K W Cit G A S R A A (0002-32)
H Q H W R Cit G A S R A A (0002-42)
H Q F R F Cit G Cit S R A A (0002-36)
H Q E R R Cit G E S R A A (020699-2)
H Q K W R Cit G F S R A A (0102-74)
H Q R W K Cit G G S R A A (0002-28)
H Q R R T Cit G G S R A A (0002-31)
H Q R R G Cit G G S R A A (0002-33)
H Q Cit F R Cit G H S R A A (0002-43)
G F F S A Cit G H R P L D (0101-7)
H Q E R G Cit G K S R A A (020699-1)
H Q E K R Cit G K S R A A (020699-4)
H Q R W L Cit G K S R A A (0002-30)
H Q K R N Cit G K S R A A (0002-38)
E G G G V Cit G P R V V E (0101-5)
H Q W R H Cit G R S Cit A A (0002-34)
H Q K W N Cit G R S R A A (0002-24)
H Q K F W Cit G R S R A A (0002-25)
H Q K Cit K Cit G R S R A A (0002-26)
H Q K W R Cit G R S Cit A A (0002-37)
H Q A W R Cit G R S Cit A A (0002-40)
H Q N Q W Cit G R S R A A (0002-44)
H Q N S K Cit G R S R A A (0002-45)
H Q K R R Cit G R S R A A (0102-76)
H Q K R F Cit G R S R A A (0102-77)
H Q K R Y Cit G R S R A A (0102-78)
H Q K R H Cit G R S R A A (0102-79)
H Q E R A Cit G S S R A A (020699-3)
H Q E K M Cit G V S R A A (020699-S)
H Q K R G Cit G W S R A A (0002-27)
H Q R R V Cit G W S R A A (0002-29)
H Q W N R Cit G W S R A A (0002-35)
H Q Q R M Cit G W S R A A (0002-41)
H Q S H R Cit G W S R A A (0002-39)
H Q F R F Cit G W S R A A (0002-63)
H Q K R R Cit G W S R A A (0102-75)
G V K G H Cit G Y P G L D (0101-3)
从上述数据中可得出对特定位置表现出具有优先选择的氨基酸的共有序列。优选被RA血清识别的XG肽单元因而可以由如下表示:
-3 -2 -1 0 +1 +2
K R R X G R
R W W
E K
所有这些肽都显示出好到优异的结果。特别是肽0002-35,0002-36和0002-63非常令人满意。在大多数情况下,这种肽的环状变异体的反应甚至更好(见下文)。偶尔,这也不总是这样。例如,线性肽0101-7与55%的血清反应。而该肽的环状变异体“仅”与186份RA-血清中的45%发生反应。正如所料,这些肽的精氨酸变异体(其中瓜氨酸被精氨酸置换)不与RA血清反应。
实施例5:XG肽的环状变异体
下文所述的肽按照半胱氨酸-溴乙酸方法来环化。测试了几种环状变异体,特别是肽0002-27,0002-29,0002-31,0002-36,和0002-63的环状变异体被证实令人感兴趣。
环大小:多种充分反应的肽用于合成另外的环状肽,其中每一个具有不同的环大小。最终测试了其中的8,9,10,11和12-聚体(mer)。所有这些肽都分别与48份RA血清和8份正常血清进行ELISA检测。其中,8-和9-聚体与一些血清反应(分别为22%(滴度0,47)和28%(滴度0,5)),但滴度(发现的OD值)远低于采用较大的环时(10-聚体33%,滴度值为0.60;11-和12-聚体50%,平均滴度为0.74)。
表2:采用环状肽0002-36的血清分析结果
上表代表了与获自患有RA的患者和患有多种其他自身免疫疾病的患者的血清的ELISA。这显示了RA血清对肽如0002-36的高度特异性。几乎没有一例显示出获自其他自身免疫疾病的血清和来自于正常健康个体的材料呈阳性。同时还测试了肽0002-36的精氨酸变异体(R位于0和+2位置上,即代替了通式中的Cit),并显示出对所有测试的RA和正常血清都为阴性。
表3:与来自[PCT/NL97/00624]的肽cfc1相比较,肽36与132份RA血清的ELISA
肽 | cfc1(线性) | cfc1(环状) | 0002-36(线性) | 0002-36(环状) |
阳性血清 | 48/13236% | 83/13263% | 80/13261% | 94/13271% |
通过采用环状cfc1以及环状的0002-36,可增加额外的2%敏感性(总73%,见表4),只要其不伴随着特异性的下降,这对于这类应用是一个受欢迎的改进。后者似乎不是这种情况。因此,在XG组的肽中,关于其与RA抗体反应的能力存在多样性。
表4:cf1,0002-36,和0002-63的环状变异体与186份RA血清的ELISA
肽 | cfc1(环状) | 0002-63(环状) | 0002-36(环状) | cfc1+0002-36(环状) |
阳性血清 | 51% | 71% | 71% | 73% |
在2组RA血清(总共318份血清)中比较0002-36的线性和环状变异体,环状变异体显示出比线性变异体反应频率更高(和更好)。更好是由于环状变异体的OD值也比线性组合物高得多。无论环状变异体是通过两个半胱氨酸之间的-S-S-键产生,还是通过形成硫醚,例如,通过半胱氨酸和溴乙酰基团反应(由半胱氨酸侧链上的硫羟与N-末端溴乙酰基团反应形成,形成硫醚),这都无关紧要。在肽合成后,通过使与微粒珠结合的肽(肽基树脂)与同一肽中的溴乙酸的N-羟基琥珀酰亚胺酯反应,从而形成N-末端溴乙酰基团。在pH=8的磷酸盐缓冲的乙腈水溶液中,发生环闭合。
实施例6:XnonG肽家族
令人惊奇的是,还发现一类肽,其非来源于丝聚蛋白(原),纤维蛋白,纤维蛋白原,波形纤维蛋白,细胞角蛋白1和细胞角蛋白9,且能被不与或仅轻微地与上述XG家族的肽反应的RA血清识别。这些肽的特征在于Cit的C-末端侧的氨基酸为碱性(R,K,H),芳族(W,Y,F),脂族(M,I,V)或Cit,S或P(见表5),但不为G。因此,将其命名为XnonG家族。值得注意的是,在-2,-1,+1和+2位置上,XnonG肽包括了相对较多的带正电荷的氨基酸。因此,这些RA 清中的抗体在一种不同的肽背景中与瓜氨酸反应。
所提到的XnonG肽都与一种或多种XG-阴性血清反应。例如,肽0107-32,0107-35,和0107-45与大约15-18%的XG阴性血清反应。与环状cfc1和环状0002-36的组合相比,基于一种或多种这些肽的ELISA测试引起敏感性提高至少5%(从73%上升到78%)。十分重要的是,提到的XnonG肽中没有一个与对照血清反应。
表5:XnonG家族的肽:
R H G R Q Cit Cit K Y I I Y (0107-33)
R H G R Q Cit Cit Cit Y I I Y(0107-34)
I R Cit Y K Cit I T N R K F (0107-37)
A R F Q M Cit H Cit R L I R (0107-35)
Q Cit Y K W Cit K I E R K R (0107-43)
K P Y T V Cit K F M R K P (0107-31)
K P Y T V Cit K F M R R P (0107-32)
R N L R L Cit R E R N H A (0107-36)
R R R Cit Y Cit R A V I T A (0107-38)
R F K S N Cit R T P N R W (0107-42)
R G K S N Cit R T Y N R W (0107-39)
R F K S N Cit R T Y N R W (0107-40)
R G K S N Cit R T P N R W (0107-41)
R W V S Q Cit R R T P T R (0102-71)
M K P R Y Cit R R I V V V (0102-73)
K S F V W Cit S H A R P R (0107-44)
Y S F V W Cit S H A R P R (0107-45)
R N M N R Cit W R G M Cit R (0107-30)
R M G R P Cit W I R F P V (0102-72)
以及
I N Cit R A S Cit K Cit H R R 0215-46
I Cit K R L Y Cit M Cit I R R 0219-44
K Cit Cit Y N I Cit Cit F R R N 0222-56
R L Y F I Cit Cit R A Q T T 0222-57
I R Q G A R Cit R G Y P K 0223-12
Cit E R Cit V Q Cit R R P P Q 150202RA02
Cit H Q R I T Cit V G Cit R K 150202RA03
RICit R V Cit Cit T P I P R 061102RA01
G R N Q R Y Cit L Y T I H 061102RA02
R Cit R Q H P Cit H R I K A 061102RA03
Cit Cit R Cit V A Cit F Cit R V R 061102RA05
R P K Q H V Cit H T R R P 061102RA06
R K Cit G Cit R Cit Cit T I R P 061102RA07
R Cit Cit R N T Cit H I K Cit R 061102RA08
R Cit Q Cit F T Cit Cit R N V V 061102RA09
Q L V Y L Q Cit Cit Cit R R Y 061102RA11
Q Y N R F K Cit Cit Cit R P R 061102RA12
Cit L R H I R Cit Q T R Cit Cit 061102RA14
P R Cit Cit Cit K Cit R Cit Cit G R 061102RA15
R Cit Q V R Y Cit Cit L Cit R Cit 061102RA16
G R Cit H A H Cit P R V R Cit 061102RA17
A R H V I R Cit Cit V P R T 181102RA01
R Cit G H M F Cit V Y Cit F R 181102RA02
G R N I R V Cit Cit A R Cit Cit 181102RA04
Q I F Y L Cit Cit H R Q Cit R 221102RA01
R Q G P I A Cit L H I R R 221102RA02
G V Y L V R Cit L Cit M M R 0218-36
N Cit Cit R R V Cit M Cit R I Cit 271102RA01
K Cit R L Cit Y Cit P V R K S 271102RA02
G R R Cit Cit L Cit R P Cit Cit R 271102RA03
R M P H Cit H Cit S Cit R R K 271102RA04
从上述数据中,可以推导出对某些特定位置有优先选择的氨基酸的共有序列。因此,优选被RA血清识别的XnonG肽单元可由以下表示:
-5 -4 3 -2 -1 0 +1 +2 +3 +4 +5
R R R R R X R R R R R
N Y V Q H T I I K
F I Y Y P P
H S V N
G
实验表明,例如,环状形式的肽0107-35与18%的不与环状0002-36反应的血清反应。采用其他肽还可使该敏感性进一步增加。例如,采用环状肽0107-32还可进一步增加8%。这可使敏感性增加至80%。对肽0107-45发现了类似值。52份XG-阴性血清中的总共17份(32%)显示出与一种或多种XnonG肽反应。这意味着采用多于2种XG和XnonG肽的组合(本发明的优选实施方案),可实现敏感性超过80%。因此,这优于通过具有通式IV的肽和由PCT/NL97/00624中已知的那些肽的组合所能实现的。
通过采用更多的肽,敏感性可更进一步增加。当采用环状XG肽(例如0002-63或0002-36)与线性或环状XnonG肽(例如0107-35)一起测试RA血清时,对于318份RA血清,获得78%的敏感性。加入第3个,第4个,甚至可能的第5个肽,增加敏感性至85%(分别为肽0107-32,0107-42,0107-34)。318份RA血清中仅有48份不与一种所提到的肽反应。
实施例7:包含XG和XnonG肽单元的诊断测试的敏感性和特异
性
采用上述方法,测试了7种XG肽单元与表2中提到的来自于患有类风湿性关节炎的患者的318份血清的反应性。借助于在表2中提到的来自于对照患者和正常供体的血清,确定了其特异性。表6显示了各个肽单元的特异性和敏感性。
表6
根据本文中所述的方法,测试了5种XnonG肽单元与表2中提到的来自于患有类风湿性关节炎的患者的相同的318份血清的反应性。同样,借助于在表2中提到的来自对照患者和正常供体的血清,确定了其特异性。表7显示了各个肽单元的特异性和敏感性。
表7
采用如上文所述的318份血清组中不与表6中的任何XG肽反应的80份血清来测试表7中提到的XnonG肽单元的反应性。因此,表8中提到的百分比显示出包含对XnonG肽单元的抗体,但不包含XG反应性抗体的血清百分比。
表8
上述结果显示,如果将表6的每一XG肽单元与表7中的每一肽单元组合,可预期敏感性增加。所有下文给出的肽单元组合均采用了上述来自于患有类风湿性关节炎的患者的318份血清组中的代表性部分进行了检测。该实验事实上显示获得了敏感性平均增加6%,将这种组合测试的总敏感性升至75-78%。
测试的肽单元组合涉及:肽单元0002-27与0107-32;0002-27与0107-35;0002-27与0107-45;0002-27与0113-30;0002-27与0218-36;0002-29与0107-32;0002-29与0107-35;0002-29与0107-45;0002-29与0113-30;0002-29与0218-36;0002-31与0107-32;0002-31与0107-35;0002-31与0107-45;0002-31与0113-30;0002-31与0218-36;0002-32与0107-32;0002-32与0107-35;0002-32与0107-45;0002-32与0113-30;0002-32与0218-36;0002-36与0107-32;0002-36与0107-35;0002-36与0107-45;0002-36与0113-30;0002-36与0218-36;0002-37与0107-32;0002-37与0107-35;0002-37与0107-45;0002-37与0113-30;0002-37与0218-36;0002-63与0107-32;0002-63与0107-35;0002-63与0107-45;0002-63与0113-30和最后0002-63与0218-36。
关于表6和表8的结果,还应该注意到,各种肽单元还检测出不同的血清组群。由此可以推论:如果加入第3种肽单元或甚至是第4种或更多的肽单元,则上述提到的XG和XnonG肽单元组合还能产生敏感性的进一步增加。取决于所选择的肽单元组合,本发明所述的诊断测试的确可以达到88-92%的敏感性。
序列表
<110>.Stichting Technische Wetenschappen
Venrooij,Walther J
Drijfhout,Jan W
Boekel,Martinus A
Pruijn,Gerardus J
<120>从患有类风湿性关节炎的患者中检测自身抗体的方法、肽和检测试剂盒
<130>NL 45032
<150>NL 1019540
<151>2001-12-11
<160>207
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<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=瓜氨酸
<400>43
Phe Met Arg Arg Pro
1 5
<210>44
<211>5
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=瓜氨酸
<400>44
Glu Arg Asn His Ala
1 5
<210>45
<211>5
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=瓜氨酸
<400>45
Ala Val Ile Thr Ala
1 5
<210>46
<211>5
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=瓜氨酸
<400>46
Thr Pro Asn Arg Trp
1 5
<210>47
<211>5
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=瓜氨酸
<400>47
Thr Tyr Asn Arg Trp
1 5
<210>48
<211>5
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=瓜氨酸
<400>48
Arg Thr Pro Thr Arg
1 5
<210>49
<211>5
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=瓜氨酸
<400>49
Arg Ile Val Val Val
1 5
<210>50
<211>5
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=瓜氨酸
<400>50
His Ala Arg Pro Arg
1 5
<210>51
<211>5
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=瓜氨酸
<400>51
Arg Gly Met Xaa Arg
1 5
<210>52
<211>5
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=瓜氨酸
<400>52
Ile Arg Phe Pro Val
1 5
<210>53
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>53
Ile Asn Xaa Arg Ala Ser
1 5
<210>54
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>54
Ile Xaa Lys Arg Leu Tyr
1 5
<210>55
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=瓜氨酸
<400>55
Lys Xaa Xaa Tyr Asn Ile
1 5
<210>56
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>56
Arg Leu Tyr Phe Ile Xaa
1 5
<210>57
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>57
Ile Arg Gln Gly Ala Arg
1 5
<210>58
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>58
Xaa Glu Arg Xaa Val Gln
1 5
<210>59
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>59
Xaa His Gln Arg Ile Thr
1 5
<210>60
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>60
Arg Ile Xaa Arg Val Xaa
1 5
<210>61
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>61
Gly Arg Asn Gln Arg Tyr
1 5
<210>62
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>62
Arg Xaa Arg Gln His Pro
1 5
<210>63
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>63
Xaa Xaa Arg Xaa Val Ala
1 5
<210>64
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>64
Arg Pro Lys Gln His Val
1 5
<210>65
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>65
Arg Lys Xaa Gly Xaa Arg
1 5
<210>66
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>66
Arg Xaa Xaa Arg Asn Thr
1 5
<210>67
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>67
Arg Xaa Gln Xaa Phe Thr
1 5
<210>68
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>68
Gln Leu Val Tyr Leu Gln
1 5
<210>69
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>69
Gln Tyr Asn Arg Phe Lys
1 5
<210>70
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>70
Xaa Leu Arg His Ile Arg
1 5
<210>71
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC FEATURE
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>71
Pro Arg Xaa Xaa Xaa Lys
1 5
<210>72
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>72
Arg Xaa Gln Val Arg Tyr
1 5
<210>73
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>73
Gly Arg Xaa His Ala His
1 5
<210>74
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>74
Ala Arg His Val Ile Arg
1 5
<210>75
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>75
Arg Xaa Gly His Met Phe
1 5
<210>76
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>76
Gly Arg Asn Ile Arg Val
1 5
<210>77
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>77
Gln Ile Phe Tyr Leu Xaa
1 5
<210>78
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>78
Arg Gln Gly Pro Ile Ala
1 5
<210>79
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>79
Gly Val Tyr Leu Val Arg
1 5
<210>80
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>80
Asn Xaa Xaa Arg Arg Val
1 5
<210>81
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>81
Lys Xaa Arg Leu Xaa Tyr
1 5
<210>82
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>82
Gly Arg Arg Xaa Xaa Leu
15
<210>83
<211>6
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=瓜氨酸
<400>83
Arg Met Pro His Xaa His
1 5
<210>84
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>84
Xaa His Arg Arg
1
<210>85
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>85
Xaa Ile Arg Arg
1
<210>86
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>86
Phe Arg Arg Asn
1
<210>87
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>87
Ala Gln Thr Thr
1
<210>88
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>88
Gly Tyr Pro Lys
1
<210>89
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>89
Arg Pro Pro Gln
1
<210>90
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>90
Gly Xaa Arg Lys
1
<210>91
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>91
Pro Ile Pro Arg
1
<210>92
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>92
Tyr Thr Ile His
1
<210>93
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>93
Arg Ile Lys Ala
1
<210>94
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>94
Xaa Arg Val Arg
1
<210>95
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>95
Thr Arg Arg Pro
1
<210>96
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>96
Thr Ile Arg Pro
1
<210>97
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>97
Ile Lys Xaa Arg
1
<210>98
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>98
Arg Asn Val Val
1
<210>99
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>99
Xaa Arg Arg Tyr
1
<210>100
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>100
Xaa Arg Pro Arg
1
<210>101
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>101
Thr Arg Xaa Xaa
1
<210>102
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>102
Xaa Xaa Gly Arg
1
<210>103
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>103
Leu Xaa Arg Xaa
1
<210>104
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>104
Arg Val Arg Xaa
1
<210>105
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>105
Val Pro Arg Thr
1
<210>106
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>106
Tyr Xaa Phe Arg
1
<210>107
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>107
Ala Arg Xaa Xaa
1
<210>108
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>108
Arg Gln Xaa Arg
1
<210>109
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>109
His Ile Arg Arg
1
<210>110
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>110
Xaa Met Met Arg
1
<210>111
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>111
Xaa Arg Ile Xaa
1
<210>112
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<400>112
Val Arg Lys Ser
1
<210>113
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>113
Pro Xaa Xaa Arg
1
<210>114
<211>4
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(4)
<223>X=瓜氨酸
<400>114
Xaa Arg Arg Lys
1
<210>115
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>115
Arg His Gly Arg Gln Xaa Xaa Lys Tyr Ile Ile Tyr
1 5 10
<210>116
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>116
Ile Arg Xaa Tyr Lys Xaa Ile Thr Asn Arg Lys Phe
1 5 10
<210>117
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>117
Arg His Gly Arg Gln Xaa Xaa Xaa Tyr Ile Ile Tyr
1 5 10
<210>118
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>118
Ala Arg Phe Gln Met Xaa His Xaa Arg Leu Ile Arg
1 5 10
<210>119
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>119
Gln Xaa Tyr Lys Trp Xaa Lys Ile Glu Arg Lys Arg
1 5 10
<210>120
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>120
Lys Pro Tyr Thr Val Xaa Lys Phe Met Arg Lys Pro
1 5 10
<210>121
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>121
Lys Pro Tyr Thr Val Xaa Lys Phe Met Arg Arg Pro
1 5 10
<210>122
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>122
Arg Asn Leu Arg Leu Xaa Arg Glu Arg Asn His Ala
1 5 10
<210>123
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>123
Arg Arg Arg Xaa Tyr Xaa Arg Ala Val Ile Thr Ala
1 5 10
<210>124
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>124
Arg Phe Lys Ser Asn Xaa Arg Thr Pro Asn Arg Trp
1 5 10
<210>125
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>125
Arg Gly Lys Ser Asn Xaa Arg Thr Tyr Asn Arg Trp
1 5 10
<210>126
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>126
Arg Phe Lys Ser Asn Xaa Arg Thr Tyr Asn Arg Trp
1 5 10
<210>127
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>127
Arg Gly Lys Ser Asn Xaa Arg Thr Pro Asn Arg Trp
1 5 10
<210>128
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>128
Arg Trp Val Ser Gln Xaa Arg Arg Thr Pro Thr Arg
1 5 10
<210>129
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>129
Met Lys Pro Arg Tyr Xaa Arg Arg Ile Val Val Val
1 5 10
<210>130
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>130
Lys Ser Phe Val Trp Xaa Ser His Ala Arg Pro Arg
1 5 10
<210>131
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>131
Tyr Ser Phe Val Trp Xaa Ser His Ala Arg Pro Arg
1 5 10
<210>132
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>132
Arg Asn Met Asn Arg Xaa Trp Arg Gly Met Xaa Arg
1 5 10
<210>133
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>133
Arg Met Gly Arg Pro Xaa Trp Ile Arg Phe Pro Val
1 5 10
<210>134
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>134
Ile Asn Xaa Arg Ala Ser Xaa Lys Xaa His Arg Arg
1 5 10
<210>135
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>135
Ile Xaa Lys Arg Leu Tyr Xaa Met Xaa Ile Arg Arg
1 5 10
<210>136
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>136
Lys Xaa Xaa Tyr Asn Ile Xaa Xaa Phe Arg Arg Asn
1 5 10
<210>137
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>137
Arg Leu Tyr Phe Ile Xaa Xaa Arg Ala Gln Thr Thr
1 5 10
<210>138
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>138
Ile Arg Gln Gly Ala Arg Xaa Arg Gly Tyr Pro Lys
1 5 10
<210>139
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>139
Xaa Glu Arg Xaa Val Gln Xaa Arg Arg Pro Pro Gln
1 5 10
<210>140
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>140
Xaa His Gln Arg Ile Thr Xaa Val Gly Xaa Arg Lys
1 5 10
<210>14l
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>141
Arg Ile Xaa Arg Val Xaa Xaa Thr Pro Ile Pro Arg
1 5 10
<210>142
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>142
Gly Arg Asn Gln Arg Tyr Xaa Leu Tyr Thr Ile His
1 5 10
<210>143
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>143
Arg Xaa Arg Gln His Pro Xaa His Arg Ile Lys Ala
1 5 10
<210>144
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>144
Xaa Xaa Arg Xaa Val Ala Xaa Phe Xaa Arg Val Arg
1 5 10
<210>145
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>145
Arg Pro Lys Gln His Val Xaa His Thr Arg Arg Pro
1 5 10
<210>146
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>146
Arg Lys Xaa Gly Xaa Arg Xaa Xaa Thr Ile Arg Pro
1 5 10
<210>147
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>147
Arg Xaa Xaa Arg Asn Thr Xaa His Ile Lys Xaa Arg
1 5 10
<210>148
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>148
Arg Xaa Gln Xaa Phe Thr Xaa Xaa Arg Asn Val Val
1 5 10
<210>149
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>149
Gln Leu Val Tyr Leu Gln Xaa Xaa Xaa Arg Arg Tyr
1 5 10
<210>150
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>150
Gln Tyr Asn Arg Phe Lys Xaa Xaa Xaa Arg Pro Arg
1 5 10
<210>151
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>151
Xaa Leu Arg His Ile Arg Xaa Gln Thr Arg Xaa Xaa
1 5 10
<210>152
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>152
Pro Arg Xaa Xaa Xaa Lys Xaa Arg Xaa Xaa Gly Arg
1 5 10
<210>153
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>153
Arg Xaa Gln Val Arg Tyr Xaa Xaa Leu Xaa Arg Xaa
1 5 10
<210>154
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>154
Gly Arg Xaa His Ala His Xaa Pro Arg Val Arg Xaa
1 5 10
<210>155
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>155
Ala Arg His Val Ile Arg Xaa Xaa Val Pro Arg Thr
1 5 10
<210>156
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>156
Arg Xaa Gly His Met Phe Xaa Val Tyr Xaa Phe Arg
1 5 10
<210>157
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>157
Gly Arg Asn Ile Arg Val Xaa Xaa Ala Arg Xaa Xaa
1 5 10
<210>158
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>158
Gln Ile Phe Tyr Leu Xaa Xaa His Arg Gln Xaa Arg
1 5 10
<210>159
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>159
Arg Gln Gly Pro Ile Ala Xaa Leu His Ile Arg Arg
1 5 10
<210>160
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>160
Gly Val Tyr Leu Val Arg Xaa Leu Xaa Met Met Arg
1 5 10
<210>161
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>161
Asn Xaa Xaa Arg Arg Val Xaa Met Xaa Arg Ile Xaa
1 5 10
<210>162
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>162
Lys Xaa Arg Leu Xaa Tyr Xaa Pro Val Arg Lys Ser
1 5 10
<210>163
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>163
Gly Arg Arg Xaa Xaa Leu Xaa Arg Pro Xaa Xaa Arg
1 5 10
<210>164
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>164
Arg Met Pro His Xaa His Xaa Ser Xaa Arg Arg Lys
1 5 10
<210>165
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>165
His Gln Arg Lys Trp Xaa Gly Ala Ser Arg Ala Ala
1 5 10
<210>166
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>166
His Gln His Trp Arg Xaa Gly Ala Ser Arg Ala Ala
1 5 10
<210>167
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>167
His Gln Phe Arg Phe Xaa Gly Xaa Ser Arg Ala Ala
1 5 10
<210>168
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>168
His Gln Glu Arg Arg Xaa Gly Glu Ser Arg Ala Ala
1 5 10
<210>169
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>169
His Gln Lys Trp Arg Xaa Gly Phe Ser Arg Ala Ala
1 5 10
<210>170
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>170
His Gln Arg Trp Lys Xaa Gly Gly Ser Arg Ala Ala
1 5 10
<210>171
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>171
His Gln Arg Arg Thr Xaa Gly Gly Ser Arg Ala Ala
1 5 10
<210>172
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>172
His Gln Arg Arg Gly Xaa Gly Gly Ser Arg Ala Ala
1 5 10
<210>173
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>173
His Gln Xaa Phe Arg Xaa Gly His Ser Arg Ala Ala
1 5 10
<210>174
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>174
Gly Phe Phe Ser Ala Xaa Gly His Arg Pro Leu Asp
1 5 10
<210>175
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>175
His Gln Glu Arg Gly Xaa Gly Lys Ser Arg Ala Ala
1 5 10
<210>176
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>176
His Gln Glu Lys Arg Xaa Gly Lys Ser Arg Ala Ala
1 5 10
<210>177
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>177
His Gln Arg Trp Leu Xaa Gly Lys Ser Arg Ala Ala
1 5 10
<210>178
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>178
His Gln Lys Arg Asn Xaa Gly Lys Ser Arg Ala Ala
1 5 10
<210>179
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>179
Glu Gly Gly Gly Val Xaa Gly Pro Arg Val Val Glu
1 5 10
<210>180
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>180
His Gln Trp Arg His Xaa Gly Arg Ser Arg Ala Ala
1 5 10
<210>181
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>181
His Gln Lys Trp Asn Xaa Gly Arg Ser Arg Ala Ala
1 5 10
<210>182
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>182
His Gln Lys Phe Trp Xaa Gly Arg Ser Arg Ala Ala
1 5 10
<210>183
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>183
His Gln Lys Xaa Lys Xaa Gly Arg Ser Arg Ala Ala
1 5 10
<210>184
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>184
His Gln Lys Trp Arg Xaa Gly Arg Ser Xaa Ala Ala
1 5 10
<210>185
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>185
His Gln Ala Trp Arg Xaa Gly Arg Ser Xaa Ala Ala
1 5 10
<210>186
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<22l>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>186
His Gln Asn Gln Trp Xaa Gly Arg Ser Arg Ala Ala
1 5 10
<210>187
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>187
His Gln Asn Ser Lys Xaa Gly Arg Ser Arg Ala Ala
1 5 10
<210>188
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>188
His Gln Lys Arg Arg Xaa Gly Arg Ser Arg Ala Ala
1 5 10
<210>189
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>189
His Gln Lys Arg Phe Xaa Gly Arg Ser Arg Ala Ala
1 5 10
<210>190
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>190
His Gln Lys Arg Tyr Xaa Gly Arg Ser Arg Ala Ala
1 5 10
<210>191
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>191
His Gln Lys Arg His Xaa Gly Arg Ser Arg Ala Ala
1 5 10
<210>192
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>192
His Gln Glu Arg Ala Xaa Gly Ser Ser Arg Ala Ala
1 5 10
<210>193
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>193
His Gln Glu Lys Met Xaa Gly Val Ser Arg Ala Ala
1 5 10
<210>194
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>194
His Gln Lys Arg Gly Xaa Gly Trp Ser Arg Ala Ala
1 5 10
<210>195
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>195
His Gln Arg Arg Val Xaa Gly Trp Ser Arg Ala Ala
1 5 10
<210>196
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>196
His Gln Trp Asn Arg Xaa Gly Trp Ser Arg Ala Ala
1 5 10
<210>197
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>197
His Gln Gln Arg Met Xaa Gly Trp Ser Arg Ala Ala
1 5 10
<210>198
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>198
His Gln Ser His Arg Xaa Gly Trp Ser Arg Ala Ala
1 5 10
<210>199
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>199
His Gln Phe Arg Phe Xaa Gly Trp Ser Arg Ala Ala
1 5 10
<210>200
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>200
His Gln Lys Arg Arg Xaa Gly Trp Ser Arg Ala Ala
1 5 10
<210>201
<211>12
<212>PRT
<213>人工序列
<220>
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(1)..(12)
<223>X=瓜氨酸
<400>201
Gly Val Lys Gly His Xaa Gly Tyr Pro Gly Leu Asp
1 5 10
<210>202
<211>12
<212>PRT
<213>人工序列
<220>
<223>肽文库
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=除cys和trp以外的任何氨基酸
<220>
<221>MISC_FEATURE
<222>(6)..(6)
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(7)..(12)
<223>X=除cys和trp以外的任何氨基酸
<400>202
His Gln Glu Xaa Xaa Xaa Xaa Xaa Ser Arg Ala Ala
1 5 10
<210>203
<211>12
<212>PRT
<213>人工序列
<220>
<223>肽文库
<220>
<221>MISC_FEATURE
<222>(7)..(12)
<223>X=除cys以外的任何氨基酸
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=除cys以外的任何氨基酸
<220>
<221>MISC_FEATURE
<222>(6)..(6)
<223>X=瓜氨酸
<400>203
His Gln Xaa Xaa Xaa Xaa Gly Xaa Ser Arg Ala Ala
1 5 10
<210>204
<211>12
<212>PRT
<213>人工序列
<220>
<223>肽文库
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=除cys以外的任何氨基酸
<220>
<221>MISC_FEATURE
<222>(6)..(6)
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(10)..(10)
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(7)..(9)
<223>X=除cys以外的任何氨基酸
<400>204
His Gln Xaa Xaa Xaa Xaa Gly Xaa Ser Xaa Ala Ala
1 5 10
<210>205
<211>12
<212>PRT
<213>人工序列
<220>
<223>肽文库
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=除cys以外的任何氨基酸
<220>
<221>MISC_FEATURE
<222>(7)..(12)
<223>X=除cys以外的任何氨基酸
<220>
<221>MISC_FEATURE
<222>(6)..(6)
<223>X=瓜氨酸
<400>205
His Gln Glu Xaa Xaa Xaa Xaa Xaa Ser Arg Ala Ala
1 5 10
<210>206
<211>12
<212>PRT
<213>人工序列
<220>
<223>肽文库
<220>
<221>MISC_FEATURE
<222>(1)..(5)
<223>X=除cys以外的任何氨基酸
<220>
<221>MISC_FEATURE
<222>(7)..(9)
<223>X=除cys以外的任何氨基酸
<220>
<221>MISC_FEATURE
<222>(6)..(6)
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(10)..(10)
<223>X=瓜氨酸
<400>206
His Gln Glu Xaa Xaa Xaa Xaa Xaa Ser Xaa Ala Ala
1 5 10
<210>207
<211>12
<212>PRT
<213>人工序列
<220>
<223>肽文库
<220>
<221>MISC_FEATURE
<222>(1)..(6)
<223>X=除cys以外的任何氨基酸
<220>
<221>MISC_FEATURE
<222>(7)..(7)
<223>X=瓜氨酸
<220>
<221>MISC_FEATURE
<222>(8)..(12)
<223>X=除cys以外的任何氨基酸
<400>207
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10
Claims (12)
1. 肽单元,包含选自以下的序列:
肽 0002-27 H Q K R G Cit G W S R A A
肽 0002-29 H Q R R V Cit G W S R A A
肽 0002-31 H Q R R T Cit G G S R A A
肽 0002-32 H Q R K W Cit G A S R A A
肽 0002-36 H Q F R F Cit G Cit S R A A
肽 0002-37 H Q K W R Cit G R S Cit A A
肽 0002-63 H Q F R F Cit G W S R A A
肽 0107-32 K P Y T V Cit K F M R R P
肽 0107-35 A R F Q M Cit H Cit R L I R
肽 0107-45 Y S F V W Cit S H A R P R
肽 0113-30 A R F Q M R H Cit R L I R
和肽 0218-36 R N L R L Cit R E R N H A。
2. 权利要求1的肽单元,其为环状。
3. 权利要求2的肽单元,形成环结构,其中所述环包含至少8个氨基酸。
4. 包含权利要求1-3任一项的肽单元的多肽单元。
5. 一种用于确定类风湿性关节炎的自身抗体的存在的诊断测试试剂盒,其特征在于它包含至少一种如权利要求1-4任一项所述的肽,以及至少一种另外的试剂。
6. 一种选择适合于诊断类风湿性关节炎的肽的方法,其中采用从患有类风湿性关节炎的患者获得的抗体筛选肽文库,且其中所述的肽文库选自如下组:
文库(1):H Q E X X Cit X X S R A A
其中X=除半胱氨酸和色氨酸以外的任何氨基酸
文库(2):H Q X X X Cit G X S R/Cit A A
其中X=除外半胱氨酸但包括瓜氨酸的任何氨基酸
文库(3):H Q E X X Cit X X S R/Cit AA
其中X=除外半胱氨酸但包括瓜氨酸的任何氨基酸。
7. 一种可通过权利要求6的方法获得的肽用于制备对类风湿性关节炎的诊断测定剂的用途。
8. 至少一种包含瓜氨酸残基的反应性肽在制备检测类风湿性关节炎的自身抗体的试剂中的用途,其特征在于所述反应性肽包含至少一个如权利要求1-4任一项所述的肽单元。
9. 至少一种包含瓜氨酸残基的反应性肽在制备检测类风湿性关节炎的自身抗体的试剂中的用途,其特征在于所述反应性肽包含至少一个选自以下的肽单元:
肽 0002-27 H Q K R G Cit G W S R A A
肽 0002-29 H Q R R V Cit G W S R A A
肽 0002-31 H Q R R T Cit G G S R A A
肽 0002-32 H Q R K W Cit G A S R A A
肽 0002-36 H Q F R F Cit G Cit S R A A
肽 0002-37 H Q K W R Cit G R S Cit A A
和肽 0002-63 H Q F R F Cit G W S R A A
和至少一个选自以下的肽单元:
肽 0107-32 K P Y T V Cit K F M R R P
肽 0107-35 A R F Q M Cit H Cit R L I R
肽 0107-45 Y S F V W Cit S H A R P R
肽 0113-30 A R F Q M R H Cit R L I R
和肽 0218-36 R N L R L Cit R E R N H A。
10. 权利要求9的用途,其特征在于至少一种所述肽单元为环状肽单元。
11. 权利要求10的用途,其中所述至少一种环状肽单元形成环结构,其中所述环包含至少8个氨基酸。
12. 权利要求8-11任一项的用途,其中所述肽单元为多肽单元的一部分。
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AUPQ776100A0 (en) * | 2000-05-26 | 2000-06-15 | Australian National University, The | Synthetic molecules and uses therefor |
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