CN111533800B - 新型生长激素释放激素类似肽改构和二聚体化制备及其应用 - Google Patents
新型生长激素释放激素类似肽改构和二聚体化制备及其应用 Download PDFInfo
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Abstract
本发明提供了人生长激素释放激素(hGHRH)类似肽的分子变构体和其二聚体在治疗GH缺乏症、***不育症、老年痴呆症、糖尿病和增强免疫力中的应用。本发明二聚体是两个相同含有单个半胱氨酸分子变构的hGHRH类似肽单体通过半胱氨酸形成的二硫键连接而成，并形成H型结构(分子内部单Ser→Cys替换)。本发明还对GHRH类似肽的其中一个赖氨酸的侧链ε‑氨基进行脂肪酸链修饰。通过脂肪酸修饰延长GHRH类似肽单体或二聚体在体内GH持续释放时间，最长达17天。本发明发现，具有长效活性的GHRH二聚体具有Aib→2Ala代换、18C‑18C二硫键形成、C20脂肪酸链修饰以及C端酰胺化结构。
Description
技术领域
本发明属于医药生物领域，具体涉及多种人新型生长激素释放激素类似肽单体和二聚体制备及其治疗中的应用。
背景技术
中枢性生长激素释放激素-生长激素-***(GHRH-GH-IGFs)内分泌轴，调节机体细胞生长和性细胞生殖。人GHRH完整序列为hGHRH(1-44)NH2，hGHRH(1-29)为核心肽，具有51％生物活性。通过体外垂体保温或体内皮下注射，测定生长激素(GH)释放值来确定新型hGHRH类似肽及其二聚体的体外或体内活性。
新的研究发现，hGHRH分子对外周组织的作用与对中枢的作用机制有所不同，比如在中枢，下丘脑GHRH—垂体GHRH受体—垂体GH有轴特异效应，在成熟动物的卵巢或睾丸，虽然它们也含有GHRH、GHRH受体和GH分子信号，但是它们不一定产生这种轴特异效应。一些新型GHRH类似肽或其二聚体分子的体内注射会产生生殖细胞GHRH受体上调增加受孕率，而不会促进体内GH增加，显示受试成熟动物的生殖与GH没有直接的关系。在体外，这类肽(在体内不产生GH)的体外垂体保温会诱导垂体GH的分泌。因此，通过测定受试动物体内GH、体外垂体GH分泌和其代表性GHRH受试动物的怀孕率，体现GH与成熟动物生殖关系，显示这类肽在治疗上有新的可能性。
GHRH肽具有广泛药理活性，如治疗***不育症、调节免疫、老年痴呆症、促进伤口愈合、心肌细胞重构、提高睡眠质量、减肥或治疗糖尿病等。
虽然hGHRH类似物在生物医学和农学领域有着巨大的应用潜在，但是它们的短半衰期或低活性限制了它们的应用。结构-活性关系表明，N-末端1Y是GHRH体内垂体GH释放所必需的。1P-GHRH显示体外高垂体GH释放，但体内没有GH释放。1F-GHRH体内外显示极低GH释放。随着序列向C端延伸，其活性和半衰期都逐渐增加。当GHRH分子N末端两个氨基酸残基被血中氨基二肽酶(DPP-4)切除，分子失去活性。hGHRH(1-29)NH2的半衰期为13分钟，天然hGHRH(1-44)NH2半衰期17分钟。到目前为止，hGHRH(1-44)NH2是这些类似物中活性最强的。
许多蛋白质前体在内质网内需要与长脂肪链结合，增加成熟加工能力，或分布在细胞膜、内质网膜或高尔基体膜等部位的一些蛋白质分子会通过长脂肪酸链锚定到这些膜相***上，以增加定位能力。这些脂肪酰化GHRH分子明显增加半衰期，同时成倍增加其分子活性。本发明利用这些技术，产生一系列新型长效GHRH分子，应用于***不育症、调节免疫、老年痴呆症、促进伤口愈合、心肌细胞重构、提高睡眠质量、减肥或糖尿病的治疗。
发明内容
本发明的目的在于克服上述现有技术的不足之处而提供生长激素释放激素(GHRH)类似肽单体。本发明的GHRH类似肽对主肽链的分子变构，一方面，在单体肽内部单个C→S或同型半胱氨酸(Hcy)→T代换，且对半胱氨酸在肽链中的位置进行了研究。另一方面，肽链中赖氨酸(K)的侧链ε-氨基被谷氨酰基脂肪酸或谷氨酰基脂肪二酸或[2×AEEAC-γ-Glu(N-α-脂肪二酸)]取代基修饰。
为实现上述目的，本发明采取的技术方案为：一种生长激素释放激素(GHRH)类似肽单体，所述肽链上的丝氨酸S被半胱氨酸C取代，或苏氨酸T被同型半胱氨酸(Hcy)取代，且主肽链上的其中一个赖氨酸为侧链ε-氨基上被谷氨酰基脂肪酸[γ-Glu(N-α-脂肪酸)]或谷氨酰脂肪二酸[γ-Glu(N-α-fatty diacid)]或[2×AEEAC-γ-Glu(N-α-脂肪二酸)]取代基修饰的赖氨酸。
优选地，所述类似肽单体的具体序列为以下任意一种：
(1)(NH2)X1-X2-DAIFTNCY-X11-X12-VLGQLSA-X20-X21-LLQDIMSR-NH2或；
(2)(NH2)X1-X2-DAIFTNSY-X11-X12-VLGQLCA-X20-X21-LLQDIMSR-NH2或；
(3)(NH2)X1-X2-DAIFTNSY-X11-X12-VLGQLSA-X20-X21-LLQDIMCR-NH2或；
(4)(NH2)X1-X2-DAIF-Hcy-NSY-X11-X12-VLGQLSA-X20-X21-LLQDIMS-X29-NH2或；
(5)(NH2)X1-X2-DAIFTNCY-X11-X12-VLGQLSA-X20-X21-LLQDIMS-X29-QQGESNQE-X38-GA-X41-A-X43-L-NH2或；
(6)(NH2)X1-X2-DAIFTNSY-X11-X12-VLGQLCA-X20-X21-LLQDIMS-X29-QQGESNQE-X38-GA-X41-A-X43-L-NH2或；
(7)(NH2)X1-X2-DAIFTNSY-X11-X12-VLGQLSA-X20-X21-LLQDIMC-X29-QQGESNQE-X38-GA-X41-A-X43-L-NH2或；
(8)(NH2)X1-X2-DAIFTNSY-X11-X12-VLGQLSA-X20-X21-LLQDIMS-X29-QQGECNQE-X38-GA-X41-A-X43-L-NH2或；
(9)(NH2)X1-X2-DAIF-Hcy-NSY-X11-X12-VLGQLSA-X20-X21-LLQDIMS-X29-QQGESNQE-X38-GA-X41-A-X43-L-NH2
其中，X1为Y或P或F；X2为A或α-氨基异丁酸(αAib)；X11或X12或X20或X21或X29或X38或X41或X43为K，或为R，或为侧链ε-氨基上谷氨酰脂肪酸[γ-Glu(N-α-fatty acid)]或谷氨酰脂肪二酸[γ-Glu(N-α-fatty diacid)](脂肪链为18或20碳)修饰的赖氨酸，或为侧链ε-氨基上[2×AEEAC-γ-Glu(N-α-脂肪二酸)](脂肪二酸为18或20碳)修饰的赖氨酸。其中，所述大写单字母为L-ɑ-氨基酸的缩写或氨基酸取代符号，***数字为氨基酸残基排列顺序，NH2代表N末端或者C端酰胺基结构。
优选地，当X11或X12或X20或X21或X29或X38或X41或X43为侧链ε-氨基上谷氨酰脂肪酸[γ-Glu(N-α-fatty acid)]或谷氨酰脂肪二酸[γ-Glu(N-α-fatty diacid)]修饰的赖氨酸时，其结构如化学式1所示；当X11或X12或X20或X21或X29或X38或X41或X43为侧链ε-氨基上[2×AEEAC-γ-Glu(N-α-脂肪二酸)]修饰的赖氨酸时，其结构如化学式2所示：
化学式1：
化学式2：
本发明还提供一种GHRH类似肽同源二聚体，所述二聚体由上所述的相同单体之间通过半胱氨酸形成的二硫键连接而成，构成H型类似肽同源二聚体。
优选地，所述二聚体的氨基酸序列为以下中的任意一种：
其中，X1为Y或P或F；X2为A或α-氨基异丁酸(αAib)；X11或X12或X20或X21或X29或X38或X41或X43为K，或为R，或为侧链ε-氨基上谷氨酰脂肪酸[γ-Glu(N-α-fatty acid)]或谷氨酰脂肪二酸[γ-Glu(N-α-fatty diacid)]修饰的赖氨酸，或为侧链ε-氨基上[2×AEEAC-γ-Glu(N-α-脂肪二酸)]修饰的赖氨酸。其中，所述大写单字母为L-ɑ-氨基酸的缩写或氨基酸取代符号，***数字为氨基酸残基排列顺序，NH2代表N末端或者C端酰胺基结构。
优选地，当X11或X12或X20或X21或X29或X38或X41或X43为侧链ε-氨基上谷氨酰脂肪酸[γ-Glu(N-α-fatty acid)]或谷氨酰脂肪二酸[γ-Glu(N-α-fatty diacid)]修饰的赖氨酸时，其结构如化学式1所示；当X11或X12或X20或X21或X29或X38或X41或X43为侧链ε-氨基上[2×AEEAC-γ-Glu(N-α-脂肪二酸)]修饰的赖氨酸时，其结构如化学式2所示。
本发明还提供所述的生长激素释放激素类似肽，或所述的同源二聚体在制备治疗GH缺乏症(生长激素缺乏症)、***不育症、老年痴呆症、增强免疫或糖尿病的药物中应用。
本发明还提供一种治疗GH缺乏症、***不育症、老年痴呆症、增强免疫或糖尿病的药物，其特征在于，所述药物为所述的生长激素释放激素类似肽，或所述的同源二聚体在药学上可接受的盐作为活性成分。
本发明的有益效果在于：本发明的生长激素释放激素类似肽二聚体可提高体外或/和体内生长激素释放活性，所以可以治疗GH分泌低下的疾病。通过体外垂体GH释放活性实验，可以得到以下优势：(1)本发明的单体肽与标准S1或S2肽比较，具有N末端1Y-或1P-GHRH类似肽单体显示了至少2倍以上的体外GH释放活性，1F-GHRH显示体内外低GH释放活性；(2)本发明的二聚体活性：2Y系列显示体内外高GH释放活性，2P系列仅显示体外活性，2F系列显示体内外极低GH释放活性；(3)N末端为1Y-或1P(1-29)NH2二聚体肽的活性仅是1Y-或1P(1-44)NH2二聚体肽的50％左右；(4)赖氨酸侧链ε-氨基修饰【(AEEA)2-γGlu-脂肪二酸】肽活性较【N-ε-γGlu(N-α-脂肪酸)】修饰有略微增加，修饰脂肪酸链越长，活性越高，以脂肪酸链C20为最佳。本实验反映了，所述的生长激素释放激素类似肽二聚体比对应单体肽有更长半衰期，或者K修饰肽比不修饰肽具有更长持续活性。
附图说明
图1为实验动物睾丸重量分析图。
图2为老年痴呆症小鼠血清胆碱酯酶分析图。
图3为糖尿病小鼠血清胆碱酯酶分析结果示意图。
图4为给药前后不同天数动物单核细胞总数统计分析图。
图5为给药前和药后18天后动物单核细胞百分统计分析图。
图6为实验动物单核细胞总数分析图。
图7为实验脾脏重量统计分析图。
图8为免疫力低下模型治疗的H-E染色分析[图A为H-E染色图片(4×10倍，100μm)；B:实验动物脾脏红髓百分比分析)。
具体实施方式
为了更加简洁明了的展示本发明的技术方案、目的和优点，下面结合具体实施例及其附图对本发明做进一步的详细描述。
实施例1：单体肽和二聚体的制备
一、单体肽合成过程：手工固相多肽合成操作步骤。
1、树脂溶涨：将氨基树脂(C末端酰胺化序列用氨基树脂)(购自天津市南开合成科技有限公司)，放入反应锅中，加二氯甲烷(DCM，Dikma Technologies Inc.)15ml/g树脂，振荡30min。SYMPHONY型12通道多肽合成仪(SYMPHONY型号，软件Version.201，ProteinTechnologies Inc.)。
2、接第一个氨基酸：通过沙芯抽滤除去溶剂，加入3倍摩尔的C端第一个Fmoc-氨基酸(所有Fmoc-氨基酸由苏州天马医药集团精细化学品有限公司提供)，再加入10倍摩尔量的4-二甲氨基吡啶(DMAP)和N,N'-二环己基碳二亚胺(DCC)，最后加入二甲基甲酰胺(DMF)(购自Dikma Technologies Inc.)溶解，振荡30min。用醋酸酐封闭。
3、脱保护：去掉DMF，加20％哌啶-DMF溶液(15ml/g)，5min，过滤去掉溶剂，再加20％哌啶-DMF溶液(15ml/g)，15min。哌啶由国药集团上海化学试剂公司提供。
4、检测：抽掉溶剂。取十几粒树脂，用乙醇洗三次，加入茚三酮、KCN和苯酚溶液各一滴，105-110℃加热5min，变深蓝色为阳性反应。
5、洗树脂：依次DMF(10ml/g)洗两次，甲醇(10ml/g)洗两次，DMF(10ml/g)洗两次。
6、缩合：根据具体合成条件，以下方法可以在多肽合成中单独或混搭使用：
方法a：三倍量的保护氨基酸和三倍量的2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯(HBTU，苏州天马医药集团精细化学品有限公司)，均用尽量少DMF溶解，加入反应锅中。立刻加入十倍量的N-甲基吗啉(NMM，苏州天马医药集团精细化工有限公司)，反应30min，检测呈阴性。
方法b：三倍量的保护氨基酸FMOC-氨基酸和三倍量1-羟基苯并***(HOBt，苏州天马医药集团精细化学品有限公司)，均用尽量少DMF溶解，加入反应管，立刻加入三倍量的N,N'-二异丙基碳二亚胺(DIC)，反应30min.，检测呈阴性。
7、洗树脂：依次DMF(10ml/g)洗一次，甲醇(10ml/g)洗两次，DMF(10ml/g)洗两次。
8、重复2至6步操作，如表1中氨基酸所示，从右到左依次连接相应氨基酸。带有K脂肪酸修饰的，按照如下9方法合成。
9、合成K{N-ε-[γ-Glu-(N-α-脂肪酸)]}或K{N-ε-[γ-Glu-(N-α-脂肪二酸)]}：加入10ml2％水合肼反应30min去除Fmoc-Lys(Dde)-OH的保护基Dde，侧链氨基裸露，用DMF和甲醇交替洗涤六次，茚三酮检测为蓝色。称取550mg的Fmoc-Glu-OTBU，HOBT 250mg，用DMF溶解，加入0.3ml的DIC，混匀，加入到反应器中与赖氨酸侧链氨基反应1h，抽干，DMF洗涤4次，茚三酮检测为无色。向反应器中加入5ml 20％哌啶DMF溶液反应20min，去除Fmoc-Glu-OTBU的氨基保护集团Fmoc,用DMF和甲醇交替洗涤六次，茚三酮检测为蓝色。称取300mg脂肪酸或脂肪二酸，HOBT 250mg，用DMF溶解，并且加入0.3ml的DIC，混匀，加入到反应器中反应1h，抽干，DMF洗涤4次，茚三酮检测为无色，用甲醇洗涤2次抽干。
合成K{N-ε-[2×AEEAC-γ-Glu-(N-α-脂肪二酸)]}：在Dde-Lys(fmoc)脱fmoc基团后，加入2mM的Fmoc-AEEAC-OH和2mM六氟磷酸苯并***-1-氧基三吡咯烷基磷(PyBOP)，45mM的HOBt，用DMF溶解，冰水浴下加入0.375mM的N,N'-二异丙基乙胺(DIPEA)活化3min，加入反应锅反应2h，以茚三酮法检测判断实验终点。反应结束，20％哌啶-DMF溶液(15ml/g)脱除Fmoc，DMF洗涤6次。同样方法再次偶联Fmoc-AEEAC-OH、Fmoc-Glu-OtBu和脂肪二酸基团。用含2％水合肼反应30min去除序列赖氨酸保护基Dde，经过步骤8接在赖氨酰侧链ε氨基上。
10、将缩合完成的多肽经过DMF(10ml/g)两次，DCM(10ml/g)两次，DMF(10ml/g)两次，抽干10min。茚三酮检测阴性。
11、脱除肽链最后N端氨基酸的FMOC保护基，检测呈阳性，溶液抽干备用。
12、按照下列方法洗树脂，依次DMF(10ml/g)两次，甲醇(10ml/g)两次，DMF(10ml/g)两次，DCM(10ml/g)两次，10min抽干。
13、从树脂上切割多肽：配制切割液(10毫升/g)：TFA 94％(J.T.Baker ChemicalCompany)、水2.5％、ethanedithiol(EDT,Sigma-Aldrich Chemistry)2.5％和triisopropylsilane(TIS,Sigma-Aldrich Chemistry)1％。切割时间：120min。
14、吹干洗涤：将裂解液用氮气尽量吹干，用***洗六次，然后常温挥干。
15、用如下方法HPLC纯化多肽、鉴定和置于-20℃避光保存。
二、检验方法如下：
1、用HPLC纯化多肽：将粗肽用纯水或者加少量乙腈或其它溶剂溶解，按照下列条件纯化：高效液相色谱仪(分析型；软件Class-VP.Sevial System；厂商日本SHIMADZU)和Venusi MRC-ODS C18色谱柱(30×250mm，天津Bonna-Agela Technologies)。流动相A液：0.1％三氟醋酸水溶液，流动相B液：0.1％三氟乙酸+99.9％乙腈溶液(乙腈FisherScientific公司购买)。流速：1.0ml/min，上样体积30μl，检测波长220nm。洗脱程序：0～5min：90％A液+10％B液；5～30min：90％A液/10％B液→20％A液/80％B液。
2、最后将纯化后的有效溶液冻干(冻干机Freezone Plus 6型号，L ABCONCO厂商)，既得到成品。
3、鉴定：分别取少量的成品多肽，做HPLC分析其纯度：高效液相色谱仪(厂商日本SHIMADZU)和Venusi MRC-ODS C18色谱柱(4.6x150mm，天津Bonna-Agela Technologies)。流动相A液：0.1％三氟乙酸水溶液，流动相B液：99.9％乙腈+0.1％三氟乙酸溶液，流速：1.0ml/min，上样体积10μl，检测波长220nm。洗脱程序：0～5min：100％A液；5～30min：100％A液→20％A液/80％B液。要求测定纯度大于95％。具体方法参见我们授权专利(中国专利ZL201410612382.3)。
MS法鉴定多肽分子量：取纯度合格的多肽加入水溶解，加入5％乙酸+8％乙腈+87水溶解测试电喷雾离子化质谱测定分子量，具体方法参见我们授权专利(中国专利ZL201410612382.3)。
4、将粉末状的多肽，密封包装，-20℃避光保存。
三、二聚体的形成：将浓度为1mg/ml的肽链内部带有单半胱氨酸的单体肽，在pH＝9.5磷酸氢二钠水溶液中，37℃保温过夜，形成同源二聚体肽。许多溶解差的二聚体肽，每分钟4000转离心20分钟，取沉淀为纯二聚体肽。对于溶解的单体肽或二聚体肽通过Sephadex G-25层析分离(在2×60cm G-25层析柱和自然流速下，用生理盐水或NaCl-PB溶液为流动项，二聚体组份通常为第一峰，其后为单体肽或杂质组份)。二聚体肽可以通过无巯基还原剂的肽SDS-PAGE电泳或质谱加以鉴定，具体方法参见我们授权专利(中国专利ZL201410612382.3)。
四、GHRH类似肽单体及其二聚体由本研究室或委托商业公司合成，发明人通过HPLC纯度、ESI或激光飞行质谱和半胱氨酸氧化确认其结构。本发明合成的GHRH单体肽按表1所示，同源二聚体肽的氨基酸序列按表2所示。
五、肽种类：按照上述方法合成的GHRH单体类似肽的氨基酸序列如表1所示，其HPLC纯度>95％，以hGHRH(1-29)NH2(S1)或hGHRH(1-44)NH2(S2)作为阳性对照。
表1本发明合成的新型GHRH单体肽的氨基酸序列和其单次注射持续GH释放活性
注：CFA(carbon fatty acid)或CFDA(carbon fatty diacid)为碳脂肪酸或碳脂肪二酸；所述K[N-ε-(γ-Glu-N-α-CFA)]、K[N-ε-(2×AEEAC-γ-Glu-N-α-CFDA)]表示赖氨酸K侧链ε-氨基的脂肪酰或脂肪二酸基谷氨酰修饰，具体结构如式1或2所示。
表2本发明合成的GHRH二聚体肽的氨基酸序列和其单次注射持续GH释放活性
注：CFA(carbon fatty acid)为碳脂肪酸，CFDA(carbon fatty diacid)为碳脂肪二酸；所述K[N-ε-(γ-Glu-N-α-CFA或CFDA)]、K[N-ε-(2×AEEAC-γ-Glu-N-α-CFDA)]表示赖氨酸K侧链ε-氨基的脂肪酰或脂肪二酸谷氨酰修饰，具体结构如式1或2所示。“”表示二硫键。
实施例2：生长激素释放活性测定
1.小鼠体内生长激素(GH)释放测试：昆明小鼠(雌性，体重18-22g，购自广州中医药大学实验动物中心，n＝6)。所有实验动物的护理和使用制度与实验动物指导方针一致。在饲养中，小鼠经过12:12小时明暗交替饲养，饲养温度26±1℃。按0.0133μmol/kg剂量在昆明小鼠臀部皮下注射肽，分别在给药后1小时摘眼球取血，6000转/分离心30min取血清，用于GH测定。实验中，所有新型单体肽或二聚体肽用T-NaCl-PB溶液(给药设置中有详细说明)溶解，阴性对照组注射T-NaCl-PB溶液。鼠GH激素使用ELISA试剂盒(上海联迈生物工程有限公司,中国)进行测试。结果见表1和2。
2.给药浓度设置：因为许多单体肽或二聚体溶解性差，所以在本测试下的阳性肽、新型单体肽用T-NaCl溶液(pH6.5)溶解或二聚体肽用T-NaCl-PB(pH8.0)溶液配制：取适量纯肽粉末，滴加终浓度为3％的纯药用吐温80(南京威尔化工有限公司，中国)，磁搅拌子900转/分搅拌5-10分钟。待肽分散到吐温中后，缓慢滴加生理盐水(单体肽溶解)或NaCl-PB溶液(磷酸氢二钠缓存的生理盐水溶液pH8.0，二聚体溶解)，不停搅拌直到加入全部设定的溶液，继续快速搅拌两次，每次20分钟，期间静止15分钟。3000转/分离心10分钟，取上清液使用(沉淀为纯肽，可以反复溶解使用)。所有肽浓度用LOWRY方法测定，T-NaCl-PB或T-NaCl溶液做空白对照(含3％吐温80的NaCl-PB或NaCl溶液)。
我们预实验显示，0.0133μmol/kg的1Y-GHRH肽可诱导小鼠体内或大鼠垂体体外明显释放GH，所以在本测试中，所有测定肽使用剂量皆为0.0133μmol/kg。在小鼠GH释放持续时间测定中，对于1-29氨基酸序列的新型GHRH肽，阳性对照组采用hGHRH(1-29)NH2(S1)；对于1-44氨基酸序列的新型GHRH肽采用阳性药对照hGHRH(1-44)NH2(S2)。
3.体外大鼠垂体生长激素释放活性：S-D雌鼠(体重200±20g，广中医大学实验中心购买)。大鼠经过脱臼猝死，在30分钟摘取脑垂体。用灭菌的lactated Ringer’s buffer(LRB)冲洗后，垂体立即放到内有1ml LRB的1×10cm玻璃管中，37℃保温。所有的玻璃管总保温5h(P1,P2,I3,I4和I5，代表5小时保温的不同时段，每个时段代表1小时)，同时每5min轻轻晃动一次。每1小时后，全部吸出缓冲液进行垂体GH激素测试，同时加入1毫升新鲜的不带有或带有GHRH类似肽的LRB到该垂体中保温。在前2小时(P1和P2)预保温后，随后在第3-6小时保温(I3、I4和I5)中，开始增加多肽，实验中用空白LRB溶液作对照。肽的净GH释放水平为[肽(I3+I4+I5)-空白(I3+I4+I5)]。大鼠垂体鼠GH激素使用ELISA试剂盒(上海联迈生物工程有限公司,中国)进行测试。结果见表1和2。
4.新型GHRH类似肽体内持续释放GH测定：将昆明小鼠(雌性，体重18-22g，n＝6)，按0.0133μmol/kg剂量在昆明小鼠臀部单次皮下注射肽，分别在给药前、给药后不同天每天早上准时9点内眦采血50微升，直到GH分泌达正常值，实验空白对照组注射T-NaCl(单体肽)或T-NaCl-PB(二聚体)溶液。内眦血6000转/分离心30min，取血清测定GH。结果见表1和2。
5.结论：(1)对于Y或2Y系列GHRH肽，不论是体内还是体外，明显刺激垂体GH分泌，所以这类肽可以用于GH缺乏的治疗；(2)对于P或2P系列GHRH肽，在体外测试明显刺激垂体GH分泌，但体内没有显著性GH释放，显示这类肽体内可能不作用于垂体；(3)对于F或2F系列GHRH肽，不论是体内还是体外，刺激垂体GH分泌很低；(4)根据这些结果，Y或2Y系列肽观察到明显体内长效GH持续释放时间，但是P或2P系列肽没有观察到这个时间，或F或2F系列肽因为活性很低，在观察剂量下，显示较短的GH持续释放时间；(5)根据氨基二肽酶(DPP-4)水解机制，新型GHRH的N端两个氨基酸被水解后，肽即失去活性，所以本发明除N端第一个氨基酸不同外，其他序列相同的GHRH肽应该有相似半衰期，如其他序列相同的Y、P和F系列，或2Y、2P和2F系列有相似半衰期。尽管P和2P系列肽或F和2F系列肽没有或很低显示了体内GH数值，但是它们的半衰期应该与对应的Y和2Y序列相似；(6)GHRH(1-29)包含51％活性，因其合成方便简单和成本低，在科学和商业中，有重要应用价值，本发明单独体现这部分内容。对于含1-29肽或1-44肽，采用(S1)hGHRH(1-29)NH2或(S2)hGHRH(1-44)NH2做标准，更好反应本发明的肽活性；(7)与对于单体肽比较，二聚体显示了至少2倍以上的体内持续时间。根据二硫键位置，体内GH释放时间为Y1系列2-6天，Y2系列5-8天，Y3系列2-5天，Y4系列3-5天，Y5系列2-8天，Y6系列3-5天，Y7系列3-5天，Y8系列2-4天，2Y1系列4-11天，2Y2系列10-15天，2Y3系列4-9天，2Y4系列4-8天，2Y5系列5-17天，2Y6系列6-9天，2Y7系列6-9天和2Y8系列3-7天，显然必要的长效结构包括Aib→2Ala替换、18C-18C二硫键形成、K20或K21脂肪酸修饰和C-末端酰胺化结构，二硫键位置接近C端，GH持续释放时间越短。
实施例3：二聚体肽对***不育模型的治疗
1.不育***模型试验方法：取130只中华地鼠雄鼠或65只中华地鼠雌鼠(五周龄，18-22g/只，由四川达硕实验动物中心提供。因为预实验显示，雄鼠对肽敏感性明显弱于雌鼠，所以雄鼠不育模型n＝20，而雌鼠***模型n＝10。因为中华地鼠的GHRH与人有最高93％同源性)，分为空白对照组(雄鼠20、雌鼠10)和模型鼠(雄鼠110、雌鼠55)。所有模型组按20毫克/kg腹腔注射环磷酰胺(江苏恒瑞医药股份有限公司，国药准字H32020857，批号12032925)，每周一次，共五次。在第四周注射环磷酰胺后，根据地鼠无差异体重，将模型鼠分为模型对照组(Placebo)、人***hMG组和二聚体肽剂量组2Y-47、2P-104或2F-120，每组雄鼠模型n＝20或每组雌鼠模型n＝10(环磷酰胺注射会引起动物死亡，所以增大制备模型数量)。每组给药前称重并计算给药量，二聚体肽肌肉注射0.0133μmol/kg剂量(溶于T-NaCl-PB溶液)，阳性对照hMG组肌肉注射200单位/kg(16.65μmol/kg)(溶于T-NaCl-PB溶液)(尿促性素hMG，规格肌注400U/mg或12.012U/μmol，珠海丽珠药业生产)。空白对照组和Placebo组注射T-NaCl-PB溶液，每天给药一次，直到实验结束。在第6-8周，模型地鼠和正常地鼠异性同笼1:1交配，此后仅给治疗药物，观察老鼠动情期间的生理变化(精神、活动、分泌物等)和观察老鼠是否怀孕。第十周结束，脱臼杀小鼠，解剖计数怀孕鼠。怀孕判断：雌性鼠输卵管能看到红色串珠状颗粒；新生鼠：在十周前已经出生。
2.地鼠怀孕率统计：器官重量分析显示，与空白对照组比较，Placebo组显示明显睾丸减轻(P<0.05)。与Placebo组比较，hMG组和2Y-47组睾丸重量显著性增大(P<0.05或0.01)，显示hMG和2Y-47显著性刺激睾丸作用。与hMG组或2Y-47组比较，2P-104或2F-120组睾丸重量有不同程度减轻(图1)。雌性模型的卵巢重量分析也显示类似变化。
与空白对照组和Placebo组比较，不论是雌鼠或雄鼠模型，hMG组、2Y-47和2P-104组显示了总怀孕率显著性增加，它们与空白对照组或Placebo组之间，有统计学差异，而2F-120组显示降低怀孕率，与空白对照组或Placebo组比较，没有显示差异(表3和4)，显示成年动物地鼠生殖能力与GH没有关系。
表3雌鼠模型组怀孕率统计(Mean±SD)
*P<0.05,a,b vs空白对照组组,Placebo组比较，卡方检验。
表4雄鼠模型组怀孕率统计(Mean±SD)
*P<0.05,a,b vs空白对照组组,Placebo组比较，卡方检验。
3.结论：(1)成年60kg病人每天肌注hMG 75-150U/次，与地鼠等剂量比值为9.1倍，折算地鼠剂量平均为17.05U/kg(1.41968μmol/kg)，但是hMG对地鼠反应性较低，经过多次摸索，200U/kg(16.65μmol/kg)达到与某些肽相似怀孕率，可见2Y-47和2P-104的剂量是hMG的1/500；(2)在体内，中枢GHRH-GHRH受体-GH内分泌轴通路是特异性的，但睾丸或卵巢细胞存在GHRH、GHRH受体和GH分子，它们不一定诱导GH在体内和体外一致性反应；(3)2Y-47和2P-104相似的高怀孕率显示，体内高GH分泌与怀孕率没有关系。
实施例4：二聚体肽对老年痴呆症模型的治疗
1.老年痴呆症模型制备和治疗方法：C57BL/6小鼠(SPF级，雄性，购自广州中医药大学实验动物中心，购入时20-25g/只)12/12小时光/暗周期调节，温度23±1℃恒温，湿度50～60％，自由进食进水。动物购进后，进行适应性饲养3天后开始实验。
小鼠按照体重随机分组，分为空白对照组、Placebo组(模型对照组)、阳性对照组和二聚体肽2Y-47、2P-104和2F120给药组，每组10只。模型对照组、二聚体肽给药组和阳性对照组小鼠每日灌胃10mg/kg三氯化铝和同时腹腔注射120mg/kg的D-半乳糖(造模药物：三氯化铝+D-半乳糖)，空白对照组每日灌胃同体积的蒸馏水和同时腹腔注射同体积的生理盐水，各组小鼠连续给造模药物到24周。各组小鼠腹腔注射造模药物后第13周第1天开始给药组皮下注射二聚体肽0.0133μmol/kg(溶于T-NaCl-PB溶液)，空白对照组和模型对照组皮下注射T-NaCl-PB溶液，阳性对照组皮下注射38.74mg/kg注射用双羟萘酸多奈哌齐药物(用T-NaCl-PB溶液稀释)(阳性药临床批件2018L02708，规格3mL:255.4mg，浙江华海药业股份有限公司生产；按照小鼠和成年人有9.1倍等效剂量计算，小鼠剂量应该38.74mg/kg)。各组每两周皮下注射给药一次，连续给药12周，在整个给药期间，常规每天给造模药物。
2.水迷宫测试方法：小鼠的学***均错误次数和平均潜伏期值，实验数据为平均数±标准差(Mean±SD)，t检验统计分析。
3.结果：表5结果显示，造模第12周末，与空白对照组比较，模型各组在潜伏期和错误次数方面明显增加(P<0.05)，显示老年痴呆症模型是成功的。与给药前或给药后的各组潜伏期或错误次数比较，Placebo组显示显著性增加(P<0.05或0.01)。对于给药后各组的潜伏期或错误次数，与Placebo比较，2Y-47和阳性对照组显示显著性降低，但2P-104和2F-120组没有显著性差异。在上述实验中，并未发现给药组小鼠与空白对照组小鼠有体重下降和烦躁不安等实验现象，提示药物对小鼠具有良好的耐受性。综上所述，本发明的2Y-47效果较好，初步显示：老年痴呆症治疗效果与高GH分泌相关。
表5：12周药物治疗前后各实验组对痴呆模型小鼠记忆能力统计分析(Mean±SD)
P<0.05*或0.01**，双希腊字母定位比较统计学分析，t检验。
4.胆碱酯酶分析：胆碱酯酶测定试剂盒(北京九强生物技术股份有限公司生产)和日立全自动生化分析仪(型号7180，日本)测定，具体试剂盒和仪器请参见厂家说明书。结果如图2所示：与Placebo组比较，阳性药和2Y-47组出现显著性差异(P<0.05)，动物血清胆碱酯酶测定显示剂量依赖性降低。与空白对照组比较，Placebo、2P-104和2F-120组胆碱酯酶显示显著增加。结果显示，2Y-47对老年痴呆症有一定治疗作用。
实施例5：对II糖尿病模型的治疗
1.II糖尿病模型建立方法：将C57Bl6/J小鼠放置于标准饮食的SPF级别环境中，自由饮水。所有的实验操作按照实验动物伦理与使用制度指导原则。按照标准饮食饲养天后，将5周龄的C57B16/J雄性小鼠分为6组：空白对照组、Placebo组(T2D模型对照组)、利拉鲁肽组、2Y-47低中高组(L-2Y-47、M-2Y-47、H-2Y-47)。所有T2D模型喂60kcal％的高脂饮食(D12492,常州鼠一鼠二生物技术有限公司)，直到实验结束。空白对照组保持标准饮食直到实验结束。糖尿病模型的建立方法：高脂喂养小鼠4周后，腹腔注射75mg/kg链脲佐菌素(STZ，美国西格玛化学公司)，3天后用50mg/kg剂量的STZ重新腹腔注射，3周后血糖等于或大于11mM为糖尿病小鼠。这些组在高脂饮食的基础上，再进行35天的治疗研究。利拉鲁肽组皮下注射1.126nmol/100μL利拉鲁肽，2Y-47组皮下注射3.378、1.126、0.375nmol/100μ(用T-NaCl-PB溶液稀释)，空白对照和Placebo组注射T-NaCl-PB溶液。
2.结果如图3所示：2Y-47注射后，血糖没有显示显著性变化，血清胆碱酯酶显示剂量依赖性降低。与空白对照组比较，Placebo、利拉鲁肽和各2Y-47组胆碱酯酶增加明显(P<0.05)。与利拉鲁肽组比较，M-和H-2Y-47组没有出现显著性，显示2Y-47能降低胆碱酯酶，可以增加糖尿病认知功能。
实施例6：本发明二聚体对动物免疫力低下的治疗作用
1.药物对正常小鼠免疫力的影响：取Balb/c雄性小鼠24只，体重18-22g。在饲养2天后，按照无体重差异，随机分空白对照组和2Y-47给药组，每组6只。2Y-47肽臀部皮下单次注射0.0133μmol剂量，中午12点注射，以后每天中午12点准时眼眶内眦取血50微升抗凝血，测定血常规(Sysmex XS-500i及配套试剂，日本)，直到18天实验结束。2Y-47组测试结果减去空白对照组测试结果为最后结果。
2.实验结果：血常规分析发现，注射2Y-47肽后，仅单核细胞总数和百分数在不同时间点有明显差异，对其他红细胞、白细胞或血小板及其相关指标都没有显示影响。给药后第1天，各项指标均降低，可能是动物的应激性反应，第二天回到正常。图4可见，与药前和药后第1天结果比较，第2、7、14、15天的单核细胞总数显著性增加(P<0.05)。图5可见，与药前和/或药后第1天结果比较，第2、7、14、15天单核细胞百分数显著性增加(P<0.05、0.01或0.001)，其中第15天结果达峰值，18天降到正常。这些结果初步显示，2Y-47肽促进单核细胞增殖，提高免疫力的作用。
3.免疫力低下模型制备和治疗方法：Balb/c小鼠60只，体重18-22g，按照无体重差异，随机分空白对照组和模型组(Placebo组、阳性对照组、L-2Y-47、M-2Y-47和H-2Y-47组)，每组10只(雌雄各半)。所有模型组小鼠腹腔注射环磷酰胺80mg/kg，每天一次，连续3天。实验第7天后给治疗药物，阳性对照组每只皮下注射0.2427mg(0.07808μmol)的注射用胸腺法新(商品名基泰，规格1.6mg，批准文号H20030407，产品批号16070106，海南双城药业股份有限公司产，用T-NaCl-PB溶液溶解)，各2Y-47组皮下注射0.2342、0.07808和0.02603μmol，空白对照组和Placebo组注射T-NaCl-PB溶液。各组每周注射2次，共4周。在治疗期前一天和治疗4周后，小鼠内眦取抗凝血50微升，测定血常规，杀死小鼠取脾脏称重和H-E染色。红髓统计：将每组三只动物的H-E染色切片，每只动物取5切片拍照，用IPP软件计数红髓细胞占整个视野的百分比，即为红髓统计结果。方法参见刘长江等论文[刘长江等，环磷酰胺诱导小鼠免疫功能能低下模型建立和评价，潍坊医学院学报37(1).4-6,2015]。
4.结果评价：实验结束后，血液单核细胞总数分析(图6)显示，与Placebo组比较，胸腺法新组显示淋巴细胞增加明显，但单核细胞没有明显增加，2Y-47组单核细胞数呈剂量依赖性增加，H-2Y-47组显示显著性增高(P<0.05)。脾脏重量比较分析(图7)显示，与空白对照组比较，胸腺法新组和H-2Y-47组动物脾脏重量显著性增加(P<0.05)。脾脏H-E染色(图8A)显示，胸腺法新组白髓明显增加，而2Y-47组红髓增加明显。与空白对照组和Placebo组比较，M-和H-2Y-47组脾脏红髓显著性增高(P<0.05)(图8B)。这些初步结果显示，以2Y-47为代表的2Y-GHRH序列通过增加红髓区的巨噬细胞数，增强免疫力。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
SEQUENCE LISTING
<110> 浙江湖州纳福生物医药有限公司
<120> 新型生长激素释放激素类似肽改构和二聚体化制备及其应用
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<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 26
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg
20 25
<210> 27
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 27
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg
20 25
<210> 28
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 28
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Cys Arg
20 25
<210> 29
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 29
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg
20 25
<210> 30
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 30
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg
20 25
<210> 31
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 31
Tyr Ala Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 32
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 32
Tyr Ala Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 33
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 33
Tyr Ala Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 34
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 34
Tyr Ala Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 35
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 35
Tyr Xaa Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 36
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 36
Tyr Xaa Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 37
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 37
Tyr Xaa Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 38
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 38
Tyr Xaa Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 39
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Arg[N-ε-(γGlu-N-α-18CFA)]
<400> 39
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 40
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Arg[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 40
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 41
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 41
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 42
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (29)..(29)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 42
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Xaa Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 43
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (38)..(38)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 43
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Xaa Gly Ala Arg Ala Arg Leu
35 40
<210> 44
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (41)..(41)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 44
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Xaa Ala Arg Leu
35 40
<210> 45
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (43)..(43)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 45
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Xaa Leu
35 40
<210> 46
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Arg[N-ε-(γGlu-N-α-18CFA)]
<400> 46
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 47
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Arg[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 47
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 48
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 48
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 49
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 49
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Lys Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 50
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]-
<400> 50
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 51
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-γGlu-20CFDA]
<400> 51
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 52
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 52
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 53
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 53
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Cys Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 54
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 54
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 55
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 55
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Cys Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 56
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 56
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 57
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 57
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Cys Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 58
<211> 45
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 58
Tyr Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Lys Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln
20 25 30
Gly Glu Cys Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40 45
<210> 59
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 59
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Cys Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 60
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 60
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Cys Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 61
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 61
Tyr Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Cys Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 62
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 62
Tyr Ala Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 63
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 63
Tyr Ala Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Lys Ala Arg Leu
35 40
<210> 64
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 64
Tyr Ala Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 65
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 65
Tyr Xaa Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 66
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 66
Tyr Xaa Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Lys Ala Arg Leu
35 40
<210> 67
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 67
Tyr Xaa Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 68
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 68
Pro Ala Asp Ala Ile Phe Thr Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 69
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 69
Pro Ala Asp Ala Ile Phe Thr Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 70
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 70
Pro Ala Asp Ala Ile Phe Thr Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 71
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 71
Pro Ala Asp Ala Ile Phe Thr Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 72
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 72
Pro Xaa Asp Ala Ile Phe Thr Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 73
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 73
Pro Xaa Asp Ala Ile Phe Thr Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 74
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 74
Pro Xaa Asp Ala Ile Phe Thr Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Arg Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 75
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 75
Pro Xaa Asp Ala Ile Phe Thr Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 76
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 76
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 77
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 77
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 78
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 78
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 79
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 79
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 80
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(AEEA)2-γGlu-20CFDA]
<400> 80
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 81
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(AEEA)2-γGlu-20CFDA]
<400> 81
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 82
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 82
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 83
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 83
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 84
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 84
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Arg Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 85
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 85
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 86
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 86
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 87
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 87
Pro Ala Asp Ala Ile Phe Thr Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg
20 25
<210> 88
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 88
Pro Ala Asp Ala Ile Phe Thr Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg
20 25
<210> 89
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 89
Pro Xaa Asp Ala Ile Phe Thr Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg
20 25
<210> 90
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 90
Pro Xaa Asp Ala Ile Phe Thr Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg
20 25
<210> 91
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 91
Pro Ala Asp Ala Ile Phe Xaa Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 92
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 92
Pro Ala Asp Ala Ile Phe Xaa Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 93
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 93
Pro Ala Asp Ala Ile Phe Xaa Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 94
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 94
Pro Ala Asp Ala Ile Phe Xaa Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 95
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (22)..(22)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 95
Pro Xaa Asp Ala Ile Phe Xaa Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 96
<211> 29
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 96
Pro Xaa Asp Ala Ile Phe Xaa Asn Cys Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 97
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Arg[N-ε-(γGlu-N-α-18CFA)]
<400> 97
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 98
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Arg[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 98
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 99
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 99
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 100
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (29)..(29)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 100
Pro Ala Asp Ala Ile Phe Ser Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Xaa Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 101
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (38)..(38)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 101
Pro Ala Asp Ala Ile Phe Ser Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Xaa Gly Ala Arg Ala Arg Leu
35 40
<210> 102
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (41)..(41)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 102
Pro Ala Asp Ala Ile Phe Ser Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Xaa Ala Arg Leu
35 40
<210> 103
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (43)..(43)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 103
Pro Ala Asp Ala Ile Phe Ser Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Xaa Leu
35 40
<210> 104
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Arg[N-ε-(γGlu-N-α-18CFA)]
<400> 104
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 105
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Arg[N-ε-(AEEA)2-γGlu-20CFDA]
<400> 105
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 106
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-18CFA)]
<400> 106
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 107
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 107
Pro Xaa Asp Ala Ile Phe Ser Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Lys Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 108
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(AEEA)2-γGlu-20CFDA]
<400> 108
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 109
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-γGlu-20CFDA]
<400> 109
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 110
<211> 44
<212> DNA
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 110
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 111
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε-(AEEA)2-γGlu-20CFDA]
<400> 111
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Cys Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 112
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 112
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 113
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 113
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Cys Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 114
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 114
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Cys Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 115
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 115
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Cys Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 116
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 116
Pro Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Cys Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 117
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 117
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Cys Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 118
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 118
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Cys Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 119
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 119
Pro Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Cys Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 120
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 120
Pro Ala Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 121
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 121
Pro Ala Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 122
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 122
Pro Xaa Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 123
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa is Hcy
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 123
Pro Xaa Asp Ala Ile Phe Xaa Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 124
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Arg[N-ε-(γGlu-N-α-18CFA)]
<400> 124
Phe Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 125
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Arg[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 125
Phe Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 126
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 126
Phe Ala Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 127
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Arg[N-ε-(γGlu-N-α-18CFA)]
<400> 127
Phe Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 128
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa is Arg[N-ε- (AEEA)2-γGlu-20CFDA]
<400> 128
Phe Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Xaa Lys Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 129
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(γGlu-N-α-20CFA)]
<400> 129
Phe Xaa Asp Ala Ile Phe Ser Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Lys Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 130
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-(AEEA)2-γGlu-20CFDA]
<400> 130
Phe Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
<210> 131
<211> 44
<212> PRT
<213> 合成
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa is Aib
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa is Lys[N-ε-γGlu-20CFDA]
<400> 131
Phe Xaa Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Cys Ala Arg Xaa Leu Leu Gln Asp Ile Met Ser Arg Gln Gln Gly
20 25 30
Glu Ser Asn Gln Glu Arg Gly Ala Arg Ala Arg Leu
35 40
Claims (4)
1.一种生长激素释放激素(GHRH)类似肽单体，其特征在于，所述类似肽单体的具体序列为以下任意一种：
1)(NH2)X1-X2-DAIFTNCY-X11-X12-VLGQLSA-X20-X21-LLQDIMSR-NH2或；
2)(NH2)X1-X2-DAIFTNSY-X11-X12-VLGQLCA-X20-X21-LLQDIMSR-NH2或；
3)(NH2)X1-X2-DAIFTNSY-X11-X12-VLGQLSA-X20-X21-LLQDIMCR-NH2或；
4)(NH2)X1-X2-DAIF-Hcy-NSY-X11-X12-VLGQLSA-X20-X21-LLQDIMS-X29-NH2或；
5)(NH2)X1-X2-DAIFTNSY-X11-X12-VLGQLCA-X20-X21-LLQDIMS-X29-QQGESNQE-X38-GA-X41-A-X43-L-NH2或；
6)(NH2)X1-X2-DAIFTNSY-X11-X12-VLGQLSA-X20-X21-LLQDIMC-X29-QQGESNQE-X38-GA-X41-A-X43-L-NH2或；
7)(NH2)X1-X2-DAIFTNSY-X11-X12-VLGQLSA-X20-X21-LLQDIMS-X29-QQGECNQE-X38-GA-X41-A-X43-L-NH2或；
8)(NH2)X1-X2-DAIF-Hcy-NSY-X11-X12-VLGQLSA-X20-X21-LLQDIMS-X29-QQGESNQE-X38-GA-X41-A-X43-L-NH2；
其中，X1为Y；X2为A或α-氨基异丁酸(αAib)；X11或X12或X20或X21或X29或X38或X41或X43为K，或为R，或为侧链ε-氨基上谷氨酰脂肪酸[γ-Glu(N-α-fatty acid)]或谷氨酰脂肪二酸[γ-Glu(N-α-fatty diacid)]修饰的赖氨酸，或为侧链ε-氨基上[2×AEEAC-γ-Glu(N-α-脂肪二酸)]修饰的赖氨酸；
其中，当所述单体的具体序列为结构式1)时，具体为以下结构中的任一种：
(1)(NH2)YADAIFTNCYR-K[N-ε-(γGlu-N-α-18CFA)]-VLGQLSARKLLQDIMSR-NH2
(2)(NH2)YADAIFTNCYRKVLGQLSA-K[N-ε-(γGlu-N-α-18CFA)]-KLLQDIMSR-NH2
(3)(NH2)YADAIFTNCYRKVLGQLSAR-K[N-ε-(γGlu-N-α-18CFA)]-LLQDIMSR-NH2
(4)(NH2)YADAIFTNCYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMSR-NH2
(5)(NH2)YADAIFTNCYRKVLGQLSA-K[N-ε-(AEEA)2-γGlu-20CFDA]-KLLQDIMSR-NH2
(6)(NH2)YADAIFTNCYRKVLGQLSAR-K[N-ε-(AEEA)2-γGlu-20CFDA]-LLQDIMSR-NH2
(7)(NH2)Y-Aib-DAIFTNCYRKVLGQLSA-K[N-ε-(γGlu-N-α-20CFA)]-KLLQDIMSR-NH2
(8)(NH2)Y-Aib-DAIFTNCYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMSR-NH2
(9)(NH2)Y-Aib-DAIFTNCYRKVLGQLSAR-K[N-ε-(AEEA)2-γGlu-20CFDA]-LLQDIMSR-NH2
(10)(NH2)Y-Aib-DAIFTNCYRKVLGQLSA-K[N-ε-(AEEA)2-γGlu-20CFDA]-RLLQDIMSR-NH2
(11)(NH2)Y-Aib-DAIFTNCYRKVLGQLSA-K[N-ε-(γGlu-N-α-18CFA)]-KLLQDIMSR-NH2
(12)(NH2)Y-Aib-DAIFTNCYRKVLGQLSA-K[N-ε-(γGlu-N-α-20CFA)]-KLLQDIMSR-NH2
(13)(NH2)Y-Aib-DAIFTNCYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMSR-NH2
当所述单体的具体序列为结构式2)时，具体为以下结构中的任一种：
(14)(NH2)YADAIFTNSYRKVLGQLCA-K[N-ε-(γGlu-N-α-18CFA)]-KLLQDIMSR-NH2
(15)(NH2)YADAIFTNSYRKVLGQLCAR-K[N-ε-(γGlu-N-α-18CFA)]-LLQDIMSR-NH2
(16)(NH2)YADAIFTNSYRKVLGQLCA-K[N-ε-(γGlu-N-α-20CFA)]-KLLQDIMSR-NH2
(17)(NH2)YADAIFTNSYRKVLGQLCAR-K[N-ε-(γGlu-N-α-20CFA)]LLQDIMSR-NH2
(18)(NH2)YADAIFTNSYRKVLGQLCA-K[N-ε-(AEEA)2-γGlu-20CFDA]-KLLQDIMSR-NH2
(19)(NH2)YADAIFTNSYRKVLGQLCAR-K[N-ε-(AEEA)2-γGlu-20CFDA]LLQDIMSR-NH2
(20)(NH2)Y-Aib-DAIFTNSYRKVLGQLCAR-K[N-ε-(γGlu-N-α-18CFA)]-LLQDIMSR-NH2
(21)(NH2)Y-Aib-DAIFTNSYRKVLGQLCA-K[N-ε-(γGlu-N-α-18CFA)]-KLLQDIMSR-NH2
(22)(NH2)Y-Aib-DAIFTNSYRKVLGQLCA-K[N-ε-(γGlu-N-α-20CFA)]-RLLQDIMSR-NH2
(23)(NH2)Y-Aib-DAIFTNSYRKVLGQLCAR-K[N-ε-(AEEA)2-γGlu-20CFDA]-LLQDIMSR-NH2
(24)(NH2)Y-Aib-DAIFTNSYRKVLGQLCA-K[N-ε-(AEEA)2-γGlu-20CFDA]-KLLQDIMSR-NH2
当所述单体的具体序列为结构式3)时，具体为以下结构中的任一种：
(25)(NH2)YADAIFTNSYRKVLGQLSA-K[N-ε-(γGlu-N-α-18CFA)]-KLLQDIMCR-NH2
(26)(NH2)YADAIFTNSYRKVLGQLSAR-K[N-ε-(AEEA)2-γGlu-20CFDA]-LLQDIMCR-NH2
(27)(NH2)YADAIFTNSYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMCR-NH2
(28)(NH2)Y-Aib-DAIFTNSYRKVLGQLSAK[N-ε-(γGlu-N-α-18CFA)]-KLLQDIMCR-NH2
(29)(NH2)Y-Aib-DAIFTNSYRKVLGQLSAR-K[N-ε-(AEEA)2-γGlu-20CFDA]-LLQDIMCR-NH2
(30)(NH2)Y-Aib-DAIFTNSYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMCR-NH2
当所述单体的具体序列为结构式4)时，具体为以下结构中的任一种：
(31)(NH2)YADAIF-Hcy-NSYRKVLGQLSAK[N-ε-(γGlu-N-α-18CFA)]-KLLQDIMSR-NH2
(32)(NH2)YADAIF-Hcy-NSYRKVLGQLSAR-K[N-ε-(γGlu-N-α-18CFA)]-LLQDIMSR-NH2
(33)(NH2)YADAIF-Hcy-NSYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMSR-NH2
(34)(NH2)YADAIF-Hcy-NSYRKVLGQLSAR-K[N-ε-(AEEA)2-γGlu-20CFDA]-LLQDIMSR-NH2
(35)(NH2)Y-Aib-DAIF-Hcy-NSYRKVLGQLSAK[N-ε-(γGlu-N-α-18CFA)]-KLLQDIMSR-NH2
(36)(NH2)Y-Aib-DAIF-Hcy-NSYRKVLGQLSAR-K[N-ε-(γGlu-N-α-18CFA)]-LLQDIMSR-NH2
(37)(NH2)Y-Aib-DAIF-Hcy-NSYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMSR-NH2
(38)(NH2)Y-Aib-DAIF-Hcy-NSYRKVLGQLSAR-K[N-ε-(AEEA)2-γGlu-20CFDA]-LLQDIMSR-NH2
当所述单体的具体序列为结构式5)时，具体为以下结构中的任一种：
(39)(NH2)YADAIFTNSYRKVLGQLCAR[N-ε-(γGlu-N-α-18CFA)]-KLLQDIMSRQQGESNQERGARARL-NH2
(40)(NH2)YADAIFTNSYRKVLGQLCAR[N-ε-(AEEA)2-γGlu-20CFDA]-KLLQDIMSRQQGESNQERGARARL-NH2
(41)(NH2)YADAIFTNSYRKVLGQLCAR-K[N-ε-(γGlu-N-α-18CFA)]-LLQDIMSRQQGESNQERGARARL-NH2
(42)(NH2)YADAIFTNSYRKVLGQLCARKLLQDIMS-K[N-ε-(γGlu-N-α-20CFA)]-QQGESNQERGARARL-NH2
(43)(NH2)YADAIFTNSYRKVLGQLCARKLLQDIMSRQQGESNQE-K[N-ε-(γGlu-N-α-20CFA)]-GARARL-NH2
(44)(NH2)YADAIFTNSYRKVLGQLCARKLLQDIMSRQQGESNQERGA-K[N-ε-(γGlu-N-α-20CFA)]-ARL-NH2
(45)(NH2)YADAIFTNSYRKVLGQLCARKLLQDIMSRQQGESNQERGARA-K[N-ε-(γGlu-N-α-20CFA)]-L-NH2
(46)(NH2)Y-Aib-DAIFTNSYRKVLGQLCA-R[N-ε-(γGlu-N-α-18CFA)]-KLLQDIMSRQQGESNQERGARARL-NH2
(47)(NH2)Y-Aib-DAIFTNSYRKVLGQLCA-R[N-ε-(AEEA)2-γGlu-20CFDA]-KLLQDIMSRQQGESNQERGARARL-NH2
(48)(NH2)Y-Aib-DAIFTNSYRKVLGQLCAR-K[N-ε-(γGlu-N-α-18CFA)]-LLQDIMSRQQGESNQERGARARL-NH2
(49)(NH2)Y-Aib-DAIFTNSYRKVLGQLCAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMSKQQGESNQERGARARL-NH2
(50)(NH2)Y-Aib-DAIFTNSYRKVLGQLCAR-K[N-ε-(AEEA)2-γGlu-20CFDA]-LLQDIMSRQQGESNQERGARARL-NH2
(51)(NH2)Y-Aib-DAIFTNSYRKVLGQLCAR-K[N-ε-γGlu-20CFDA]-LLQDIMSRQQGESNQERGARARL-NH2
当所述单体的具体序列为结构式6)时，具体为以下结构中的任一种：
(52)(NH2)YADAIFTNSYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMCRQQGESNQERGARARL-NH2
(53)(NH2)YADAIFTNSYRKVLGQLSAK[N-ε-(AEEA)2-γGlu-20CFDA]-KLLQDIMCRQQGESNQERGARARL-NH2
(54)(NH2)Y-Aib-DAIFTNSYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMCRQQGESNQERGARARL-NH2
(55)(NH2)Y-Aib-DAIFTNSYRKVLGQLSAK[N-ε-(AEEA)2-γGlu-20CFDA]-KLLQDIMCRQQGESNQERGARARL-NH2
(56)(NH2)Y-Aib-DAIFTNSYRKVLGQLSAR-K[N-ε-(AEEA)2-γGlu-20CFDA]-LLQDIMCRQQGESNQERGARARL-NH2
当所述单体的具体序列为结构式7)时，具体为以下结构中的任一种：
(57)(NH2)YADAIFTNSYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMSRQQGECNQERGARARL-NH2
(58)(NH2)YADAIFTNSYRKVLGQLSAK[N-ε-(AEEA)2-γGlu-20CFDA]-KLLQDIMSRQQGECNQERGARARL-NH2
(59)(NH2)Y-Aib-DAIFTNSYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMSRQQGECNQERGARARL-NH2
(60)(NH2)Y-Aib-DAIFTNSYRKVLGQLSAK[N-ε-(AEEA)2-γGlu-20CFDA]-KLLQDIMSRQQGECNQERGARARL-NH2
(61)(NH2)Y-Aib-DAIFTNSYRKVLGQLSAR-K[N-ε-(AEEA)2-γGlu-20CFDA]-LLQDIMSRQQGECNQERGARARL-NH2
当所述单体的具体序列为结构式8)时，具体为以下结构中的任一种：
(62)(NH2)YADAIF-Hcy-NSYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMSRQQGESNQERGARARL-NH2
(63)(NH2)YADAIF-Hcy-NSYRKVLGQLSA-K[N-ε-(γGlu-N-α-18CFA)]-KLLQDIMSRQQGESNQERGAKARL-NH2
(64)(NH2)YADAIF-Hcy-NSYRKVLGQLSAR-K[N-ε-(AEEA)2-γGlu-20CFDA]-LLQDIMSRQQGESNQERGARARL-NH2
(65)(NH2)Y-Aib-DAIF-Hcy-NSYRKVLGQLSAR-K[N-ε-(γGlu-N-α-20CFA)]-LLQDIMSRQQGESNQERGARARL-NH2
(66)(NH2)Y-Aib-DAIF-Hcy-NSYRKVLGQLSA-K[N-ε-(γGlu-N-α-18CFA)]-KLLQDIMSRQQGESNQERGAKARL-NH2
(67)(NH2)Y-Aib-DAIF-Hcy-NSYRKVLGQLSAR-K[N-ε-(AEEA)2-γGlu-20CFDA]-LLQDIMSRQQGESNQERGARARL-NH2；
其中，当X11或X12或X20或X21或X29或X38或X41或X43为侧链ε-氨基上谷氨酰脂肪酸[γ-Glu(N-α-fatty acid)]或谷氨酰脂肪二酸[γ-Glu(N-α-fatty diacid)]修饰的赖氨酸时，其结构如化学式1所示，当X11或X12或X20或X21或X29或X38或X41或X43为侧链ε-氨基上[2×AEEAC-γ-Glu(N-α-脂肪二酸)]修饰的赖氨酸时，其结构如化学式2所示，
化学式1：
化学式2：
其中具体序列中的18CFA为十八碳脂肪酸；20CFA为二十碳脂肪酸；20CFDA为二十碳脂肪二酸。
2.一种GHRH类似肽同源二聚体，其特征在于，所述二聚体由权利要求1所述的相同单体之间通过半胱氨酸形成的二硫键连接而成，构成H型类似肽同源二聚体；其氨基酸序列为以下结构中的任意一种：
其中，X1为Y；X2为A或α-氨基异丁酸(αAib)；X11或X12或X20或X21或X29或X38或X41或X43为K，或为R，或为侧链ε-氨基上谷氨酰脂肪酸[γ-Glu(N-α-fatty acid)]或谷氨酰脂肪二酸[γ-Glu(N-α-fatty diacid)]修饰的赖氨酸，或为侧链ε-氨基上[2×AEEAC-γ-Glu(N-α-脂肪二酸)]修饰的赖氨酸；
其中，当所述二聚体的具体序列为结构式1)时，具体为以下结构中的任一种：
当所述二聚体的具体序列为结构式2)时，具体为以下结构中的任一种：
当所述二聚体的具体序列为结构式3)时，具体为以下结构中的任一种：
当所述二聚体的具体序列为结构式4)时，具体为以下结构中的任一种：
当所述二聚体的具体序列为结构式5)时，具体为以下结构中的任一种：
当所述二聚体的具体序列为结构式6)时，具体为以下结构中的任一种：
当所述二聚体的具体序列为结构式7)时，具体为以下结构中的任一种：
当所述二聚体的具体序列为结构式8)时，具体为以下结构中的任一种：
其中，当X11或X12或X20或X21或X29或X38或X41或X43为侧链ε-氨基上谷氨酰脂肪酸[γ-Glu(N-α-fatty acid)]或谷氨酰脂肪二酸[γ-Glu(N-α-fatty diacid)]修饰的赖氨酸时，其结构如权利要求1所述的化学式1所示；当X11或X12或X20或X21或X29或X38或X41或X43为侧链ε-氨基上[2×AEEAC-γ-Glu(N-α-脂肪二酸)]修饰的赖氨酸时，其结构如权利要求1所述的化学式2所示，其中具体序列中的18CFA为十八碳脂肪酸；20CFA为二十碳脂肪酸；20CFDA为二十碳脂肪二酸。
3.如权利要求1所述的生长激素释放激素类似肽单体，或如权利要求2所述的同源二聚体在制备治疗GH缺乏症、***不育症、老年痴呆症、增强免疫或糖尿病的药物中应用。
4.一种治疗GH缺乏症、***不育症、老年痴呆症、增强免疫或糖尿病的药物，其特征在于，所述药物以权利要求1所述的生长激素释放激素类似肽单体，或如权利要求2所述的同源二聚体和其药学上可接受的盐作为活性成分。
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