CN114920818A - 基于胃泌酸调节素类似物glp-1r/gcgr双靶点激动剂多肽治疗胆汁性肝硬化 - Google Patents
基于胃泌酸调节素类似物glp-1r/gcgr双靶点激动剂多肽治疗胆汁性肝硬化 Download PDFInfo
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Abstract
本发明涉及一类具有胰高血糖素样肽‑1受体(Glucagon‑like peptide‑1receptor，GLP‑1R)和胰高血糖素受体(Glucagon receptor，GCGR)双激动效应的多肽化合物的用途，其具有高酶解稳定性、高生物活性、无不良反应等特点，能够明显改善BDL诱导的大鼠胆汁淤积性肝纤维化程度,对胆汁性肝硬化等疾病具有显著的治疗作用。该类双靶点激动剂多肽可用于预防或治疗胆汁性肝硬化及相关肝纤维化疾病。
Description
本申请为2018年10月19日递交的申请号为201880069666.9,发明名称为“基于胃泌酸调节素类似物GLP-1R/GCGR双靶点激动剂多肽治疗胆汁性肝硬化”的发明专利申请的分案申请。
技术领域
本发明属于生物化学技术领域，具体地，涉及一类GLP-1R/GCGR双靶点激动剂多肽。本发明还涉及上述双靶点激动剂多肽对治疗胆汁性肝硬化等疾病的预防和/或治疗用途。
背景技术
近年来，全世界死于肝硬化的人数已增加到50万。西欧因肝硬化致死人数居死亡原因第5位，美国则位居第4位。肝脏纤维化是肝脏对各种原因所致的肝损伤的创伤愈合反应，表现为肝内结缔组织增生与沉积，是慢性肝病重要的病理特征，也是进一步向肝硬化发展的重要环节。任何破坏肝脏内环境稳定的过程，炎症、毒性损害、肝血流改变、肝脏感染，先天性代谢障碍，化学物质和药物毒性、肝内循环紊乱和胆汁流动阻塞、先天性异常等都可导致肝纤维化。其中，胆汁淤积是引起肝纤维化的重要因素，长期慢性胆汁淤积，由于胆酸及胆红素的作用引起的肝细胞变性、坏死及肝纤维化，最终导致肝硬化，病理学上称为胆汁性肝硬化。已知原因的胆汁淤积性肝硬化称之为继发性胆汁性肝硬化(SBC)；未知原因的肝内胆汁淤积性肝硬化称之为原发性胆汁性肝硬化(PBC)，而肝脏纤维化程度能对肝硬化起到良好的预测作用(Angulo,P.et al.Liver fibrosis,but no other histologicfeatures,is associated with long-term outcomes of patients with nonalcoholicfatty liver disease.Gastroenterology,2015,149,389-397.e10.)。
胆总管结扎(刘玲，胆总管结扎致肝纤维化动物模型研究现状，重庆医学，2013,8,2793-2796.)建造肝脏纤维化模型的原理是，通过切断胆管，人为地造成肝外胆道梗阻，从而引起梗阻部位以上胆管扩张、胆汁淤积，胆道内压力增高，并可引发肝内胆小管破裂，胆汁中的胆红素和一部分胆汁酸可使线粒体受损，能量生成障碍、自由基产生、钙离子进入细胞内等，导致肝细胞的溶解、坏死(bile duct ligation,BDL)。另外，由于肝内血管受到扩张胆管的压迫，也可造成肝细胞发生缺血和坏死，最终导致纤维组织增生向胆管伸展，包饶肝小叶并散布于肝细胞周围，形成肝纤维化；Shen等(Shen H,Fan Y,Yang X,etal.Increased expression of cystic fibrosis transmembrance conductanceregulator in rat liver after common bile duct ligation.J Cell Physiol,2005,203,599-603.)的研究表明，在肝管汇合处下方和胆总管汇入十二指肠前进行双重结扎，2周时可见胆管细胞增生，4周时胆管细胞增生更加明显，并伴有肝组织结构的变形，6周时肝内假小叶形成。另有研究表明，BDL后肝细胞增殖显著增加，其增殖在术后4天达到高峰，为正常组织的24倍，与此相似，胆管上皮细胞也在术后发生增殖，但这种增殖是短暂的，在术后24小时达最大，为正常组织的50倍，BDL40天后，肝细胞所占比例减少，而胆管细胞及基质所占比例增加，胆管基质增加支持新胆管组织而不存在过度的纤维化，这种改变与胆汁淤积时间密切相关。肝细胞的绝对数量可能在胆汁淤积期有所减少，因为其整个阶段都有肝体积增加.
BDL所致肝脏病变类似人的胆汁性肝硬化，秦冬梅等(秦冬梅，赵文惠，胡利萍等。胆总管结扎术造大鼠肝纤维化模型的研究。时珍国医国药，2012,23,803-805.)对60只Wistar大鼠通过胆总管结扎复制模型，采用HE染色发现第5天汇管区纤维组织以及小叶间胆管增生明显，中央静脉周围血管扩张淤血，间质周围也已经出现炎症细胞浸润。该模型造模时间相对较短，实验者和动物不与有毒物质接触，且纤维化形成较快、自发逆转率低,稳定性良好。Kazuyoshi等人(Kazuyoshi T,Yuko K,Kenichi IK,et al.Death receptor 5mediated-apoptosis contributes to cholestatic liver disease.PNAS,2008,10895-10900.)用小鼠BDL模型研究TRAIL/DR5介导的信号通路在胆汁性肝脏疾病进程中的作用。且大鼠来源充足，费用低廉，体积小，便于转运，易于批量的饲养，是肝纤维化造模常用的实验动物。
奥贝胆酸(商品名：Ocaliva)，即熊脱氧胆酸被授予孤儿药批准后的20年内的、第二个用于原发性胆管炎(PBC)患者的用药，于2016年5月31日，被FDA批准联合熊脱氧胆酸(UDCA)用于UDCA单药治疗应答不佳的原发性胆汁性胆管炎(PBC)成人患者，或单药用于无法耐受的PBC成人患者。另外，对于奥贝胆酸的有效剂量还有待评估(刘松涛,廖慧钰。奥贝胆酸的临床研究进展。北京医学,2015,37,1174-1176)。目前，奥贝胆酸的不良反应成为最受关注的问题。最常见的不良反应是是瘙痒、低密度脂蛋白升高和高密度脂蛋白降低(Kowdley KV,Jones D,Luketic V,et al.An international study evaluating thefarnesoid X receptor agonist obeticholic acid as monotherapy inPBC.J.Hepatol,2011,54,13.)。文献报道，瘙痒的发生率达到30％-94％，而且有随着剂量增加，发生率也随之升高的趋势。部分患者由于瘙痒严重而中断服药。
迄今为止，没有特异性的治疗药物。近年来治疗胆汁性肝硬化等疾病药物的探索越来越受到关注，而且研究工作者通过尝试不同环节的药物合成及功能保健来减轻或治疗胆汁性肝硬化进程。但目前，仅仅已获准上市的奥贝胆酸对部分患者治疗有明显改善。虽然有一些细胞因子制剂对治疗胆汁性肝硬化有一定的治疗效果，但至今没有一种能用于临床治疗。因此，积极开发防治胆汁性肝硬化新药是目前医药科研工作中的热点。
发明内容
本发明人发现中国专利号：ZL 201510237027.7中，通过对胃泌酸调节素(Oxyntomudulin,OXM)分子进行改造，获得了作为胃泌酸调节素类似物的一类GLP-1R/GCGR双靶点激动剂，其具有更长的半衰期，促胰岛素活性，无不良反应，可用于糖尿病等疾病的治疗。本发明人继续深入实验，并提供了该类GLP-1R/GCGR双靶点激动剂多肽的新生物活性及其治疗和适应症用途。
本发明的目的在于提供该类GLP-1R/GCGR双靶点激动剂多肽在抑制和改善胆汁性肝硬化及相关肝纤维化病程方面的生物活性及治疗用途。
本发明人经过大量的实验研究，证明该类GLP-1R/GCGR双靶点激动剂多肽能够显著抑制体外人肝星状细胞LX-2的活化，提示活性多肽具有良好的体外抗肝纤维化效应。同时该类多肽能够明显改善BDL诱导的大鼠胆汁淤积性肝纤维化程度。证明该类GLP-1R/GCGR双靶点激动剂多肽对胆汁性肝硬化等疾病具有显著的治疗作用。
本发明的再又一个目的在于提供该类GLP-1R/GCGR双靶点激动剂多肽新的适应症治疗用途。该类GLP-1R/GCGR双靶点激动剂多肽有望作为新一代对胆汁性肝硬化及相关肝纤维化疾病的预防或治疗药物。
本发明中涉及含有以下氨基酸序列表示的母体肽的GLP-1R/GCGR双靶点激动剂多肽：
His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Xaa10-Ser-Lys-Xaa13-Leu-Asp-Xaa16-Xaa17-Xaa18-Ala-Xaa20-Xaa21-Phe-Xaa23-Xaa24-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-COR1
其中，R1＝-NH2；
Xaa2＝Aib或D-Ser；
Xaa10＝Lys或Tyr；
Xaa13＝Lys或Tyr；
Xaa16＝Ser，Aib，Lys或Glu；
Xaa17＝Lys或Arg；
Xaa18＝Arg或Ala；
Xaa20＝His，Gln或Lys；
Xaa21＝Asp或Glu；
Xaa23＝Ile，Val；
Xaa24＝Glu或Gln；
Xaa27＝Met，Leu，Nle；
Xaa28＝Asn，Asp，Arg，Ser或不存在；
Xaa29＝Gly，Thr或不存在；
Xaa30＝Gly或不存在；
Xaa31＝Gly或不存在；
Xaa32＝Pro或不存在；
Xaa33＝Ser，Val或不存在；
Xaa34＝Ser或不存在；
Xaa35＝Gly或不存在；
Xaa36＝Ala或不存在；
Xaa37＝Pro或不存在；
Xaa38＝Pro或不存在；
Xaa39＝Pro或不存在；
Xaa40＝Ser或不存在；
所述氨基酸序列中，Xaa10，Xaa16，Xaa17或Xaa20中至少一个为Lys，所述至少一个Lys或所述序列的第12位Lys的侧链与亲脂性的取代基相连，连接方式为所述亲脂性的取代基以其羧基与一个桥接基团的氨基形成酰胺键，桥接基团的氨基酸残基的羧基与母体肽的Lys的N-末端残基上形成一个酰胺键连接到母体肽上；所述桥接基团为Glu，Asp和/或(PEG)m，其中m为2-10的整数；所述亲脂性取代基为选自CH3(CH2)nCO-或HOOC(CH2)nCO-的酰基，其中n是10-24的整数。优选的桥接基团可以为Glu-(PEG)m或Asp-(PEG)m或(PEG)m，连接方式如下：
本发明中涉及的化合物基于理论分子内桥可以稳定分子的螺旋结构，从而提高了针对GLP-1R或GCGR的效力和/或选择性。本发明化合物在序列中携带一个或多个分子内桥。这样的桥是由两个氨基酸残基的侧链之间形成，所述两个氨基酸残基通常被线性序列中的三个氨基酸所分隔。例如所述桥可在残基对12与16、16与20、17与21或者20与24侧链之间形成。两个侧链可通过离子相互作用或通过共价键彼此相连接。因此，这些残基对可包含带相反电荷的侧链，从而通过离子相互作用形成盐桥。例如，一个残基可以是Glu或Asp，而另一残基可以是Lys或Arg，Lys与Glu配对以及Lys与Asp配对分别还能够反应形成内酰胺环。
本发明还提供含有本发明的GLP-1R/GCGR双靶点激动剂多肽的药物组合物，以所述GLP-1R/GCGR双靶点激动剂多肽作为活性成分添加药学上可接受的载体和/或辅料制成药物组合物。
本发明多肽对胆汁性肝硬化及相关肝纤维化病程疾病具有改善和治疗作用。本发明多肽可用于直接或间接治疗由胆汁性肝硬化及相关肝纤维化病程所引起的或者以其为特征的病症。
本领域技术人员可以理解，本发明的药物组合物适用于各种给药方式，例如口服给药、经皮给药、静脉给药、肌肉内给药、局部给药、经鼻给药等。根据所采用的给药方式，可将本发明的多肽药物组合物制成各种合适的剂型，其中包含至少一种有效量的本发明的多肽和至少一种药学上可接受的药用载体。
适当剂型的实例为片剂、胶囊、糖衣片剂、粒剂、口服溶液和糖浆、用于皮肤表面的油膏和药贴、气雾剂、鼻喷剂、以及可用于注射的无菌溶液。
含有本发明多肽的药物组合物可以制成溶液或者冻干粉以用于胃肠外给药，在使用前可加入适当溶剂或其他可药用的载体将粉末重新配制，液体配方一般是缓冲液、等渗溶液和水溶液。
本发明多肽在药物组合物中的用量可以在较大范围内变动，本领域技术人员可以根据一些客观的因素如疾病的种类、病情严重程度、患者体重、剂型、给药途径等因素很容易地加以确定。
本发明的优点在于：
1)具有良好的生物学活性；
2)在药物的药代实验中显示稳定性，稳定性好，易于放大生产，成本低；
3)与小分子化合物相比具有更低毒性，安全窗口更大，用量更小。
在具体的实施方案中，涉及下述GLP-1R/GCGR双靶点激动剂多肽，其具有序列：
化合物1(涉及SEQ ID NO:1)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYS-K(PEG2-PEG2-γGlu-CO(CH2)14CH3)-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物2(涉及SEQ ID NO:2)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG2-PEG2-CO(CH2)16CO2H)-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYS-K(PEG2-PEG2-CO(CH2)16CO2H)-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物3(涉及SEQ ID NO:3)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG2-PEG2-CO(CH2)16CH3)-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYS-K(PEG2-PEG2-CO(CH2)16CH3)-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物4(涉及SEQ ID NO:4)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)14CH3)-SKYLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS
化合物5(涉及SEQ ID NO:5)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-SKYLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物6(涉及SEQ ID NO:6)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-K(PEG2-PEG2-γGlu-CO(CH2)14CH3)-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物7(涉及SEQ ID NO:7)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Aib-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-Aib-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-RAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物8(涉及SEQ ID NO:8)：
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-Aib-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)14CH3)-SKYLD-Aib-RRAQDFVQWLLDGGPSSGAPPPS-NH2
化合物9(涉及SEQ ID NO:9)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG2-PEG2-CO(CH2)14CH3)-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYS-K(PEG2-PEG2-CO(CH2)14CH3)-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物10(涉及SEQ ID NO:10)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Aib-Lys(PEG2-PEG2-CO(CH2)16CO2H)-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-Aib-K(PEG2-PEG2-CO(CH2)16CO2H)-RAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物11(涉及SEQ ID NO:11)：
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)14CO2H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-Aib-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)14CO2H)-SKYLD-Aib-RRAQDFVQWLLDGGPSSGAPPPS-NH2
化合物12(涉及SEQ ID NO:12)：
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)16CH3)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-Aib-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)16CH3)-SKYLD-Aib-RRAQDFVQWLLDGGPSSGAPPPS-NH2
化合物13(涉及SEQ ID NO:13)：
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)14CO2H)-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-Aib-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)14CO2H)-SKYLDERRAQDFVQWLLDGGPSSGAPPPS-NH2
化合物14(涉及SEQ ID NO:14)：
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)16CH3)-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-Aib-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)16CH3)-SKYLDERRAQDFVQWLLDGGPSSGAPPPS-NH2
化合物15(涉及SEQ ID NO:15)：
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-Aib-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-SKYLDERRAQDFVQWLLDGGPSSGAPPPS-NH2
化合物16(涉及SEQ ID NO:16)：
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-Aib-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)14CH3)-SKYLDERRAQDFVQWLLDGGPSSGAPPPS-NH2
化合物17(涉及SEQ ID NO:17)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Ala-Ala-His-Asp-Phe-Val-Glu-Trp-Leu-Leu-Arg-Ala-NH2
H-(d-S)-QGTFTSDYSKYLDS-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-AAHDFVEWLLRA-NH2
化合物18(涉及SEQ ID NO:18)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Arg-Ala-NH2
H-(d-S)-QGTFTSDYSKYLDEKAA-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-EFIEWLLRA-NH2
化合物19(涉及SEQ ID NO:19)：
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asp-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-Aib-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-SKYLD-Aib-RRAQDFVQWLLDGGPSSGAPPPS-NH2
化合物20(涉及SEQ ID NO:20)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Lys-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYS-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-KLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物21(涉及SEQ ID NO:21)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Ala-Ala-His-Asp-Phe-Val-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLDS-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-AAHDFVEWLLNGGPSSGAPPPS-NH2
化合物22(涉及SEQ ID NO:22)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Lys(PEG2-PEG2-γGlu-CO(CH2)16CH3)-Ala-Ala-His-Asp-Phe-Val-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLDS-K(PEG2-PEG2-γGlu-CO(CH2)16CH3)-AAHDFVEWLLNGGPSSGAPPPS-NH2
化合物23(涉及SEQ ID NO:23)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Arg-Ala-NH2
H-(d-S)-QGTFTSDYSKYLDEKAA-K(PEG2-PEG2-γGlu-CO(CH2)14CH3)-EFIEWLLRA-NH2
化合物24(涉及SEQ ID NO:24)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2-PEG2-γGlu-CO(CH2)16CH3)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Arg-Ala-NH2
H-(d-S)-QGTFTSDYSKYLDEKAA-K(PEG2-PEG2-γGlu-CO(CH2)16CH3)-EFIEWLLRA-NH2
化合物25(涉及SEQ ID NO:25)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Lys(PEG2-PEG2-γGlu-CO(CH2)16CH3)-Ala-Ala-His-Asp-Phe-Val-Glu-Trp-Leu-Leu-Arg-Ala-NH2
H-(d-S)-QGTFTSDYSKYLDS-K(PEG2-PEG2-γGlu-CO(CH2)16CH3)-AAHDFVEWLLRA-NH2
化合物26(涉及SEQ ID NO:26)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLDEKAA-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-EFIEWLLNGGPSSGAPPPS-NH2
化合物27(涉及SEQ ID NO:27)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2-PEG2-γGlu-CO(CH2)14CO2H)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLDEKAA-K(PEG2-PEG2-γGlu-CO(CH2)14CO2H)-EFIEWLLNGGPSSGAPPPS-NH2
化合物28(涉及SEQ ID NO:28)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2-PEG2-γGlu-CO(CH2)16CH3)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLDEKAA-K(PEG2-PEG2-γGlu-CO(CH2)16CH3)-EFIEWLLNGGPSSGAPPPS-NH2
化合物29(涉及SEQ ID NO:29)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Ala-Ala-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Glu-Phe-Ile-Glu-Trp-Leu-Leu-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLDEKAA-K(PEG2-PEG2-γGlu-CO(CH2)14CH3)-EFIEWLLNGGPSSGAPPPS-NH2
化合物30(涉及SEQ ID NO:30)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-CO(CH2)16CO2H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSD-K(PEG2-PEG2-CO(CH2)16CO2H)-SKYLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物31(涉及SEQ ID NO:31):
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-CO(CH2)14CH3)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSD-K(PEG2-PEG2-CO(CH2)14CH3)-SKYLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物32(涉及SEQ ID NO:32)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-CO(CH2)16CH3)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSD-K(PEG2-PEG2-CO(CH2)16CH3)-SKYLD-Aib-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物33(涉及SEQ ID NO:33)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Aib-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-Aib-K(PEG2-PEG2-γGlu-CO(CH2)14CH3)-RAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物34(涉及SEQ ID NO:34)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物35(涉及SEQ ID NO:35)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2-PEG2-CO(CH2)16CO2H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-K(PEG2-PEG2-CO(CH2)16CO2H)-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物36(涉及SEQ ID NO:36)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)16CH3)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-K(PEG2-PEG2-γGlu-CO(CH2)16CH3)-RRAQDFVQWLMNTGGPSSGAPPPS-NH2
化合物37(涉及SEQ ID NO:37)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-K(PEG2-PEG2-γGlu-CO(CH2)14CH3)-RRAQDFVQWL-Nle-NTGGPSSGAPPPS-NH2
化合物38(涉及SEQ ID NO:38)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-RRAQDFVQWL-Nle-NTGGPSSGAPPPS-NH2
化合物39(涉及SEQ ID NO:39)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-RRAQDFVQWLLNTGGPSSGAPPPS-NH2
化合物40(涉及SEQ ID NO:40)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-K(PEG2-PEG2-γGlu-CO(CH2)14CH3)-RRAQDFVQWLLNTGGPSSGAPPPS-NH2
化合物41(涉及SEQ ID NO:41)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2-PEG2-CO(CH2)16CO2H)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-K(PEG2-PEG2-CO(CH2)16CO2H)-RRAQDFVQWL-Nle-NTGGPSSGAPPPS-NH2
化合物42(涉及SEQ ID NO:42)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2-PEG2-CO(CH2)14CH3)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSDYSKYLD-K(PEG2-PEG2-CO(CH2)14CH3)-RRAQDFVQWLLNTGGPSSGAPPPS-NH2
化合物43(涉及SEQ ID NO:43)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)14CH3)-SKYLD-Aib-RRAQDFVQWLLNTGGPSSGAPPPS
化合物44(涉及SEQ ID NO:44)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-CO(CH2)14CH3)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSD-K(PEG2-PEG2-CO(CH2)14CH3)-SKYLD-Aib-RRAQDFVQWLLNTGGPSSGAPPPS
化合物45(涉及SEQ ID NO:45)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-CO(CH2)14CH3)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSD-K(PEG2-PEG2-CO(CH2)14CH3)-SKYLD-Aib-RRAQDFVQWL-Nle-NTGGPSSGAPPPS
化合物46(涉及SEQ ID NO:46)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-CO(CH2)16CO2H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSD-K(PEG2-PEG2-CO(CH2)16CO2H)-SKYLD-Aib-RRAQDFVQWL-Nle-NTGGPSSGAPPPS
化合物47(涉及SEQ ID NO:47)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Leu-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-SKYLD-Aib-RRAQDFVQWLLNTGGPSSGAPPPS
化合物48(涉及SEQ ID NO:48)：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-Ser-Lys-Tyr-Leu-Asp-Aib-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Nle-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
H-(d-S)-QGTFTSD-K(PEG2-PEG2-γGlu-CO(CH2)16CO2H)-SKYLD-Aib-RRAQDFVQWL-Nle-NTGGPSSGAPPPS
本发明中所用缩写具体含义如下:
Boc为叔丁氧羰基，Fmoc为芴甲氧羰基，t-Bu为叔丁基，ivDDe为1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基-丁基的脱除与亲脂取代基，resin为树脂，TFA为三氟乙酸，EDT为1,2-乙二硫醇，Phenol为苯酚，FBS为胎牛血清，BSA为牛血清白蛋白，HPLC为高效液相，GLP-1R为胰高血糖素样肽1受体，GCGR为胰高血糖素受体，GLP-1为胰高血糖素样肽，mPEG为单甲氧基聚乙烯二醇，OXM为胃泌酸调节素，His为组氨酸，Ser为丝氨酸，D-Ser为D-型丝氨酸，Gln为谷氨酰胺，Gly为甘氨酸，Glu为谷氨酸，Ala为丙氨酸，Thr为苏氨酸，Lys为赖氨酸，Arg为精氨酸，Tyr为酪氨酸，Asp为天冬氨酸，Trp为色氨酸，Phe为苯丙氨酸，Ile为异亮氨酸，Leu为亮氨酸，Cys为半胱氨酸，Pro为脯氨酸，Val为缬氨酸，Met为蛋氨酸，Asn为天冬酰胺，HomoLys为高赖氨酸，Orn为鸟氨酸，Dap为二氨基庚二酸，Dab为2,4-二氨基丁酸，Nle为正亮氨酸，Aib为2-氨基异丁酸，AEEA为[2-[2-(氨基)乙氧基]乙氧基]乙酸。
附图说明
图1为显示大鼠肝脏HE染色病理切片图。
图2为显示大鼠肝脏Sirius Red染色病理切片图。
图3为显示大鼠肝脏IHC染色染色病理切片图。
图4为显示大鼠肝脏Sirius Red染色病理切片统计柱状图(****：表示与对照相比在99％置信度内(p<0.0001))。
图5为显示大鼠肝脏IHC染色病理切片α-SMA统计柱状图(****：表示与对照相比在99％置信度内(p<0.0001))。
图6为显示大鼠血清学指标谷丙转氨酶ALT含量测定统计柱状图(****：表示与对照相比在99％置信度内(p<0.0001))。
图7为显示大鼠肝组织羟脯氨酸(HYP)含量测定统计柱状图(****：表示与对照相比在99％置信度内(p<0.0001))。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。除非另有说明，否则所用试剂或仪器均可以通过市购获得。
实施例1、多肽化合物的合成
材料:
所有的氨基酸购自NovaBiochem公司。如果没有特别说明，其他所有试剂均为分析纯，购自Sigma公司。采用Protein Technologies PRELUDE 6通道多肽合成仪。PhenomenexLuna C18制备柱(46mm x 250mm)用来纯化多肽。高效液相色谱仪为Waters公司产品。质谱分析采用Agilent质谱仪进行测定。
以多肽化合物6为例说明本发明多肽化合物的合成方法：
结构序列：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
a)主肽链组装：
按照Fmoc/t-Bu策略在CS336X多肽合成仪(美国CS Bio公司)上合成0.25mmol规模的如下多肽：
Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(ivDde)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide树脂
(1)第一步：将0.75克Rink amide MBHA-LL树脂(Novabiochem，上样0.34mmol/g)在二氯甲烷(DCM)中溶胀一个小时，用N,N-二甲基甲酰胺(DMF)充分洗涤树脂3次；
(2)第二步：以Rink amide树脂为载体，以偶联剂由6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(HCTU)，有机碱N,N-二异丙基乙胺(DIEPA)两者按物质的量比1:1，以N,N-二甲基甲酰胺(DMF)为溶剂，进行程序反应，依次进行缩合反应连接
Fmoc-Ser(t-Bu)-OH，Fmoc-Pro-OH(3x)，Fmoc-Ala-OH，Fmoc-Gly-OH，Fmoc-Ser(t-Bu)-OH(2x)，Fmoc-Pro-OH，Fmoc-Gly-OH(2x)，Fmoc-Thr(t-Bu)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Met-OH，Fmoc-Leu-OH，Fmoc-Trp(Boc)-OH，Fmoc-Glu(OtBu)-OH，Fmoc-Val-OH，Fmoc-Phe-OH，Fmoc-Asp(OtBu)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ala-OH，Fmoc-Arg(Pbf)-OH(2x)，Fmoc-Lys(ivDde)-OH，Fmoc-Asp(OtBu)-OH，Fmoc-Leu-OH，Fmoc-Tyr(t-Bu)-OH，Fmoc-Lys(Boc)-OH，Fmoc-Ser(t-Bu)-OH，Fmoc-Tyr(t-Bu)-OH，Fmoc-Asp(OtBu)-OH，Fmoc-Ser(t-Bu)-OH，Fmoc-Thr(t-Bu)-OH，Fmoc-Phe-OH，Thr(t-Bu)-OH，Fmoc-Gly-OH，Fmoc-Gln(Trt)-OH，Fmoc-D-Ser(t-Bu)-OH，Boc-His(Boc)-OH得到：
Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(ivDde)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide树脂。此后依次用N,N-二甲基甲酰胺(DMF)，二氯甲烷(DCM)，甲醇(Methanol)，二氯甲烷(DCM)，N,N-二甲基甲酰胺(DMF)充分洗涤树脂各3次。
在反应中，1)第一个氨基酸Fmoc-Ser(t-Bu)-OH的用量与树脂用量的物质的量比为1:1～6:1；2)接下来的每次缩合反应中Fmoc保护氨基酸，6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(HCTU)，有机碱N,N-二异丙基乙胺(DIEPA)的用量均过量2～8倍，反应时间为1～5个小时。
b)1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基-丁基(ivDde)的脱除与亲脂取代基的引入：
用N,N-二甲基甲酰胺(DMF)/二氯甲烷(DCM)＝1:1(体积比)的溶液中将树脂洗涤两次，加入新鲜制备的3.0％的肼水合物N,N-二甲基甲酰胺(DMF)溶液，将该反应混合物在室温下振荡10～30分钟进行阱处理步骤，然后过滤。将肼处理步骤重复5次得到：
Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide树脂。此后依次用N,N-二甲基甲酰胺(DMF)，二氯甲烷(DCM)，甲醇(Methanol)，二氯甲烷(DCM)，N,N-二甲基甲酰胺(DMF)充分洗涤树脂各3次。
加入FmocNH-PEG2-OH(Quanta BioDesign)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)，二异丙基乙基胺(DIEPA)的N,N-二甲基甲酰胺(DMF)混合偶联液(均过量5倍)，振荡2小时后，过滤。此后依次用N,N-二甲基甲酰胺(DMF)，二氯甲烷(DCM)，甲醇(Methanol)，二氯甲烷(DCM)，N,N-二甲基甲酰胺(DMF)充分洗涤树脂各3次得到：
Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(Fmoc-PEG2)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pr o-Ser(t-Bu)-rink amide树脂。此后依次用N,N-二甲基甲酰胺(DMF)，二氯甲烷(DCM)，甲醇(Methanol)，二氯甲烷(DCM)，N,N-二甲基甲酰胺(DMF)充分洗涤树脂各3次。
20％的哌啶(Piperidine)/N,N-二甲基甲酰胺(DMF)溶液脱除Fmoc基团(30分钟，重复脱除两次)，加入Fmoc-PEG2-OH，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)，二异丙基乙基胺(DIEPA)的N,N-二甲基甲酰胺(DMF)混合偶联液(均过量5倍)，进行偶联反应得到Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(Fmoc-PEG2-PEG2)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide树脂。此后依次用N,N-二甲基甲酰胺(DMF)，二氯甲烷(DCM)，甲醇(Methanol)，二氯甲烷(DCM)，N,N-二甲基甲酰胺(DMF)充分洗涤树脂各3次。
20％的哌啶(Piperidine)/N,N-二甲基甲酰胺(DMF)溶液脱除Fmoc基团(30分钟，重复脱除两次)，然后按照常规条件依次偶联Fmoc-γGlu-OtBu，加入十六酸(棕榈酸)得到：
Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(PEG2-PEG2-C16)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide树脂。此后依次用N，N-二甲基甲酰胺(DMF)，二氯甲烷(DCM)，甲醇(Methanol)，二氯甲烷(DCM)充分洗涤树脂各3次后，真空抽干。
c)多肽全保护的脱除：
Boc-His(Boc)-D-Ser(t-Bu)-Gln(OtBu)-Gly-Thr(t-Bu)-Phe-Thr(t-Bu)-Ser(tBu)-Asp(OtBu)-Tyr(t-Bu)-Ser(t-Bu)-Lys(Boc)-Tyr(t-Bu)-Leu-Asp(OtBu)-Lys(PEG2-PEG2-C16)-Arg(Pbf)-Arg(Pbf)-Ala-Gln(Trt)-Asp(OtBu)-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Met-Asn(Trt)-Thr(t-Bu)-Gly-Gly-Pro-Ser(t-Bu)-Ser(t-Bu)-Gly-Ala-Pro-Pro-Pro-Ser(t-Bu)-rink amide树脂加入切割液TFA/Phenol/thioanisole/EDT/H2O(82.5:5:5:2.5:5，体积比)中，升温，控制裂解液温度25℃，反应2.5小时。过滤，滤饼用少量裂解液洗涤3次，合并滤液。滤液在搅拌下缓慢倒入冰乙醚中。静置2小时以上，待沉淀完全，离心，用冰乙醚洗涤沉淀3次，得到粗品化合物：
His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)14CH3)-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
d)多肽化合物的精制纯化：
将所得粗品化合物溶于乙腈(ACN)/H2O＝1:2(体积比)的溶液中，通过5.0mm反相C18填充的46mm x 250mm柱上进行制备型HPLC纯化。用30％乙腈(含0.05％三氟乙酸)/H2O(含0.05％三氟乙酸)为起始，以梯度(1.33％/min的速度增加乙腈的比例)，流速为15mL/min将该柱洗脱30分钟，收集含有肽的组分，冷冻抽干，得到HPLC纯度大于95％的纯品。用液质联用分析分离出的产物。
基于以上合成步骤，合成本发明的如下多肽化合物(表1)：
表1、本发明实施例中所合成的多肽化合物结构：
实施例2、GLP-1R/GCGR双激动剂多肽对肝纤维化的体外抑制效应
选用人肝星状细胞株LX-2，研究并观察不同剂量受试物对LX-2细胞活化标志物α-SMA表达量的影响。
将人肝星状细胞LX-2铺板于35mm细胞培养皿，用DMEM(高糖)+10％FBS+1％双抗培养基(Thermo Fisher)进行培养，在37℃，5％CO2条件下待细胞生长至70％汇合时无血清过夜，翌日早上，用上述GLP-1R/GCGR双激动剂多肽1-48(溶于PBS)处理48小时后提取细胞蛋白，进行Western Blot，以β-actin为内参，以Image J 1.50i灰度分析α-SMA和β-actin的表达量。阴性对照仅加入与实验组相同体积的PBS。
采用浓度10.0μM的上述多肽化合物进行处理，可见它们在所有浓度下，均能够降低α-SMA的表达，并有一定的量-效关系；而阴性对照对α-SMA的表达没有影响(表2)。
下表2中示出选用10.0μM浓度的本发明的化合物1-48，利拉鲁肽(Liraglutide)标准品(购于吉尔生化(上海)有限公司，纯度>98％，醋酸利拉鲁肽Cas No.:204656-20-2.)和艾塞那肽(Exenatide)标准品(购买于杭州湃肽生化科技有限公司，纯度>98％，醋酸艾塞那肽，Cas No.:141732-76-5)进行肝纤维化体外抑制实验结果。以阴性对照组中α-SMA/β-actin的整合灰度为100％，分析受试多肽的肝纤维化体外抑制活性。
表2.将化合物1-48对人肝星状细胞株LX-2的细胞活化标志物α-SMA相对表达量的影响。
由以上表2可见，本发明的双靶点激动剂多肽化合物1-48跟GLP-1类似物利拉鲁肽和艾塞那肽相比均显示出更优异的体外抑制LX-2细胞活化标志物α-SMA表达。其中我们选取化合物3、6、7、10、17、20、37、38、39、40、44、46、奥贝胆酸(CAS:459789-99-2，购买于浙江华纳药业有限公司)和利拉鲁肽进一步进行体内动物学评价。
实施例3、GLP-1R/GCGR双激动剂多肽对胆总管结扎(BDL)诱导的大鼠肝脏纤维化(胆汁性肝硬化大鼠模型)的改善治疗作用
1.试验药物：多肽化合物3、6、7、10、17、20、37、38、39、40、44、46、奥贝胆酸(简写：OCA,CAS:459789-99-2，购买于浙江华纳药业有限公司)和利拉鲁肽。保存条件-20℃。
2.试验方法：
将128只雄性SD大鼠，体重200-230g，随机分成16组，分别为：
1).假手术组(Shame组，仅游离胆总管，不予结扎n＝8)；
2).BDL+生理盐水对照组(NaCl组，BDL术后给予生理盐水皮下注射，n＝8)；
3).BDL+3(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
4).BDL+6(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
5).BDL+7(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
6).BDL+10(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
7).BDL+17(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
8).BDL+20(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
9).BDL+37(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
10).BDL+38(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
11).BDL+39(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
12).BDL+40(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
13).BDL+44(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
14).BDL+46(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
15).BDL+OCA(7.5mg/Kg)组(BDL术后给与7.5mg/Kg腹腔注射，n＝8)；
16).BDL+Liraglutide(50μg/Kg)组(BDL术后给与50μg/Kg皮下注射，n＝8)；
SPF级SD大鼠，200-230g，雄性兰州大学实验动物中心提供。大鼠入室(SPF环境)检疫一周后，模型鼠及假手术组大鼠均采用0.6％戊巴比妥钠溶液腹腔注射麻醉，麻醉后于超净台施行手术，模型鼠分离胆总管后双侧结扎，假手术组大鼠仅分理处胆总管，不予结扎，术后第二天开始给药。
于术后第一天开始给药，3、6、7、10、17、20、37、38、39、40、44、46和利拉鲁肽每2日皮下注射一次，给药剂量50μg/Kg；奥贝胆酸给药组每日腹腔注射一次，给药剂量7.5mg/Kg；生理盐水组每日一次，给药过程中每日观察大鼠生命体征的变化。
并于给药周期2周(14天)结束后，处死大鼠取材进行后续生物测定实验。取出肝脏进行HE染色、天狼星红(Sirius Red)染色和IHC染色。用Image-pro plus和Graph pad软件统计。
大鼠肝脏HE染色病理切片图1、天狼星红染色病理切片图2、IHC染色病理切片图3，统计图4和5结果显示：胆总管结扎给生理盐水对照组(NaCl组)中央静脉区域周围有炎性细胞浸润，肝细胞水肿变性，汇管区及肝小叶间隔有大量胶原纤维沉积；多肽化合物3、6、7、10、17、20、37、38、39、40、44和46给药组对胶原纤维沉积抑制显著，并且能显著降低胆管结扎诱导的小鼠肝纤维化和炎症。表明多肽化合物3、6、7、10、17、20、37、38、39、40、44、46跟利拉鲁肽和奥贝胆酸相比，更能明显治疗改善BDL诱导的大鼠胆汁淤积性肝纤维化程度。
肝组织中α-SMA免疫组化表达，α-SMA蛋白免疫组织化学染色阳性表达于汇管区纤维间隔及靠近纤维间隔的肝窦成纤维细胞胞浆。多肽化合物3、6、7、10、17、20、37、38、39、40、44、46给药组对α-SMA抑制显著。多肽化合物3、6、7、10、17、20、37、38、39、40、44、46的药效明显优于利拉鲁肽和奥贝胆酸。
血清指标分析，统计图6结果显示：多肽化合物3、6、7、10、17、20、37、38、39、40、44、46对血清中ALT抑制显著。
肝纤维化时，肝内主要增加的成分为胶原纤维，羟脯氨酸为胶原纤维所特有，测定肝羟脯氨酸的含量，可换算成肝胶原蛋白的含量，以反映肝纤维化程度。测定肝组织中羟脯氨酸的含量，可反应胶原降解的情况。肝脏组织羟脯氨酸含量分析，统计图7结果显示：多肽化合物3、6、7、10、17、20、37、38、39、40、44、46对肝羟脯氨酸的含量抑制显著。
综合上述实验结果表明，多肽化合物3、6、7、10、17、20、37、38、39、40、44、46能够明显治疗改善BDL诱导的大鼠胆汁淤积性肝纤维化程度，对胆汁性肝硬化等疾病具有显著的治疗作用。该类双靶点激动剂多肽可用于预防或治疗胆汁性肝硬化及相关肝纤维化疾病。
序列表
<110> 深圳市图微安创科技开发有限公司
<120> 基于胃泌酸调节素类似物GLP-1R/GCGR双靶点激动剂多肽治疗胆汁性肝硬化
<130> GD2300-22P126732
<160> 48
<170> PatentIn version 3.3
<210> 1
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物1
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 1
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Lys Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 2
<211> 40
<212> PRT
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<223> 化合物2
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 2
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Lys Leu Asp Xaa
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Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
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Ser Ser Gly Ala Pro Pro Pro Ser
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His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Lys Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 4
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物4
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 4
His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 5
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物5
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 5
His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 6
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物6
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 6
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 7
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物7
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 7
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Lys Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 8
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物8
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> X=Aib
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 8
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 9
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物9
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 9
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Lys Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 10
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物10
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 10
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Lys Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 11
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物11
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> X=Aib
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 11
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 12
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物12
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> X=Aib
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 12
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 13
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物13
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> X=Aib
<400> 13
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 14
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物14
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> X=Aib
<400> 14
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 15
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物15
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> X=Aib
<400> 15
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 16
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物16
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> X=Aib
<400> 16
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 17
<211> 29
<212> PRT
<213> Artificial
<220>
<223> 化合物17
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 17
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala
20 25
<210> 18
<211> 29
<212> PRT
<213> Artificial
<220>
<223> 化合物18
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 18
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Ala Ala Lys Glu Phe Ile Glu Trp Leu Leu Arg Ala
20 25
<210> 19
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物19
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> X=Aib
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 19
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 20
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物20
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 20
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Lys Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 21
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物21
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 21
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 22
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物22
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 22
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 23
<211> 29
<212> PRT
<213> Artificial
<220>
<223> 化合物23
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 23
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Ala Ala Lys Glu Phe Ile Glu Trp Leu Leu Arg Ala
20 25
<210> 24
<211> 29
<212> PRT
<213> Artificial
<220>
<223> 化合物24
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 24
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Ala Ala Lys Glu Phe Ile Glu Trp Leu Leu Arg Ala
20 25
<210> 25
<211> 29
<212> PRT
<213> Artificial
<220>
<223> 化合物25
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 25
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala
20 25
<210> 26
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物26
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 26
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Ala Ala Lys Glu Phe Ile Glu Trp Leu Leu Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 27
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物27
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 27
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Ala Ala Lys Glu Phe Ile Glu Trp Leu Leu Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 28
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物28
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 28
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Ala Ala Lys Glu Phe Ile Glu Trp Leu Leu Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 29
<211> 39
<212> PRT
<213> Artificial
<220>
<223> 化合物29
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 29
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Ala Ala Lys Glu Phe Ile Glu Trp Leu Leu Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 30
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物30
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 30
His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 31
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物31
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 31
His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 32
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物32
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 32
His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 33
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物33
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 33
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Lys Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 34
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物34
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 34
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 35
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物35
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 35
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 36
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物36
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 36
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 37
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物37
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (27)..(27)
<223> X=Nle
<400> 37
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Xaa Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 38
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物38
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (27)..(27)
<223> X=Nle
<400> 38
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Xaa Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 39
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物39
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 39
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 40
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物40
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 40
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 41
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物41
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (27)..(27)
<223> X=Nle
<400> 41
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Xaa Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 42
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物42
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<400> 42
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 43
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物43
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 43
His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 44
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物44
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 44
His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 45
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物45
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<220>
<221> MISC_FEATURE
<222> (27)..(27)
<223> X=Nle
<400> 45
His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Xaa Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 46
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物46
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<220>
<221> MISC_FEATURE
<222> (27)..(27)
<223> X=Nle
<400> 46
His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Xaa Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 47
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物47
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<400> 47
His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
<210> 48
<211> 40
<212> PRT
<213> Artificial
<220>
<223> 化合物48
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> D-Ser
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> X=Aib
<220>
<221> MISC_FEATURE
<222> (27)..(27)
<223> X=Nle
<400> 48
His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Xaa Asn Thr Gly Gly Pro
20 25 30
Ser Ser Gly Ala Pro Pro Pro Ser
35 40
Claims (7)
1.胃泌酸调节素类似物GLP-1R/GCGR双激动剂多肽，所述多肽具有以下氨基酸序列表示的母体肽：
His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Xaa10-Ser-Lys-Xaa13-Leu-Asp-Xaa16-Xaa17-Xaa18-Ala-Xaa20-Xaa21-Phe-Xaa23-Xaa24-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-COR1
其中，R1＝-NH2；
Xaa2＝D-Ser；
Xaa10＝Lys或Tyr；
Xaa13＝Lys或Tyr；
Xaa16＝Ser，Aib或Lys；
Xaa17＝Lys或Arg；
Xaa18＝Arg或Ala；
Xaa20＝His或Gln；
Xaa21＝Asp；
Xaa23＝Val；
Xaa24＝Glu或Gln；
Xaa27＝Met，Leu或Nle；
Xaa28＝Asn或Arg；
Xaa29＝Thr；
Xaa30＝Gly；
Xaa31＝Gly；
Xaa32＝Pro；
Xaa33＝Ser；
Xaa34＝Ser；
Xaa35＝Gly；
Xaa36＝Ala；
Xaa37＝Pro；
Xaa38＝Pro；
Xaa39＝Pro；
Xaa40＝Ser；
其中，Xaa10或Xaa16中至少一个为Lys，所述至少一个Lys或所述序列的第12位Lys的侧链与亲脂性的取代基相连，连接方式为所述亲脂性的取代基以其羧基与一个桥接基团的氨基形成酰胺键，桥接基团的氨基酸残基的羧基与母体肽的Lys的N-末端残基上形成一个酰胺键连接到母体肽上，所述桥接基团为Glu，Asp和/或(PEG)m，其中m为2-10的整数；所述亲脂性取代基为选自CH3(CH2)nCO-或HOOC(CH2)nCO-的酰基，其中n是10-24的整数。
2.根据权利要求1所述的胃泌酸调节素类似物GLP-1R/GCGR双激动剂多肽，其特征在于，所述桥接基团为Glu-(PEG)m或Asp-(PEG)m或(PEG)m。
3.根据权利要求1所述的胃泌酸调节素类似物GLP-1R/GCGR双激动剂多肽，其特征在于，所述桥接基团在所述氨基酸序列的残基对12与16、16与20、17与21或者20与24侧链之间形成分子桥。
4.根据权利要求1所述的胃泌酸调节素类似物GLP-1R/GCGR双激动剂多肽，其特征在于，与所述亲脂性取代基连接的Lys被HomoLys、Orn、Dap或Dab代替。
5.根据权利要求1-3中任一项所述的胃泌酸调节素类似物GLP-1R/GCGR双激动剂多肽，其特征在于，当所述氨基酸序列的第10、12、16、17或20位为Lys时，与所述Lys侧链连接的亲脂性取代基为下述结构之一：
6.根据权利要求1所述的胃泌酸调节素类似物GLP-1R/GCGR双激动剂多肽，其特征在于，所述多肽具有以下氨基酸序列表示的母体肽：
His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Xaa10-Ser-Lys-Xaa13-Leu-Asp-Xaa16-Xaa17-Xaa18-Ala-Xaa20-Xaa21-Phe-Xaa23-Xaa24-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-COR1
其中，R1＝-NH2；
Xaa2＝D-Ser；
Xaa10＝Lys或Tyr；
Xaa13＝Tyr；
Xaa16＝Aib或Lys；
Xaa17＝Arg；
Xaa18＝Arg；
Xaa20＝Gln；
Xaa21＝Asp；
Xaa23＝Val；
Xaa24＝Gln；
Xaa27＝Met，Leu或Nle；
Xaa28＝Asn；
Xaa29＝Thr；
Xaa30＝Gly；
Xaa31＝Gly；
Xaa32＝Pro；
Xaa33＝Ser；
Xaa34＝Ser；
Xaa35＝Gly；
Xaa36＝Ala；
Xaa37＝Pro；
Xaa38＝Pro；
Xaa39＝Pro；
Xaa40＝Ser。
7.根据权利要求6所述的胃泌酸调节素类似物GLP-1R/GCGR双激动剂多肽，其特征在于，所述多肽的母体肽的氨基酸序列选自SEQ ID NO:38，SEQ ID NO:39，SEQ ID NO:40，SEQID NO:44和SEQ ID NO:46。
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| CN111944062B (zh) * | 2019-12-09 | 2023-11-07 | 深圳市体内生物医药科技有限公司 | 一种识别Fc片段的嵌合抗原受体及其应用 |
| CN113292646B (zh) * | 2020-05-29 | 2022-05-13 | 东莞云璟生物技术有限公司 | Glp-1/胰高血糖素双重激动剂融合蛋白 |
| CN112472794A (zh) * | 2020-11-17 | 2021-03-12 | 深圳市图微安创科技开发有限公司 | 双靶点激动剂多肽治疗anit介导的pbc及其相关的肝纤维化 |
| CN112409460B (zh) * | 2020-11-27 | 2022-02-01 | 江苏师范大学 | 一类glp-1/胰高血糖素受体双重激动剂及其应用 |
| CN112625093B (zh) * | 2020-12-29 | 2022-12-23 | 清远市图微安创科技开发有限公司 | 用于预防和/或治疗非酒精性脂肪肝炎的多肽化合物 |
| CN112791178A (zh) * | 2021-01-22 | 2021-05-14 | 深圳市图微安创科技开发有限公司 | Glp-1r/gcgr双激动剂多肽衍生物预防或治疗肾纤维化 |
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