CN110862450A - 基于cii的环状多肽及其应用 - Google Patents
基于cii的环状多肽及其应用 Download PDFInfo
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- CN110862450A CN110862450A CN201810989604.1A CN201810989604A CN110862450A CN 110862450 A CN110862450 A CN 110862450A CN 201810989604 A CN201810989604 A CN 201810989604A CN 110862450 A CN110862450 A CN 110862450A
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- Prior art keywords
- gly
- pro
- amino acid
- acid sequence
- cyclic polypeptide
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- 229920001184 polypeptide Polymers 0.000 title claims abstract description 138
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 138
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 138
- 125000004122 cyclic group Chemical group 0.000 title claims abstract description 79
- 239000004475 Arginine Substances 0.000 claims abstract description 38
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 35
- 235000001014 amino acid Nutrition 0.000 claims abstract description 16
- 235000018417 cysteine Nutrition 0.000 claims abstract description 16
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000001413 amino acids Chemical group 0.000 claims abstract description 15
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960002684 aminocaproic acid Drugs 0.000 claims abstract description 7
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 claims abstract description 5
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 235000013477 citrulline Nutrition 0.000 claims abstract description 5
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- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims abstract description 4
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- 125000003275 alpha amino acid group Chemical group 0.000 claims description 39
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- UGTHTQWIQKEDEH-BQBZGAKWSA-N L-alanyl-L-prolylglycine zwitterion Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O UGTHTQWIQKEDEH-BQBZGAKWSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 6
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- BEMGNWZECGIJOI-WDSKDSINSA-N Ala-Gly-Glu Chemical compound [H]N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O BEMGNWZECGIJOI-WDSKDSINSA-N 0.000 description 4
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 4
- UTKUTMJSWKKHEM-WDSKDSINSA-N Glu-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O UTKUTMJSWKKHEM-WDSKDSINSA-N 0.000 description 4
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Abstract
本发明涉及基因工程技术领域，公开一种基于CII的环状多肽，所述环状多肽的氨基酸序列通式为：Acp1‑Cys2‑Xaa3‑Xaa4‑Xaa5‑Xaa6‑Xaa7‑Xaa8‑Xaa9‑Xaa10‑Xaa11‑Xaa12‑Xaa13‑Xaa14‑Xaa15‑Xaa16‑Xaa17‑Cys18‑Ala19；其中，第10位的氨基酸为瓜氨酸；第2位的半胱氨酸(Cys)和第18位的半胱氨酸(Cys)形成分子内二硫键；丙氨酸(Ala)连接在半胱氨酸(Cys)的碳端，6‑氨基己酸(Acp)连接在半胱氨酸(Cys)的氮端；所述CII具有SEQ ID NO:1所示的氨基酸序列，其上含有54个精氨酸(Arg)；环状多肽中第3位至第9位的氨基酸、第11位至第17位的氨基酸为环状多肽中的瓜氨酸与CII氨基酸序列中的第N个精氨酸(Arg)位置重合时，分别按照CII氨基酸序列向两边扩展的7个氨基酸；所述N为4,5,6,19,22,28,34,38,46或49。
Description
技术领域
本发明涉及基因工程技术领域，具体地说是一种基于CII的环状多肽及其应用。
背景技术
抗瓜氨酸化蛋白抗体(Anti-Citrullinated Protein Antiboides,ACPAs)是类风湿关节炎患者(RA)的一个重要生物标记物，具有较高的敏感性和特异性，而且可在疾病发病的几年前被检测到。ACPAs的评估通常通过检测血清对第二代环瓜氨酸肽(Cycliccitrullinated peptide-2,CCP-2)的反应来确定。该方式可以预测RA的发展和相关的关节破坏程度。有研究表面，RA患者血清中存在多种抗瓜氨酸化蛋白的抗体，例如波形蛋白，烯醇酶，纤维原蛋白等。
二型胶原蛋白(Collagen type II,CII)是RA主要的自身抗原，它属于胶原蛋家族的一员，其他还包括I型、V型，IX型和XI型胶原蛋白。CII由三条相同的α链组成，并形成三螺旋结构，多个CII聚集在一起组成原纤维。同时，IX和XI型胶原蛋白修饰纤维表面，与CII相互结合共同组成纤维束。CII是关节软骨(Articular Cartilage,AC)细胞外基质(ExtraCellular Matrix,ECM)的主要组成部分，也是RA炎症反应的主要攻击目标。CII上存在不同的免疫显性抗原表位，可以被B细胞识别，某些表位的抗体可在非B细胞或T细胞依赖性动物模型中诱导RA的发生。在RA患者血清中，可以检测到抗瓜氨酸化CII的抗体。
虽然CCP-2试剂盒可以检测血清中CCP-2抗体滴度，从而判断是否患有类风湿关节炎。但目前CCP-2的检测在RA患者中的特异性大约在75％左右，并且该试剂盒中的多肽序列和来源均未知。CCP-2试剂盒并不能检测对CII表位特异性的抗体。因此，为了开发一种可以检测CII特异性抗体的多肽，提高RA检测的特异性和灵敏度，有效地指导患者的治疗以及愈后的评估，有必要对现有技术进行改进。
发明内容
针对现有技术的不足，本发明提供了一种基于CII的环状多肽及其应用。
本发明为实现上述目的，采取以下技术方案予以实现：
一种基于CII的环状多肽，所述环状多肽的氨基酸序列通式为：
Acp1-Cys2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Cys18-Ala19；
其中，第10位的氨基酸为瓜氨酸；第2位的半胱氨酸(Cys)和第18位的半胱氨酸(Cys)形成分子内二硫键；丙氨酸(Ala)连接在半胱氨酸(Cys)的碳端，6-氨基己酸(Acp)连接在半胱氨酸(Cys)的氮端；
所述CII具有SEQ ID NO:1所示的氨基酸序列，其上含有54个精氨酸(Arg)；环状多肽中第3位至第9位的氨基酸、第11位至第17位的氨基酸为环状多肽中的瓜氨酸与CII氨基酸序列中的第N个精氨酸(Arg)位置重合时，分别按照CII氨基酸序列向两边扩展的7个氨基酸；所述N为4,5,6,19,22,28,34,38,46或49。
当N为2时，这第2个精氨酸位于SEQIDNO:1所示的氨基酸序列的第60位，所述环状多肽为：
Acp1-Cys2-Val3-Ser4-Gly5-Pro6-Met7-Gly8-Pro9-Xaa10-Gly11-Pro12-Pro13-Gly14-Pro15-Pro16-Gly17-Cys18-Ala19(记为2_Cit多肽)。
当N为4时，这第4个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第93位，所述环状多肽为：
Acp1-Cys2-Pro3-Pro4-Gly5-Pro6-Gln7-Gly8-Ala9-Xaa10-Gly11-Phe12-Pro13-Gly14-Thr15-Pro16-Gly17-Cys18-Ala19(记为4_Cit多肽)。
当N为5时，这第5个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第108位，所述环状多肽为：
Acp1-Cys2-Leu3-Pro4-Gly5-Val6-Lys7-Gly8-His9-Xaa10-Gly11-Tyr12-Pro13-Gly14-Leu15-Asp16-Gly17-Cys18-Ala19(记为5_Cit多肽)。
当N为6时，这第6个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第144位，所述环状多肽为：
Acp1-Cys2-Ser3-Pro4-Gly5-Pro6-Met7-Gly8-Pro9-Xaa10-Gly11-Leu12-Pro13-Gly14-Glu15-Arg16-Gly17-Cys18-Ala19(记为6_Cit多肽)。
当N为12时，这第12个精氨酸位于SEQIDNO:1所示的氨基酸序列的第255位，所述环状多肽为：
Acp1-Cys2-Ala3-Pro4-Gly5-Phe6-Pro7-Gly8-Pro9-Xaa10-Pro11-Pro12-Pro13-Gly14-Pro15-Gln16-Gly17-Cys18-Ala19(记为12_Cit多肽)。
当N为19时，这第19个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第378位，所述环状多肽为：
Acp1-Cys2-Glu3-Pro4-Gly5-Leu6-Pro7-Gly8-Ala9-Xaa10-Gly11-Leu12-Thr13-Gly14-Arg15-Pro16-Gly17-Cys18-Ala19(记为19_Cit多肽)。
当N为25时，这第25个精氨酸位于SEQIDNO:1所示的氨基酸序列的第516位，所述环状多肽为：
Acp1-Cys2-Ala3-Pro4-Gly5-Leu6-Val7-Gly8-Pro9-Xaa10-Gly11-Glu12-Arg13-Gly14-Phe15-Pro16-Gly17-Cys18-Ala19(记为25_Cit多肽)。
当N为38时，这第38个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第798位，所述环状多肽为：
Acp1-Cys2-Pro3-Gln4-Gly5-Leu6-Ala7-Gly8-Gln9-Xaa10-Gly11-Ile12-Val13-Gly14-Leu15-Pro16-Gly17-Cys18-Ala19(记为38_Cit多肽)。
当N为46时，这第46个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第924位，所述环状多肽为：
Acp1-Cys2-Pro3-Ser4-Gly5-Pro6-Ala7-Gly8-Ala9-Xaa10-Gly11-Ile12-Gln13-Gly14-Pro15-Gln16-Gly17-Cys18-Ala19(记为46_Cit多肽)。
当N为49时，这第49个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第951位，所述环状多肽为：
Acp1-Cys2-Glu3-Arg4-Gly5-Leu6-Lys7-Gly8-His9-Xaa10-Gly11-Phe12-Thr13-Gly14-Leu15-Gln16-Gly17-Cys18-Ala19(记为49_Cit多肽)。
优选地，所述CII为人源二型胶原蛋白。
优选地，所述环状多肽中的6-氨基己酸(Ahx)由生物素(Bio)标记。
本发明环状多肽在检测类风湿关节炎中的应用，所述环状多肽用于鉴别类风湿关节炎。
本发明环状多肽在检测关节炎中的应用，所述环状多肽用于对类风湿关节炎与骨关节炎进行分类。
与现有技术相比，本发明的有益效果如下：
本发明一种基于CII的环状多肽，对RA患者具有高灵敏度和高特异性，可以作为新的生物标记物用于RA的鉴别。
本发明一种基于CII的环状多肽，其在类风湿关节炎患者(RA)血清中的抗体反应显著高于OA和HC组，对类风湿关节炎患者(RA)有显著性差异，p<0.0005。通过检测抗环状多肽抗体可以对患者进行分类。
附图说明
图1为2_Cit多肽分别与OA和RA患者血清样本反应的MFI对比示意图；
图2为4_Cit多肽分别与OA和RA患者血清样本反应的MFI对比示意图；
图3为5_Cit多肽分别与OA和RA患者血清样本反应的MFI对比示意图；
图4为6_Cit多肽分别与OA和RA患者血清样本反应的MFI对比示意图；
图5为12_Cit多肽分别与OA和RA患者血清样本反应的MFI对比示意图；
图6为19_Cit多肽分别与OA和RA患者血清样本反应的MFI对比示意图；
图7为25_Cit多肽分别与OA和RA患者血清样本反应的MFI对比示意图；
图8为38_Cit多肽分别与OA和RA患者血清样本反应的MFI对比示意图；
图9为46_Cit多肽分别与OA和RA患者血清样本反应的MFI对比示意图；
图10为49_Cit多肽分别与OA和RA患者血清样本反应的MFI对比示意图；
图11为2_Cit多肽分别与HC和RA患者血清样本反应的MFI对比示意图；
图12为4_Cit多肽分别与HC和RA患者血清样本反应的MFI对比示意图；
图13为5_Cit多肽分别与HC和RA患者血清样本反应的MFI对比示意图；
图14为6_Cit多肽分别与HC和RA患者血清样本反应的MFI对比示意图；
图15为12_Cit多肽分别与HC和RA患者血清样本反应的MFI对比示意图；
图16为19_Cit多肽分别与HC和RA患者血清样本反应的MFI对比示意图；
图17为25_Cit多肽分别与HC和RA患者血清样本反应的MFI对比示意图；
图18为38_Cit多肽分别与HC和RA患者血清样本反应的MFI对比示意图；
图19为46_Cit多肽分别与HC和RA患者血清样本反应的MFI对比示意图；
图20为49_Cit多肽分别与HC和RA患者血清样本反应的MFI对比示意图。
具体实施方式
下面结合实施例对本发明作进一步的描述，但需要说明的是，实施例并不对本发明要求保护范围的构成限制。
实施例1：一种基于CII的环状多肽的获得
一种基于CII的环状多肽，该环状多肽的氨基酸序列通式为：
Acp1-Cys2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Cys18-Ala19。
其中，第10位的氨基酸为瓜氨酸；第2位的半胱氨酸(Cys)和第18位的半胱氨酸(Cys)形成分子内二硫键；丙氨酸(Ala)连接在半胱氨酸(Cys)的碳端，6-氨基己酸(Acp)连接在半胱氨酸(Cys)的氮端。
其中，CII为人源二型胶原蛋白。CII具有SEQ ID NO:1所示的氨基酸序列，其上含有54个精氨酸(Arg)。环状多肽中第3位至第9位的氨基酸、第11位至第17位的氨基酸为环状多肽中的瓜氨酸与CII氨基酸序列中的第N个精氨酸(Arg)位置重合时，分别按照CII氨基酸序列向两边扩展的7个氨基酸。所述N为4,5,6,19,22,28,34,38,46或49。
当N为2时，这第2个精氨酸位于SEQIDNO:1所示的氨基酸序列的第60位，所述环状多肽为：
Acp1-Cys2-Val3-Ser4-Gly5-Pro6-Met7-Gly8-Pro9-Xaa10-Gly11-Pro12-Pro13-Gly14-Pro15-Pro16-Gly17-Cys18-Ala19(记为2_Cit多肽)。
当N为4时，这第4个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第93位，所述环状多肽为：
Acp1-Cys2-Pro3-Pro4-Gly5-Pro6-Gln7-Gly8-Ala9-Xaa10-Gly11-Phe12-Pro13-Gly14-Thr15-Pro16-Gly17-Cys18-Ala19(记为4_Cit多肽)。
当N为5时，这第5个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第108位，所述环状多肽为：
Acp1-Cys2-Leu3-Pro4-Gly5-Val6-Lys7-Gly8-His9-Xaa10-Gly11-Tyr12-Pro13-Gly14-Leu15-Asp16-Gly17-Cys18-Ala19(记为5_Cit多肽)。
当N为6时，这第6个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第144位，所述环状多肽为：
Acp1-Cys2-Ser3-Pro4-Gly5-Pro6-Met7-Gly8-Pro9-Xaa10-Gly11-Leu12-Pro13-Gly14-Glu15-Arg16-Gly17-Cys18-Ala19(记为6_Cit多肽)。
当N为12时，这第12个精氨酸位于SEQIDNO:1所示的氨基酸序列的第255位，所述环状多肽为：
Acp1-Cys2-Ala3-Pro4-Gly5-Phe6-Pro7-Gly8-Pro9-Xaa10-Pro11-Pro12-Pro13-Gly14-Pro15-Gln16-Gly17-Cys18-Ala19(记为12_Cit多肽)。
当N为19时，这第19个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第378位，所述环状多肽为：
Acp1-Cys2-Glu3-Pro4-Gly5-Leu6-Pro7-Gly8-Ala9-Xaa10-Gly11-Leu12-Thr13-Gly14-Arg15-Pro16-Gly17-Cys18-Ala19(记为19_Cit多肽)。
当N为25时，这第25个精氨酸位于SEQIDNO:1所示的氨基酸序列的第516位，所述环状多肽为：
Acp1-Cys2-Ala3-Pro4-Gly5-Leu6-Val7-Gly8-Pro9-Xaa10-Gly11-Glu12-Arg13-Gly14-Phe15-Pro16-Gly17-Cys18-Ala19(记为25_Cit多肽)。
当N为38时，这第38个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第798位，所述环状多肽为：
Acp1-Cys2-Pro3-Gln4-Gly5-Leu6-Ala7-Gly8-Gln9-Xaa10-Gly11-Ile12-Val13-Gly14-Leu15-Pro16-Gly17-Cys18-Ala19(记为38_Cit多肽)。
当N为46时，这第46个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第924位，所述环状多肽为：
Acp1-Cys2-Pro3-Ser4-Gly5-Pro6-Ala7-Gly8-Ala9-Xaa10-Gly11-Ile12-Gln13-Gly14-Pro15-Gln16-Gly17-Cys18-Ala19(记为46_Cit多肽)。
当N为49时，这第49个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第951位，所述环状多肽为：
Acp1-Cys2-Glu3-Arg4-Gly5-Leu6-Lys7-Gly8-His9-Xaa10-Gly11-Phe12-Thr13-Gly14-Leu15-Gln16-Gly17-Cys18-Ala19(记为49_Cit多肽)。
上述环状多肽中的6-氨基己酸(Ahx)由生物素(Bio)标记。多肽由生物素(Bio)标记的目的是方便检测，可以结合于活化后的磁珠上用来检测。
上述环状多肽可以通过基因工程的方法获得。
实施例2
一、实验样本的基本信息
本实施例的实验样本包括来自上海光华医院的417个RA和304个OA血清样本，以及203个来自中国中医科学院的HC样本。每组大约85％的样本是女性。RA患者、OA患者和健康对照组的平均年龄为61岁(从11岁到90岁)，72岁(从46岁到91岁)和59岁(从18岁到91岁)。大多数的RA患者都是50-70岁，OA患者是60-80岁，而健康对照组也有50-70岁(表中未显示)。大多数的RA患者(67％)的临床疾病持续时间很长(5年)。在CCP测试中，321(77％)的RA患者为阳性。对于OA患者，293(96.4％)为阴性，在健康对照组中，199(98％)是阴性。具体如下表所示。
二、RA、OA患者及HC血清中抗环状多肽抗体的检测
具体包括以下步骤：
2.1、试剂准备和溶液配制
(1)活化缓冲液：称取11.99克磷酸二氢钠(分子量：119.98g/mol)溶于900毫升蒸馏水中，用5M的氢氧化钠调节pH值至6.0，继续加入蒸馏水至1000毫升。
(2)活化溶液(准备，仅在使用前进行配制)：分别取出200毫克Sulfo-NHS和200毫克EDC-HCl粉末于50毫升试管中备用。
(3)MES缓冲液：称取1.95克MES(分子量：195.24g/mol)溶于180毫升蒸馏水中，用5M的氢氧化钠调节pH至5.0，继续加入蒸馏水至200毫升。缓冲液配好后用0.2微米滤膜过滤并分装，放入-20℃冰箱保存，使用前一天取出，放于4℃冰箱缓慢解冻以维持pH稳定。
(4)PBS-T缓冲液：在2升的PBS缓冲液中加入0.05％的Tween20，混匀。
(5)磁珠保存缓冲液(吉恩特生物科技有限公司，GNT-BR05)。
(6)封闭液(3％BSA+5％奶粉)：称量1.5克BSA和2.5克脱脂奶粉溶于50毫升PBS-T中。
2.2、磁珠活化包被
(1)将若干个不同ID的磁珠从4℃冰箱中取出，放至室温(不同的磁珠ID包被不同的环状多肽)。加入96孔板，每个孔对应一个ID。磁珠在整个实验操作过程中应尽量避光进行。
(2)用活化缓冲液清洗磁珠，注意操作过程应在磁铁上完成，避免磁珠的损失。清洗后每个孔加入50微升活化缓冲液。
(3)配制活化溶液。将称量好的200毫克Sulfo-NHS和200毫克EDC-HCl粉末分别溶于10毫升活化缓冲液中。将两溶液混合并用振荡器混匀。
(4)每个孔加入50微升活化溶液，重悬磁珠并密封板子，放于摇床，650转/分，室温避光孵育20分钟。
(5)准备250微克/毫升浓度的中性抗生物素蛋白溶液和对照包被磁珠。
(6)用MES缓冲液清洗磁珠两次，每次每个孔加入100微升缓冲液。
(7)每个孔中加入100微升中性抗生物素蛋白溶液，对照组磁珠加入相应的抗体溶液(对照包括抗人IgG抗体，人血清IgG，人血清IgM，抗小鼠IgG抗体，小鼠IgG，EBNA(EB病毒核抗原)，只包被抗生物素蛋白无多肽，空白磁珠)。重悬磁珠并密封板子，放于摇床，650转/分，室温避光孵育2小时。
(8)用PBS-T(0.05％吐温)清洗磁珠三次，每次每个孔100微升。
(9)将磁珠重悬于保存缓冲液中，放于4℃冰箱过夜。
2.3、多肽包被
(1)准备环状多肽，将各个环状多肽分别溶于100微升PBS中，浓度均为50μM。
(2)取出前一天准备好的磁珠，放置至室温。用PBS-T清洗磁珠两遍，每次每个孔100微升。
(3)用准备好的环状多肽溶液重悬磁珠并密封板子，放于摇床，650转/分，室温避光孵育1小时。按照前面的方法，用PBS-T清洗磁珠四遍。
(4)将磁珠重悬于保存缓冲液中，放于4℃冰箱过夜。
2.4、RA和OA患者血清样本检测
(1)准备50毫升封闭缓冲液：在封闭液中加入5毫克中性抗生物素蛋白，混匀备用。
(2)血清样本准备：将721个样本按1:100稀释于封闭缓冲液，每个样本60微升加入96孔PCR板中，密封板子放于室避光温孵育1小时。
(3)将磁珠取出置于室温，每个ID取500个磁珠混合，并将混合好的磁珠重悬于3.6毫升PBS-T中备用。取出两个384孔Luminex板，每个孔加入5微升混合磁珠重悬液。再向个孔加入45微升稀释好的血清样本，重悬磁珠并密封板子，放于摇床，650转/分，室温避光孵育1小时。
(4)准备0.2％的PTA缓冲液40毫升。
(5)设置洗板机，PBS-T清洗磁珠6遍，每次每个孔60微升。
(6)每个孔加入50微升PTA缓冲液，重悬磁珠并密封板子，放于摇床，650转/分，室温避光孵育10分钟。
(7)准备二抗：Jackson ImmunoReseaech公司生产的羊抗人IgG抗体，1:750稀释于3％BSA中，配制40毫升。
(8)用相同方法清洗磁珠6遍。
(9)每个孔加入50微升二抗，重悬磁珠并密封板子，放于摇床，650转/分，室温避光孵育40分钟。用相同方法清洗磁珠6遍。
(10)每个孔加入60微升PBS-T，重悬磁珠，将板子放入仪器(型号：FLEXMAP 3D)中进行检测。
2.5、收集并整理数据。
三、实验样本对环状多肽的反应
实施例1中的十条环状多肽(具体为2_Cit多肽、4_Cit多肽、5_Cit多肽、6_Cit多肽、12_Cit多肽、19_Cit多肽、25_Cit多肽、38_Cit多肽、46_Cit多肽、49_Cit多肽)分别与实验样品反应(实验步骤见二、RA、OA患者血清中抗环状多肽抗体的检测，环状多肽与HC血清样本的反应同上)。
图1-10分别为十条环状多肽分别与OA、RA患者血清样本反应的MFI对比示意图；图11-20分别为十条环状多肽分别与HC、RA患者血清样本反应的MFI对比示意图。图中的虚线为环状多肽反应的阳性临界值，本实验采取平均值+5*绝对中位差(MAD)。所有的计算都是使用R软件完成的(RCoreTeam,2017)。比较RA患者和OA患者(图1-10)、RA患者和HC(图11-20)对环状多肽的反应结果，可以看出：环状多肽在RA患者血清中的抗体反应显著高于OA和HC组，p<0.0005。
临床特异度是衡量试验正确地判定无病者的能力，特异度是将实际无病的人正确地判定为真阴性的比例。灵敏度可用来衡量某种试验检测出有病者的能力，灵敏度是将实际有病的人正确地判定为真阳性的比例。其计算公式分别为：
灵敏度＝真阳性人数/(真阳性人数+假阴性人数)*100％。
特异度＝真阴性人数/(真阴性人数+假阳性人数))*100％。
通过计算，我们得到十条环状多肽的灵敏度和特异性，见表1。
表1.十条环状多肽的灵敏度和特异性
由此可见，RA患者血清中存在大量的抗环状多肽抗体，通过对这些抗体的检测可以对患者进行有效的分类。
ROC曲线指受试者工作特征曲线(receiver operating characteristic curve)，是反映敏感性和特异性连续变量的综合指标，是用构图法揭示敏感性和特异性的相互关系，它通过将连续变量设定出多个不同的临界值，从而计算出一系列敏感性和特异性，再以敏感性为纵坐标、(1-特异性)为横坐标绘制成曲线，曲线下面积越大，诊断准确性越高。我们做出每一条环状多肽的ROC曲线并计算曲线下面积(Area Under Curve，AUC)见表2。结果显示，十条环状多肽的AUC均大于0.8，说明这些环状多肽在RA患者中具有较高的反应，与OA及HC组具有显著性差异，同时这些环状多肽可作为新的生物标记物用于RA的鉴别。
表2十条环状多肽的AUC值
以上对本发明实施例所提供的技术方案进行了详细介绍，本文中应用了具体个例对本发明实施例的原理以及实施方式进行了阐述，以上实施例的说明只适用于帮助理解本发明实施例的原理；同时，对于本领域的一般技术人员，依据本发明实施例，在具体实施方式以及应用范围上均会有改变之处，综上所述，本说明书内容不应理解为对本发明的限制。
序列表
<110> 东莞光极生物科技有限公司
<120> 基于CII的环状多肽及其应用
<141> 2018-08-28
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 1058
<212> PRT
<213> Homo sapiens
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Ala Gly Ala Pro Gly Pro Gln Gly Phe Gln Gly Asn Pro Gly Glu Pro
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Gly Glu Pro Gly Val Ser Gly Pro Met Gly Pro Arg Gly Pro Pro Gly
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Pro Pro Gly Lys Pro Gly Asp Asp Gly Glu Ala Gly Lys Pro Gly Lys
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Ala Gly Glu Arg Gly Pro Pro Gly Pro Gln Gly Ala Arg Gly Phe Pro
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Gly Thr Pro Gly Leu Pro Gly Val Lys Gly His Arg Gly Tyr Pro Gly
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Leu Asp Gly Ala Lys Gly Glu Ala Gly Ala Pro Gly Val Lys Gly Glu
115 120 125
Ser Gly Ser Pro Gly Glu Asn Gly Ser Pro Gly Pro Met Gly Pro Arg
130 135 140
Gly Leu Pro Gly Glu Arg Gly Arg Thr Gly Pro Ala Gly Ala Ala Gly
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Ala Arg Gly Asn Asp Gly Gln Pro Gly Pro Ala Gly Pro Pro Gly Pro
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Val Gly Pro Ala Gly Gly Pro Gly Phe Pro Gly Ala Pro Gly Ala Lys
180 185 190
Gly Glu Ala Gly Pro Thr Gly Ala Arg Gly Pro Glu Gly Ala Gln Gly
195 200 205
Pro Arg Gly Glu Pro Gly Thr Pro Gly Ser Pro Gly Pro Ala Gly Ala
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Ser Gly Asn Pro Gly Thr Asp Gly Ile Pro Gly Ala Lys Gly Ser Ala
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Gly Ala Pro Gly Ile Ala Gly Ala Pro Gly Phe Pro Gly Pro Arg Gly
245 250 255
Pro Pro Gly Pro Gln Gly Ala Thr Gly Pro Leu Gly Pro Lys Gly Gln
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Thr Gly Glu Pro Gly Ile Ala Gly Phe Lys Gly Glu Gln Gly Pro Lys
275 280 285
Gly Glu Pro Gly Pro Ala Gly Pro Gln Gly Ala Pro Gly Pro Ala Gly
290 295 300
Glu Glu Gly Lys Arg Gly Ala Arg Gly Glu Pro Gly Gly Val Gly Pro
305 310 315 320
Ile Gly Pro Pro Gly Glu Arg Gly Ala Pro Gly Asn Arg Gly Phe Pro
325 330 335
Gly Gln Asp Gly Leu Ala Gly Pro Lys Gly Ala Pro Gly Glu Arg Gly
340 345 350
Pro Ser Gly Leu Ala Gly Pro Lys Gly Ala Asn Gly Asp Pro Gly Arg
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Pro Gly Glu Pro Gly Leu Pro Gly Ala Arg Gly Leu Thr Gly Arg Pro
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Gly Asp Ala Gly Pro Gln Gly Lys Val Gly Pro Ser Gly Ala Pro Gly
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Glu Asp Gly Arg Pro Gly Pro Pro Gly Pro Gln Gly Ala Arg Gly Gln
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Pro Gly Val Met Gly Phe Pro Gly Pro Lys Gly Ala Asn Gly Glu Pro
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Gly Lys Ala Gly Glu Lys Gly Leu Pro Gly Ala Pro Gly Leu Arg Gly
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Leu Pro Gly Lys Asp Gly Glu Thr Gly Ala Ala Gly Pro Pro Gly Pro
450 455 460
Ala Gly Pro Ala Gly Glu Arg Gly Glu Gln Gly Ala Pro Gly Pro Ser
465 470 475 480
Gly Phe Gln Gly Leu Pro Gly Pro Pro Gly Pro Pro Gly Glu Gly Gly
485 490 495
Lys Pro Gly Asp Gln Gly Val Pro Gly Glu Ala Gly Ala Pro Gly Leu
500 505 510
Val Gly Pro Arg Gly Glu Arg Gly Phe Pro Gly Glu Arg Gly Ser Pro
515 520 525
Gly Ala Gln Gly Leu Gln Gly Pro Arg Gly Leu Pro Gly Thr Pro Gly
530 535 540
Thr Asp Gly Pro Lys Gly Ala Ser Gly Pro Ala Gly Pro Pro Gly Ala
545 550 555 560
Gln Gly Pro Pro Gly Leu Gln Gly Met Pro Gly Glu Arg Gly Ala Ala
565 570 575
Gly Ile Ala Gly Pro Lys Gly Asp Arg Gly Asp Val Gly Glu Lys Gly
580 585 590
Pro Glu Gly Ala Pro Gly Lys Asp Gly Gly Arg Gly Leu Thr Gly Pro
595 600 605
Ile Gly Pro Pro Gly Pro Ala Gly Ala Asn Gly Glu Lys Gly Glu Val
610 615 620
Gly Pro Pro Gly Pro Ala Gly Ser Ala Gly Ala Arg Gly Ala Pro Gly
625 630 635 640
Glu Arg Gly Glu Thr Gly Pro Pro Gly Pro Ala Gly Phe Ala Gly Pro
645 650 655
Pro Gly Ala Asp Gly Gln Pro Gly Ala Lys Gly Glu Gln Gly Glu Ala
660 665 670
Gly Gln Lys Gly Asp Ala Gly Ala Pro Gly Pro Gln Gly Pro Ser Gly
675 680 685
Ala Pro Gly Pro Gln Gly Pro Thr Gly Val Thr Gly Pro Lys Gly Ala
690 695 700
Arg Gly Ala Gln Gly Pro Pro Gly Ala Thr Gly Phe Pro Gly Ala Ala
705 710 715 720
Gly Arg Val Gly Pro Pro Gly Ser Asn Gly Asn Pro Gly Pro Pro Gly
725 730 735
Pro Pro Gly Pro Ser Gly Lys Asp Gly Pro Lys Gly Ala Arg Gly Asp
740 745 750
Ser Gly Pro Pro Gly Arg Ala Gly Glu Pro Gly Leu Gln Gly Pro Ala
755 760 765
Gly Pro Pro Gly Glu Lys Gly Glu Pro Gly Asp Asp Gly Pro Ser Gly
770 775 780
Ala Glu Gly Pro Pro Gly Pro Gln Gly Leu Ala Gly Gln Arg Gly Ile
785 790 795 800
Val Gly Leu Pro Gly Gln Arg Gly Glu Arg Gly Phe Pro Gly Leu Pro
805 810 815
Gly Pro Ser Gly Glu Pro Gly Lys Gln Gly Ala Pro Gly Ala Ser Gly
820 825 830
Asp Arg Gly Pro Pro Gly Pro Val Gly Pro Pro Gly Leu Thr Gly Pro
835 840 845
Ala Gly Glu Pro Gly Arg Glu Gly Ser Pro Gly Ala Asp Gly Pro Pro
850 855 860
Gly Arg Asp Gly Ala Ala Gly Val Lys Gly Asp Arg Gly Glu Thr Gly
865 870 875 880
Ala Val Gly Ala Pro Gly Ala Pro Gly Pro Pro Gly Ser Pro Gly Pro
885 890 895
Ala Gly Pro Thr Gly Lys Gln Gly Asp Arg Gly Glu Ala Gly Ala Gln
900 905 910
Gly Pro Met Gly Pro Ser Gly Pro Ala Gly Ala Arg Gly Ile Gln Gly
915 920 925
Pro Gln Gly Pro Arg Gly Asp Lys Gly Glu Ala Gly Glu Pro Gly Glu
930 935 940
Arg Gly Leu Lys Gly His Arg Gly Phe Thr Gly Leu Gln Gly Leu Pro
945 950 955 960
Gly Pro Pro Gly Pro Ser Gly Asp Gln Gly Ala Ser Gly Pro Ala Gly
965 970 975
Pro Ser Gly Pro Arg Gly Pro Pro Gly Pro Val Gly Pro Ser Gly Lys
980 985 990
Asp Gly Ala Asn Gly Ile Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg
995 1000 1005
Gly Arg Ser Gly Glu Thr Gly Pro Ala Gly Pro Pro Gly Asn Pro Gly
1010 1015 1020
Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Gly Ile Asp Met Ser Ala
1025 1030 1035 1040
Phe Ala Gly Leu Gly Pro Arg Glu Lys Gly Pro Asp Pro Leu Gln Tyr
1045 1050 1055
Met Arg
Claims (6)
1.一种基于CII的环状多肽，其特征在于，所述环状多肽的氨基酸序列通式为：
Acp1-Cys2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Cys18-Ala19；
其中，第10位的氨基酸为瓜氨酸；第2位的半胱氨酸(Cys)和第18位的半胱氨酸(Cys)形成分子内二硫键；丙氨酸(Ala)连接在半胱氨酸(Cys)的碳端，6-氨基己酸(Acp)连接在半胱氨酸(Cys)的氮端；
所述CII具有SEQ ID NO:1所示的氨基酸序列，其上含有54个精氨酸(Arg)；环状多肽中第3位至第9位的氨基酸、第11位至第17位的氨基酸为环状多肽中的瓜氨酸与CII氨基酸序列中的第N个精氨酸(Arg)位置重合时，分别按照CII氨基酸序列向两边扩展的7个氨基酸；所述N为4,5,6,19,22,28,34,38,46或49。
2.根据权利要求1所述的一种基于CII的环状多肽，其特征在于，
当N为2时，这第2个精氨酸位于SEQIDNO:1所示的氨基酸序列的第60位，所述环状多肽为：
Acp1-Cys2-Val3-Ser4-Gly5-Pro6-Met7-Gly8-Pro9-Xaa10-Gly11-Pro12-Pro13-Gly14-Pro15-Pro16-Gly17-Cys18-Ala19；
当N为4时，这第4个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第93位，所述环状多肽为：
Acp1-Cys2-Pro3-Pro4-Gly5-Pro6-Gln7-Gly8-Ala9-Xaa10-Gly11-Phe12-Pro13-Gly14-Thr15-Pro16-Gly17-Cys18-Ala19；
当N为5时，这第5个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第108位，所述环状多肽为：
Acp1-Cys2-Leu3-Pro4-Gly5-Val6-Lys7-Gly8-His9-Xaa10-Gly11-Tyr12-Pro13-Gly14-Leu15-Asp16-Gly17-Cys18-Ala19；
当N为6时，这第6个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第144位，所述环状多肽为：
Acp1-Cys2-Ser3-Pro4-Gly5-Pro6-Met7-Gly8-Pro9-Xaa10-Gly11-Leu12-Pro13-Gly14-Glu15-Arg16-Gly17-Cys18-Ala19；
当N为12时，这第12个精氨酸位于SEQIDNO:1所示的氨基酸序列的第255位，所述环状多肽为：
Acp1-Cys2-Ala3-Pro4-Gly5-Phe6-Pro7-Gly8-Pro9-Xaa10-Pro11-Pro12-Pro13-Gly14-Pro15-Gln16-Gly17-Cys18-Ala19；
当N为19时，这第19个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第378位，所述环状多肽为：
Acp1-Cys2-Glu3-Pro4-Gly5-Leu6-Pro7-Gly8-Ala9-Xaa10-Gly11-Leu12-Thr13-Gly14-Arg15-Pro16-Gly17-Cys18-Ala19；
当N为25时，这第25个精氨酸位于SEQIDNO:1所示的氨基酸序列的第516位，所述环状多肽为：
Acp1-Cys2-Ala3-Pro4-Gly5-Leu6-Val7-Gly8-Pro9-Xaa10-Gly11-Glu12-Arg13-Gly14-Phe15-Pro16-Gly17-Cys18-Ala19；
当N为38时，这第38个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第798位，所述环状多肽为：
Acp1-Cys2-Pro3-Gln4-Gly5-Leu6-Ala7-Gly8-Gln9-Xaa10-Gly11-Ile12-Val13-Gly14-Leu15-Pro16-Gly17-Cys18-Ala19；
当N为46时，这第46个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第924位，所述环状多肽为：
Acp1-Cys2-Pro3-Ser4-Gly5-Pro6-Ala7-Gly8-Ala9-Xaa10-Gly11-Ile12-Gln13-Gly14-Pro15-Gln16-Gly17-Cys18-Ala19；
当N为49时，这第49个精氨酸位于SEQ ID NO:1所示的氨基酸序列的第951位，所述环状多肽为：
Acp1-Cys2-Glu3-Arg4-Gly5-Leu6-Lys7-Gly8-His9-Xaa10-Gly11-Phe12-Thr13-Gly14-Leu15-Gln16-Gly17-Cys18-Ala19。
3.根据权利要求1所述的一种基于CII的环状多肽，其特征在于，所述CII为人源二型胶原蛋白。
4.根据权利要求2所述的一种基于CII的环状多肽，其特征在于，所述环状多肽中的6-氨基己酸(Ahx)由生物素(Bio)标记。
5.权利要求1～4任一项所述环状多肽在检测类风湿关节炎中的应用，所述环状多肽用于鉴别类风湿关节炎。
6.权利要求1～4任一项所述环状多肽在检测关节炎中的应用，所述环状多肽用于对类风湿关节炎与骨关节炎进行分类。
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| CN101407541A (zh) * | 2008-11-26 | 2009-04-15 | 上海精臻生物科技有限公司 | 变性变构型环瓜氨酸多肽、及其融合蛋白、抗体和试剂盒 |
| CN101812119A (zh) * | 2009-02-25 | 2010-08-25 | 上海荣盛生物药业有限公司 | 与免疫抗体相结合的多肽及其应用 |
| US20120295280A1 (en) * | 2009-03-30 | 2012-11-22 | Prometheus Laboratories Inc. | Citrullinated peptides for diagnosing and prognosing rheumatoid arthritis |
| US20140106381A1 (en) * | 2011-05-25 | 2014-04-17 | Toscana Biomarkers S.R.L. | Method for the diagnosis of rheumatoid arthritis |
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| CN101407541A (zh) * | 2008-11-26 | 2009-04-15 | 上海精臻生物科技有限公司 | 变性变构型环瓜氨酸多肽、及其融合蛋白、抗体和试剂盒 |
| CN101812119A (zh) * | 2009-02-25 | 2010-08-25 | 上海荣盛生物药业有限公司 | 与免疫抗体相结合的多肽及其应用 |
| US20120295280A1 (en) * | 2009-03-30 | 2012-11-22 | Prometheus Laboratories Inc. | Citrullinated peptides for diagnosing and prognosing rheumatoid arthritis |
| US20140106381A1 (en) * | 2011-05-25 | 2014-04-17 | Toscana Biomarkers S.R.L. | Method for the diagnosis of rheumatoid arthritis |
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