CN112409460A - 一类glp-1/胰高血糖素受体双重激动剂及其应用 - Google Patents
一类glp-1/胰高血糖素受体双重激动剂及其应用 Download PDFInfo
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Abstract
本发明提供了一类GLP‑1/GCG受体双重激动多肽化合物，本发明的GLP‑1/GCG受体双重激动多肽化合物在更为有效的降低血糖的同时具有促进减重和防止增重作用，逆转胰岛素抵抗，调节脂质代谢。本发明的多肽化合物对GLP‑1受体和GCG受体的激动活性高于各受体的天然配体，同时对GIP受体具有更低的激动活性。本发明提供的多肽化合物化学性质稳定，具有低的免疫原性特性，适合作为治疗代谢性疾病，如糖尿病、肥胖、高血脂症、NAFLD、NASH等药物的活性成分。
Description
技术领域
本发明涉及生物医药，具体涉及一类GLP-1/胰高血糖素受体双重激动剂及其应用。
背景技术
肥胖及其相关代谢综合征已成为全球性的公众健康问题，许多代谢综合征如2型糖尿病(T2DM)、非酒精性脂肪肝病(NAFLD)、非酒精性脂肪肝炎(NASH)、血脂代谢异常的发病率与病程发展都与肥胖密切相关。研究表明，临床上80-90％的T2DM患者伴有超重或肥胖，使用减重疗法有利于预防和控制病情，包括控制血糖、减少患病率和致残(死)率等。仅靠锻炼和饮食控制来减轻体重，一般很难达到理想的减重效果。目前治疗肥胖的药物疗效较为有限，许多治疗肥胖的药物还具有较显著的副作用，如作用于中枢神经引起的精神症状和严重的心血管影响等副作用。目前仅有少数药物单独使用能实现5-10％的体重降幅，在治疗T2DM的药物中，仅有胰高血糖素样肽(GLP-1)受体激动剂和钠-葡萄糖共转运蛋白2(SGLT2)抑制剂具有较好的体重控制效果(J.Med.Chem.,2018,61,5580-5593)。减肥手术对肥胖的治疗效果显著，但是患者所遭受的手术风险较大，并且手术的长期效应仍不明确。因此，用于体重控制的药物目前仍存在巨大的临床需求，能够安全有效地控制体重兼具原发病症治疗作用的药物是理想的选择。
机体的能量和血糖调节信号系统包括多种不同的多肽类内源性胃肠道激素，胰高血糖素原(proglucagon)是一种具有160个氨基酸的前体多肽，其在不同组织中裂解后转化为不同的产物，诸如GLP-1、胰高血糖素样肽-2(GLP-2)、胰高血糖素(Glucagon，GCG)及胃泌酸调节素(Oxyntomodulin，OXM)等内源性胃肠道激素。这些内源性胃肠道激素参与胰岛素分泌、食物摄取、胃排空以及葡萄糖体内平衡等多种生理功能的调节。因此，基于内源性胃肠道激素的疗法已成为代谢综合征研究领域深受关注的研究方向。
GLP-1是由末端空肠、回肠和结肠的L细胞所分泌的一种葡萄糖依赖性降血糖多肽激素，与GLP-1受体特异性结合后发挥降糖作用。GLP-1的主要优点是具有血糖依赖性的肠促胰岛素分泌作用，避免了糖尿病治疗中常存在的产生低血糖症的危险。除了调节血糖，GLP-1也可以阻止胰腺β细胞退化，刺激β细胞的增殖和分化，能从源头上改善糖尿病进程。此外，GLP-1还具有抑制胃酸分泌、延迟胃排空、抑制食欲等作用，具有部分减重效果。目前已上市多个长效GLP-1类药物，诸如liraglutide、semaglutide和dulaglutide等。虽然GLP-1类药物具有安全的降血糖作用，但是如果需要实现较好的体重减轻作用，一般需要加大给药剂量，而大剂量给予GLP-1类药物容易产生胃肠道副作用，耐受性差而导致治疗窗较窄。因此，仍然需要更为安全耐受的，可有效减轻体重和控制血糖的治疗剂。GCG是在胰脏的α细胞中生成的激素，在机体寒冷、饥饿等应激状态下作用于肝脏，将肝脏中的糖原进行分解而提高血糖。除了其升血糖作用，GCG在体内还具有促进脂解、脂肪氧化、发热等作用(Diabetologia,2017,60,1851–1861)，长期给药可以通过增加能量代谢量而呈现出体重减轻药效，但GCG这些对能量代谢的有益作用因其固有的升血糖作用而未能得以应用。
OXM是人体内的一种内源性GLP-1受体和GCG受体双重激动剂，其对GLP-1受体和GCG受体的激动活性效力弱于各受体的天然配体(天然GLP-1或GCG)。OXM的急性生理作用包括抑制胃排空、摄食以及胃和胰腺的外分泌、提升静息能量消耗等，可产生体重减轻作用。实验表明，在动物和人体内外周给予OXM可减轻体重和降低摄食量，在肥胖对象中可提高代谢率以及和活动相关的能量消耗。此外，在临床中OXM大剂量给药在减轻体重的同时不易发生恶心、呕吐等常见胃肠道副作用。上述实验证实了基于OXM或GLP-1/GCG受体双重激动剂的疗法对代谢综合征的治疗显示了潜在的应用价值。
目前已报道的多肽类GLP-1/GCG受体双重激动剂，按序列结构可以分为基于GCG、OXM、GLP-1或毒蜥外泌肽-4(exendin-4)四类，已公开的专利文件有：CN201911103118.6、CN201780013643.1、CN201680021972.6、CN201580030150.X、CN201380048137.8、WO2008/071972、WO 2008/101017、WO 2009/155258、WO 2010/096052、WO 2010/096142、WO2011/075393、WO 2008/152403、WO 2010/070251、WO 2010/070252、WO 2010/070253、WO2010/070255、WO 2011/160630、WO 2011/006497、WO 2011/087671、WO 2011/087672、WO2011/117415、WO2011/117416、WO 2012/177443、WO 2012/177444、WO 2012/150503、WO2013/004983、WO 2013/092703、WO 2014/041195和WO 2014/041375等。
此外，还有部分研究描述了不仅能激活GLP-1受体和GCG受体，还激活葡萄糖依赖性促胰岛素多肽(GIP)受体的GLP-1/GCG/GIP受体三重激动剂描述于Brian Finan等(Nat.Med.,2015,21,27-36)，Victor A.Gault等(Biochem.Pharmacol.,2013,85,1655–1662；Diabetologia,2013,56,1417–1424)以及描述于CN104902919B、WO 2012/088116等。
两栖动物体内的GLP-1作用效果与人GLP-1类似，所以针对两栖动物GLP-1进行结构修饰，有望发现具有更高效和长效降糖作用的新型GLP-1类药物。XenGLP-1是从非洲爪蟾体内发现的一类动物源属的GLP-1类似物，与天然GLP-1相比，XenGLP-1的降糖活性和稳定性更优。此外，与GLP-1、OXM和GCG相比，除了更为耐受二肽基肽酶(DPP-IV)的降解，XenGLP-1还显示出对于中性内肽酶(NEP)的降解稳定得多。XenGLP-1是GLP-1受体的高效激动剂，然而其不会激活GCG受体。XenGLP-1具有许多用天然GLP-1观察到的葡萄糖调控作用，许多临床前研究都显示XenGLP-1具有若干有益的抗糖尿病特性，包括血糖依赖性的胰岛素合成和分泌增强、胃排空放慢、食物摄入和体重减少，以及促进β细胞增殖和恢复胰岛功能等(Biochem.Pharmacol.,2017,142,155–167；FASEB J.,2019,33,7113-7125)。这些效果不仅对于糖尿病人是有益的，并且对罹患肥胖症的患者也是有益的。患有肥胖者的患者具有更高的患上高血压、高血脂、糖尿病、NAFLD、NASH、肌肉骨骼和心血管疾病的风险。
发明内容
本发明的目的是提供一种新的具有GLP-1/GCG受体双重激动作用的多肽化合物，所述多肽是基于XenGLP-1序列设计的变体，保留XenGLP-1对糖尿病的治疗作用同时具有GCG对脂代谢和能量代谢的有益作用，从而对糖、脂、能量代谢产生协同影响，比单一受体激动剂在制备用于治疗代谢综合征，诸如肥胖、糖尿病、NAFLD、NASH等疾病的药物方面更具潜力。
为实现上述发明目的，本发明的技术方案具体如下：
一类GLP-1/GCG受体双重激动多肽化合物，该类GLP-1受体/GCG受体双重激动多肽化合物的氨基酸序列通式为：
His-Xaa1-Xaa2-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Xaa3-Xaa4-Tyr-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Ala-Xaa10-Xaa11-Phe-Ile-Glu-Trp-Leu-Xaa12-Xaa13-Gly-Xaa14-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Xaa15
其中：
Xaa1取自Ser，D-Ser或Aib；
Xaa2取自Glu或Gln；
Xaa3取自Thr或Ser；
Xaa4取自Glu、Lys或侧链被修饰的Lys；
Xaa5取自Leu、Lys或侧链被修饰的Lys；
Xaa6取自Glu或Asp；
Xaa7取自Glu或Ser；
Xaa8取自Glu或Arg；
Xaa9取自Ala或Arg；
Xaa10取自Lys或Gln；
Xaa11取自Glu或Asp；
Xaa12取自Ile或Lys；
Xaa13取自Lys或Asn；
Xaa14取自Lys或Gly；
Xaa15取自-NH2或侧链被修饰的Lys；
其中侧链被修饰的Lys选自Lys(γ-Glu-CO-(CH2)n-CH3)或Lys(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH)，
Lys(γ-Glu-CO-(CH2)n-CH3)的结构式如下式所示：
Lys(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH)的结构式如下式所示：
其中，n为自然数，且12≤n≤20。
优选的，所述n是14、16、18或20。
优选的，所述多肽化合物的氨基酸序列是下列序列之一：
(1)SEQ ID NO:1
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(2)SEQ ID NO:2
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(3)SEQ ID NO:3
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(4)SEQ ID NO:4
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(5)SEQ ID NO:5
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(6)SEQ ID NO:6
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(7)SEQ ID NO:7
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(γ-Glu-CO-(CH2)14-CH3)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(8)SEQ ID NO:8
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(γ-Glu-CO-(CH2)14-CH3)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(9)SEQ ID NO:9
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(γ-Glu-CO-(CH2)14-CH3)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(10)SEQ ID NO:10
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(11)SEQ ID NO:11
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(12)SEQ ID NO:12
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(13)SEQ ID NO:13
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-NH2
(14)SEQ ID NO:14
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-NH2
(15)SEQ ID NO:15
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-NH2
(16)SEQ ID NO:16
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-NH2
(17)SEQ ID NO:17
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-NH2
(18)SEQ ID NO:18
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-NH2
本发明还提供了一类GLP-1/GCG受体双重激动多肽化合物药学上可接受的盐。
优选的，所述的盐为GLP-1/GCG受体双重激动多肽化合物与下述化合物中的一种所形成的盐：氢溴酸、盐酸、甲磺酸、磷酸、乙磺酸、甲酸、对甲苯磺酸、乙酸、乙酰乙酸、丙酮酸、果胶酯酸、丁酸、己酸、苯磺酸、庚酸、十一烷酸、苯甲酸、水杨酸、月桂酸、2-(4-羟基苯甲酰基)苯甲酸、肉桂酸、樟脑酸、环戊烷丙酸、3-羟基-2-萘甲酸、樟脑磺酸、二葡糖酸、烟酸、扑酸、丙酸、过硫酸、、苦味酸、3-苯基丙酸、特戊酸、衣康酸、2-羟基乙磺酸、氨基磺酸、十二烷基硫酸、三氟甲磺酸、萘二磺酸、2-萘磺酸、柠檬酸、扁桃酸、抗坏血酸、酒硬脂酸、石酸、草酸、乳酸、琥珀酸、丙二酸、半硫酸、苹果酸、马来酸、藻酸、富马酸、D-葡糖酸、甘油磷酸、葡庚酸、天冬氨酸、硫氰酸或者磺基水杨酸。
本发明还提供了GLP-1/GCG受体双重激动多肽化合物的药物组合物，该药物组合物包括：以上述任一GLP-1/GCG受体双重激动多肽化合物或其药学上可接受的盐为有效原料，再加上药学上可接受的载体或稀释剂组成。
本发明还提供了含有上述GLP-1/GCG受体双重激动多肽化合物的药剂，所述的药剂是任何一种药剂学上所说的胶囊、片剂、喷雾剂、吸入剂、注射剂、贴剂、乳剂、膜剂、散剂或者复方制剂，药剂由GLP-1/GCG受体双重激动多肽化合物和药学上可接受的药用辅料、载体或稀释剂组成。
本发明还提供了本发明所述的GLP-1/GCG受体双重激动多肽化合物、其药学上可接受的盐、其药物组合物或其药剂在制备用于治疗代谢性疾病或病症的药物中的应用。在特定方面，代谢性疾病或病症为糖尿病、NAFLD、NASH、高血脂或肥胖。在特定方面，糖尿病为1型糖尿病、T2DM或妊娠糖尿病。在特定方面，所述药物用于治疗超过一种代谢疾病或病症，例如，糖尿病和NAFLD、NASH或肥胖；肥胖和NASH或NAFLD；糖尿病、NASH和肥胖；糖尿病、NAFLD和肥胖；或糖尿病和肥胖。
与现有技术相比，本发明的有益效果：
与现有的GLP-1受体激动剂相比，本发明的GLP-1/GCG受体双重激动多肽化合物在更为有效的降低血糖的同时具有促进减重和防止增重作用，逆转胰岛素抵抗，调节脂质代谢，与现有药物相比具有意想不到的有益作用。本发明的多肽化合物对GLP-1受体和GCG受体的激动活性高于各受体的天然配体，同时对GIP受体具有更低的激动活性。本发明提供的多肽化合物化学性质稳定，不易被体内的DPP-IV和NEP降解，不易被肾小球滤过，化合物的稳定性显著提高，具有支持每天一次给药或每周一次给药的药代动力学特征。本发明提供的多肽化合物具有提高的生物物理特性，在中性pH和pH 4.5的溶解性都高于天然GLP-1和GCG，具备有利于制剂的特性。本发明提供的多肽化合物具有低的免疫原性特性，对T2DM、肥胖、NAFLD、NASH和高血脂症等代谢性疾病的治疗作用优于现有上市药物。因此，本发明提供的多肽化合物，适合作为治疗代谢性疾病，如糖尿病、肥胖、高血脂症、NAFLD、NASH等药物的活性成分。
附图说明
图1显示的是各受试物单次给药在db/db小鼠非禁食状态下的长效降血糖作用；
图2显示的是各受试物在DIO小鼠长期给药21天后的口服糖耐量实验中的降血糖作用；
图3显示的是各受试物在体外的免疫原性。
具体实施方式
在本说明书全文中采用以下缩写：
英文缩写 中文
Gly 甘氨酸
Ser 丝氨酸
Ala 丙氨酸
Thr 苏氨酸
Val 缬氨酸
Ile 异亮氨酸
Leu 亮氨酸
Tyr 酪氨酸
Phe 苯丙氨酸
His 组氨酸
Pro 脯氨酸
Asp 天冬氨酸
Met 蛋氨酸
Glu 谷氨酸
Trp 色氨酸
Lys 赖氨酸
Arg 精氨酸
Asn 天冬酰胺
Gln 谷氨酰胺
Cys 半胱氨酸
Aib α-氨基异丁酸
AEEA 8-氨基-3,6二氧杂辛酸
DCM 二氯甲烷
DMF 二甲基甲酰胺
Fmoc 9-芴基甲氧基羰基
Boc 叔丁氧羰基
DMSO 二甲基亚砜
DIC N,N’-二异丙基碳二亚胺
HOBT 1-羟基-苯并三氮唑
Alloc 烯丙氧羰基
Dde 1-(4,4-二甲基-2,6-二氧代亚环己基)-乙基
Mtt 4-甲基三苯甲基
ivDde 1-(4,4-二甲基-2,6-二氧代亚环己基)3-甲基-丁基
TFA 三氟乙酸
EDT 二巯基乙烷
HPLC 高效液相色谱
LC-MS 液质联用质谱
DMEM 杜贝可氏修饰伊格氏培养基
FBS 胎牛血清
PBS 磷酸盐缓冲盐水
HEPES 2-[4-(2-羟乙基)哌嗪-1-基]乙磺酸
BSA 牛血清白蛋白
IBMX 3-异丁基-1-甲基黄嘌呤
HBSS Hanks’平衡盐溶液
AIMV 无血清细胞培养基
实施例1
SEQ ID NO:1多肽化合物的合成
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(1)树脂的溶胀
称取担载量为0.382mmol/g的Rink Amide MBHA树脂0.262g(0.1mmol当量)，放入25mL的反应器中，用7mL的DCM和甲醇交替清洗树脂1次，7mL的DCM清洗树脂2次，然后用7mL的DCM溶胀树脂1h，最后用7mL DMF清洗树脂3次。
(2)树脂Fmoc保护基的脱除
将溶胀后的树脂转入PSI200多肽合成仪，加入7mL 20％哌啶/DMF(v/v)室温反应5min，滤去脱保护溶液，7mL DMF清洗树脂一次，再加入7mL 20％哌啶/DMF(v/v)脱保护溶剂与树脂反应15min，最后7mL DMF清洗树脂4次，每次1.5min，得到脱除Fmoc保护基的Rink树脂。
(3)Fmoc-Ser-Rink amide-MBHA Resin的合成
称Fmoc-Ser(Boc)-OH(0.4mmol)，用3mL 10％DMF/DMSO(v/v)溶解，加入2mL DIC/HOBt(0.4mmol/0.44mmol)缩合剂，预活化30min后，将活化好的氨基酸加入反应器中，室温震荡反应2h，滤去反应液后用7mL DMF清洗树脂4次，使用Kaiser试剂检测反应耦合是否完全，如不完全则2次耦合。
(4)肽链的延长
按照肽链的序列，重复上述脱保护和耦合的步骤依次连接上相应的氨基酸，直至肽链合成完毕。其中12位Lys可以采用Fmoc-Lys(Alloc)-OH、Fmoc-Lys(Dde)-OH、Fmoc-Lys(Mtt)-OH或Fmoc-Lys(ivDde)-OH等。本实例中采用Fmoc-Lys(Dde)-OH保护策略，同时N末端的His使用的是Boc-His(Boc)-OH。
(5)Lys侧链的修饰
肽链合成完毕后，加入7mL 2％水合肼/DMF(v/v)选择性脱除12位Lys的Dde保护基，Dde保护基脱除后加入0.4mmol的Fmoc-Glu-OtBu，0.4mmol的DIC及0.44mmol的HOBt，震荡反应2h。然后使用上述相同方法脱除Fmoc保护基后，加入0.4mmol的棕榈酸，0.4mmol的DIC及0.44mmol的HOBt缩合反应2h，反应完全后用7mL DMF清洗树脂4次。
(6)多肽的裂解
将上述得到的连有多肽的树脂转移至圆底瓶中，使用切割剂Reagent R(TFA/苯甲硫醚/苯酚/EDT，90:5:3:2，V/V)5mL切割树脂，在油浴中恒温30℃反应2h，切割液倾入40mL冰乙醚中，冷冻离心后粗品用15mL冰乙醚洗涤3次，最后用氮气吹干，得到粗肽。
(7)多肽的纯化
将目标多肽粗品溶于水中，用0.25μm微孔滤膜过滤后进岛津制备型反相HPLC系统纯化。色谱条件为C18反相制备柱(250mm×20mm，12μm)；流动相A：0.1％TFA/水(V/V)，流动相B：甲醇(V/V)；流速为8mL/min；检测波长为214nm。采用线性梯度(20％B～70％B/30min)洗脱，收集目标峰，除去甲醇后冻干得纯品0.14g，纯度大于98％，通过LC-MS确认目标多肽的分子量。
实施例2
SEQ ID NO:2多肽化合物的合成
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
合成方法同实施例1，收集目标峰冻干得纯品0.16g。
实施例3
SEQ ID NO:3多肽化合物的合成
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
合成方法同实施例1，收集目标峰冻干得纯品0.13g。
实施例4
SEQ ID NO:4多肽化合物的合成
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(1)树脂的溶胀
称取担载量为0.382mmol/g的Rink Amide MBHA树脂0.262g(0.1mmol当量)，放入25mL的反应器中，用7mL的DCM和甲醇交替清洗树脂1次，7mL的DCM清洗树脂2次，然后用7mL的DCM溶胀树脂1h，最后用7mL DMF清洗树脂3次。
(2)树脂Fmoc保护基的脱除
将溶胀后的树脂转入PSI200多肽合成仪，加入7mL 20％哌啶/DMF(v/v)室温反应5min，滤去脱保护溶液，7mL DMF清洗树脂一次，再加入7mL 20％哌啶/DMF(v/v)脱保护溶剂与树脂反应15min，最后7mL DMF清洗树脂4次，每次1.5min，得到脱除Fmoc保护基的Rink树脂。
(3)Fmoc-Ser-Rink amide-MBHA Resin的合成
称Fmoc-Ser(Boc)-OH(0.4mmol)，用3mL 10％DMF/DMSO(v/v)溶解，加入2ml DIC/HOBt(0.4mmol/0.44mmol)缩合剂，预活化30min后，将活化好的氨基酸加入反应器中，室温震荡反应2h，滤去反应液后用7mL DMF清洗树脂4次，使用Kaiser试剂检测反应耦合是否完全，如不完全则2次耦合。
(4)肽链的延长
按照肽链的序列，重复上述脱保护和耦合的步骤依次连接上相应的氨基酸，直至肽链合成完毕。其中12位Lys可以采用Fmoc-Lys(Alloc)-OH、Fmoc-Lys(Dde)-OH、Fmoc-Lys(Mtt)-OH或Fmoc-Lys(ivDde)-OH等。本实例中采用Fmoc-Lys(Dde)-OH保护策略，同时N末端的His使用的是Boc-His(Boc)-OH。
(5)Lys侧链的修饰
肽链合成完毕后，加入7mL 2％水合肼/DMF(v/v)选择性脱除12位Lys的Dde保护基，Dde保护基脱除后加入0.4mmol的Fmoc-AEEA-OH，0.4mmol的DIC及0.44mmol的HOBt，震荡缩合反应2h。脱除Fmoc保护基后，再次加入0.4mmol的Fmoc-AEEA-OH，0.4mmol的DIC及0.44mmol的HOBt，震荡缩合反应2h。脱除Fmoc保护基后，加入0.4mmol的Fmoc-Glu-OtBu，0.4mmol的DIC及0.44mmol的HOBt，震荡缩合反应2h。脱除Fmoc保护基后，加入0.4mmol的十八烷二酸单叔丁酯，0.4mmol的DIC及0.44mmol的HOBt缩合反应2h，反应完全后用7mL DMF清洗树脂4次。
(6)多肽的裂解
将上述得到的连有多肽的树脂转移至圆底瓶中，使用切割剂Reagent R(TFA/苯甲硫醚/苯酚/EDT，90:5:3:2，V/V)5mL切割树脂，在油浴中恒温30℃反应2h，切割液倾入40mL冰乙醚中，冷冻离心后粗品用15mL冰乙醚洗涤3次，最后用氮气吹干，得到粗肽。
(7)多肽的纯化
将目标多肽粗品溶于水中，用0.25μm微孔滤膜过滤后进岛津制备型反相HPLC系统纯化。色谱条件为C18反相制备柱(250mm×20mm，12μm)；流动相A：0.1％TFA/水(V/V)，流动相B：甲醇(V/V)；流速为8mL/min；检测波长为214nm。采用线性梯度(20％B～80％B/30min)洗脱，收集目标峰，除去甲醇后冻干得纯品0.18g，纯度大于98％，通过LC-MS确认目标多肽的分子量。
实施例5
SEQ ID NO:5多肽化合物的合成
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
合成方法同实施例4，收集目标峰冻干得纯品0.17g。
实施例6
SEQ ID NO:6多肽化合物的合成
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
合成方法同实施例4，收集目标峰冻干得纯品0.15g。
实施例7
SEQ ID NO:7多肽化合物的合成
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(γ-Glu-CO-(CH2)14-CH3)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
合成方法同实施例1，收集目标峰冻干得纯品0.15g。
实施例8
SEQ ID NO:8多肽化合物的合成
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(γ-Glu-CO-(CH2)14-CH3)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
合成方法同实施例1，收集目标峰冻干得纯品0.16g。
实施例9
SEQ ID NO:9多肽化合物的合成
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(γ-Glu-CO-(CH2)14-CH3)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
合成方法同实施例1，收集目标峰冻干得纯品0.14g。
实施例10
SEQ ID NO:10多肽化合物的合成
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
合成方法同实施例4，收集目标峰冻干得纯品0.17g。
实施例11
SEQ ID NO:11多肽化合物的合成
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
合成方法同实施例4，收集目标峰冻干得纯品0.16g。
实施例12
SEQ ID NO:12多肽化合物的合成
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
合成方法同实施例4，收集目标峰冻干得纯品0.14g。
实施例13
SEQ ID NO:13多肽化合物的合成
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-NH2
合成方法同实施例1，收集目标峰冻干得纯品0.13g。
实施例14
SEQ ID NO:14多肽化合物的合成
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-NH2
合成方法同实施例1，收集目标峰冻干得纯品0.15g。
实施例15
SEQ ID NO:15多肽化合物的合成
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-NH2
合成方法同实施例1，收集目标峰冻干得纯品0.16g。
实施例16
SEQ ID NO:16多肽化合物的合成
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-NH2
合成方法同实施例4，收集目标峰冻干得纯品0.15g。
实施例17
SEQ ID NO:17多肽化合物的合成
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-NH2
合成方法同实施例4，收集目标峰冻干得纯品0.16g。
实施例18
SEQ ID NO:18多肽化合物的合成
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-NH2
合成方法同实施例4，收集目标峰冻干得纯品0.15g。
实施例19
多肽化合物对GLP-1受体、GCG受体和GIP受体的激动活性测定
通过功能测定法来确定多肽化合物对受体的激动作用，所述测定法测量稳定表达人GLP-1受体、GCG受体或GIP受体的HEK-293细胞系的cAMP响应。将稳定表达上述三种受体的细胞分入T175培养瓶并在培养基(DMEM/10％FBS)中过夜生长至接近汇合状态，然后除去培养基，并用无钙和镁的PBS洗涤细胞，然后用Accutase酶进行蛋白酶处理。洗涤脱离的细胞并将其重悬于测定缓冲液(20mM HEPES,0.1％BSA,2mM IBMX,1×HBSS)中，并确定细胞密度，并将25μL的等分试样分装至96孔板的孔中。为了测量，将25μL的测试多肽化合物在测定缓冲液中的溶液添加到孔中，然后室温温育30分钟。用Cisbio的试剂盒，基于均相时间分辨荧光(HTRF)来确定细胞的cAMP含量。添加稀释于裂解缓冲液(试剂盒组分)中的HTRF试剂后，将平板温育1小时，然后测量665/620nm处的荧光比。通过检测引起最大响应的50％激活的浓度(EC50)来对激动剂的体外效力进行量化。
将本专利申请实施例中的检测数据(nM)显示于下表1中，虽然用一定数量的有效数字来陈述检测数据，但不应该认为表示数据已确定精确为有效数字的数。
表1：多肽化合物对人GLP-1受体、GCG受体及GIP受体的EC50值(以nM表示)
如表1所示，所有多肽化合物对GLP-1受体的激动活性都高于天然GLP-1，并且绝大多数多肽化合物对GCG受体的激动活性也高于天然GCG，同时所有多肽化合物都表现出了更弱的GIP受体的激动活性。
实施例20
多肽化合物的溶解度和稳定性测试
在测试多肽化合物的溶解度和稳定性之前，首先使用HPLC确定其纯度。然后，基于确定的％纯度，在不同的缓冲体系中，溶解10mg多肽化合物在1mL溶液中，温和搅拌2小时。使用4500rpm离心20分钟后，取上清液进HPLC分析，确定峰面积。然后与相应样品标准溶液比对，计算得到受试样品溶液的相对浓度。对于稳定性测试，将溶解度获得的上清液的等分试样在40℃储存7天，然后样品在4500rpm离心20分钟，上清液进HPLC分析，确定峰面积。通过比较稳定性实验开始前的峰面积(t0)和存储7天后的峰面积(t7)，得到“％剩余肽”。按以下公式计算：％剩余肽＝[(峰面积t7)×100]/峰面积t0，稳定性表示为“％剩余肽”，计算结果如下表2所示。
表2：多肽化合物的溶解度和稳定性
如表2结果显示，本发明的多肽化合物与天然GLP-1和GCG相比，在机体可接受的注射液pH条件下的溶解性大幅改善，具备了有利于制剂的特性。本发明的多肽化合物在pH4.5也具有高溶解性，该特性可能允许用于与胰岛素或胰岛素衍生物的组合治疗的共制剂。此外，在pH 4.5和中性pH条件下本发明的多肽化合物也具有很高的稳定性。
实施例21
多肽化合物对DPP-IV和NEP酶的稳定性
受试样品于37℃与纯化的人DPP-IV或NEP酶共孵0，2，4，8小时，使用HPLC法测定各时间点溶液中的残留样品峰面积，计算样品半衰期，结果如表3所示。
表3：多肽化合物在DPP-IV酶或NEP酶体系中的半衰期(以h表示)
如表3结果显示，本发明的多肽化合物在含DPP-IV酶溶液和NEP酶溶液体系中的半衰期均超过8个小时，说明可以有效耐受DPP-IV和NEP酶的降解。
实施例22
多肽化合物在大鼠体内的药代动力学性质
大鼠给予50nmol/kg的皮下(s.c.)注射给药，在给药后0.25，0.5，1，2，4，8，16，24，36和48小时收集血样。使用乙腈沉淀蛋白质后，用LC-MS分析血浆样品。用WinonLin5.2.1(非房室模型)计算药代参数和半衰期(表4)。
表4：多肽化合物在大鼠体内的药代动力学概貌
| 样品 | T<sub>1/2</sub>(h) | C<sub>max</sub>(ng/mL) |
| Liraglutide | 2.3 | 489 |
| Semaglutide | 9.2 | 519 |
| SEQ ID NO:8 | 3.9 | 539 |
| SEQ ID NO:9 | 4.6 | 551 |
| SEQ ID NO:11 | 11.5 | 541 |
| SEQ ID NO:12 | 12.6 | 561 |
如表4结果显示，本发明的多肽化合物的体内半衰期显著延长，具有支持每天一次给药或每周一次给药的药代动力学特征。
实施例23
多肽化合物对糖尿病模型小鼠(db/db小鼠)血糖的影响
雄性db/db小鼠，随机分组，每组6只。空白组皮下注射给予生理盐水(10mg/kg)，给药组分为6组，小鼠实验期间自由进食和饮水，小鼠非空腹状态下分别皮下单次注射25nmol/kg的liraglutide，semaglutide，SEQ ID NO:8，SEQ ID NO:9，SEQ ID NO:11，SEQID NO:12。在给药前0h，以及给药后4，6，24和48h用血糖仪测量各组小鼠血糖水平。
如图1结果所示，在db/db小鼠体内的降血糖实验结果表明，本发明的多肽化合物显示出了优于阳性对照药liraglutide和semaglutide的长效降血糖活性。
实施例24
多肽化合物对饮食诱导肥胖(DIO)小鼠血糖和体重的影响
雄性C57BL/6J小鼠，体重22g左右，模型组共42只，用Research Diets公司的D12492高脂饲料饲养18周造DIO小鼠模型。空白对照组6只采用标准鼠饲料饲养(对照标准饮食组)。在给药开始前，各组DIO小鼠按照体重随机分组，共分为7组，每组6只，分别为生理盐水组(对照高脂饮食组)、阳性对照组(liraglutide和semaglutide)和受试样品组(SEQID NO:8、9、11、12)。对照标准饮食组和对照高脂饮食组每天两次皮下注射生理盐水(10mg/kg)，liraglutide，SEQ ID NO:8，SEQ ID NO:9组每天两次皮下注射(25nmol/kg)，semaglutide，SEQ ID NO:11，SEQ ID NO:12组每天一次皮下注射(25nmol/kg)，给药周期21天。每天记录小鼠体重变化，实验开始前和结束时使用核磁共振(NMR)来测量体脂量，在实验结束后，各组小鼠禁食12h后，口服给予葡萄糖(1.5g/kg)，并使用血糖仪测定给糖后15，30，60和120min各组小鼠的血糖数值(表5)。
表5：DIO小鼠在3周给药周期内的体重和体脂变化
| 样品(剂量) | 整体体重变化(％) | 体脂变化(％) |
| 对照标准饮食 | +1.3％(±0.6％) | +6.1％(±3.2％) |
| 对照高脂饮食 | +0.4％(±0.4％) | +2.1％(±1.0％) |
| Liraglutide(25nmol/kg每天两次) | -14.2％(±2.6％)<sup>***</sup> | -29.2％(±3.1％)<sup>***</sup> |
| SEQ ID NO:8(25nmol/kg每天两次) | -28.3％(±3.2％)<sup>***,###</sup> | -54.3％(±4.4％)<sup>***,###</sup> |
| SEQ ID NO:9(25nmol/kg每天两次) | -27.8％(±2.5％)<sup>***,###</sup> | -52.9％(±5.2％)<sup>***,###</sup> |
| Semaglutide(25nmol/kg每天一次) | -15.7％(±3.1％)<sup>***</sup> | -30.4％(±3.6％)<sup>***</sup> |
| SEQ ID NO:11(25nmol/kg每天一次) | -27.5％(±2.3％)<sup>***,###</sup> | -52.3％(±3.3％)<sup>***,###</sup> |
| SEQ ID NO:12(25nmol/kg每天一次) | -26.2％(±1.8％)<sup>***,###</sup> | -50.6％(±4.8％)<sup>***,###</sup> |
***：与对照高脂饮食组相比P<0.001；###：与liraglutide和semaglutide组比P<0.001
如表5结果显示，本发明的多肽化合物的在DIO小鼠体内连续给药3周，可以显著降低小鼠的体重和体脂含量，并且本发明的多肽化合物的作用显著强于阳性对照药liraglutide和semaglutide。
如图2结果所示，降血糖实验结果表明，本发明的多肽化合物显示出了与阳性对照药liraglutide和semaglutide相当的降血糖活性。
实施例25
多肽化合物对db/db小鼠糖化血红蛋白(HbA1c)和空腹血糖的影响
雄性db/db小鼠，随机分组，每组6只。适应性饲养一周后，尾部取血测量治疗开始前初始HbA1c数值和空腹血糖数值。空白组每天两次皮下注射给予生理盐水(10mg/kg)，给药组分为6组，分别皮下注射25nmol/kg的liraglutide(每天两次)，semaglutide(每天一次)，SEQ ID NO:8(每天两次)，SEQ ID NO:9(每天两次)，SEQ ID NO:11(每天一次)，SEQ IDNO:12(每天一次)。治疗周期为5周，治疗结束后小鼠禁食过夜后测量空腹血糖数值，同时取血测量HbA1c(％)数值(表6、7)。
表6：db/db小鼠在5周给药周期内的HbA1c(％)变化
| 样品(剂量) | HbA1c％(治疗前) | HbA1c％(治疗后) |
| 生理盐水 | 5.3±0.4 | 6.9±0.7 |
| Liraglutide(25nmol/kg每天两次) | 5.2±0.3 | 5.3±0.2 |
| SEQ ID NO:8(25nmol/kg每天两次) | 5.4±0.5 | 5.2±0.4 |
| SEQ ID NO:9(25nmol/kg每天两次) | 5.1±0.2 | 5.1±0.3 |
| Semaglutide(25nmol/kg每天一次) | 5.6±0.5 | 5.8±0.3 |
| SEQ ID NO:11(25nmol/kg每天一次) | 5.4±0.6 | 5.3±0.4 |
| SEQ ID NO:12(25nmol/kg每天一次) | 5.7±0.4 | 5.6±0.3％ |
如表6结果显示，本发明的多肽化合物的在db/db小鼠体内连续给药5周，可以抑制HbA1c数值的增高，说明具有很好的血糖控制作用。
表7：db/db小鼠在5周给药周期内的空腹血糖变化
***：与生理盐水组相比P<0.001；##：与liraglutide和semaglutide组比P<0.01
如表7结果显示，本发明的多肽化合物的在db/db小鼠体内连续给药5周，可以显著降低db/db小鼠空腹血糖数值，说明具有很高的血糖控制作用，并且本发明的多肽化合物的作用显著强于阳性对照药liraglutide和semaglutide。
实施例26
多肽化合物的免疫原性
采用来自50例中国人捐赠者的外周血单个核细胞(PBMC)进行了诱导T细胞增殖的免疫原性实验。PBMC在AIMV培养基中培养，并添加到24孔板(2mL)中以达到最终浓度～3×106cells/mL，然后通过在AIMV培养基中添加liraglutide，semaglutide，SEQ ID NO:8，SEQID NO:9来刺激PBMC。24孔板在37℃的二氧化碳培养箱(5％)中培养8天。第5天、第6天、第7天和第8天，将培养板各孔的细胞转移到96孔板上。用[3H]-胸腺嘧啶核苷对培养物进行处理，再培养18小时，并测定每个孔的每分钟计数(cpm)。刺激指数(SI)是通过将每个供体的试验孔的增殖反应(cpm)除以培养基处理(cpm)的增殖反应来计算的，大于2.0的SI被视为阳性。通过将整个时间过程(5-8天)内有阳性反应的捐赠者数量占接受测试的捐赠者总数的百分比来计算捐赠者的响应百分比。
如图3结果所示，本发明的多肽化合物的捐赠者反应比例低于liraglutide和semaglutide，说明本发明的多肽化合物具有低免疫原性。
最后所应说明的是，以上具体实施方式仅用以说明本发明的技术方案而非限制，尽管参照实例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围当中。
序列表
<110> 江苏师范大学
<120> 一类GLP-1/胰高血糖素受体双重激动剂及其应用
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Claims (10)
1.一类GLP-1/GCG受体双重激动多肽化合物，其特征在于，所述GLP-1/GCG受体双重激动多肽化合物的氨基酸序列通式为：
His-Xaa1-Xaa2-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Xaa3-Xaa4-Tyr-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Ala-Xaa10-Xaa11-Phe-Ile-Glu-Trp-Leu-Xaa12-Xaa13-Gly-Xaa14-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Xaa15
其中：
Xaa1取自Ser，D-Ser或Aib；
Xaa2取自Glu或Gln；
Xaa3取自Thr或Ser；
Xaa4取自Glu、Lys或侧链被修饰的Lys；
Xaa5取自Leu、Lys或侧链被修饰的Lys；
Xaa6取自Glu或Asp；
Xaa7取自Glu或Ser；
Xaa8取自Glu或Arg；
Xaa9取自Ala或Arg；
Xaa10取自Lys或Gln；
Xaa11取自Glu或Asp；
Xaa12取自Ile或Lys；
Xaa13取自Lys或Asn；
Xaa14取自Lys或Gly；
Xaa15取自-NH2或侧链被修饰的Lys；
其中，侧链被修饰的Lys是Lys(γ-Glu-CO-(CH2)n-CH3)或Lys(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH)，Lys(γ-Glu-CO-(CH2)n-CH3)的结构式如下式所示：
Lys(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH)的结构式如下式所示：
其中，n为自然数，且12≤n≤20。
2.根据权利要求1所述的一类GLP-1/GCG受体双重激动多肽化合物，其特征在于，所述n是14、16、18或20。
3.根据权利要求1所述的一类GLP-1/GCG受体双重激动多肽化合物，其特征在于，所述氨基酸序列是下列序列之一：
(1)
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(2)
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(3)
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(4)
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(5)
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(6)
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(7)
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(γ-Glu-CO-(CH2)14-CH3)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-S er-NH2
(8)
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(γ-Glu-CO-(CH2)14-CH3)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(9)
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(γ-Glu-CO-(CH2)14-CH3)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(10)
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(11)
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(12)
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(13)
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-NH2
(14)
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-NH2
(15)
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe -Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-NH2
(16)
His-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-NH2
(17)
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-NH2
(18)
His-Aib-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-NH2。
4.权利要求1中所述GLP-1/GCG受体双重激动多肽化合物的药学上可接受的盐。
5.根据权利要求4所述的GLP-1/GCG受体双重激动多肽化合物的药学上可接受的盐，其特在于，所述盐为GLP-1/GCG受体双重激动多肽化合物与下述化合物中的一种所形成的盐：氢溴酸、盐酸、甲磺酸、磷酸、乙磺酸、甲酸、对甲苯磺酸、乙酸、乙酰乙酸、丙酮酸、果胶酯酸、丁酸、己酸、苯磺酸、庚酸、十一烷酸、苯甲酸、水杨酸、月桂酸、2-(4-羟基苯甲酰基)苯甲酸、肉桂酸、樟脑酸、环戊烷丙酸、3-羟基-2-萘甲酸、樟脑磺酸、二葡糖酸、烟酸、扑酸、丙酸、过硫酸、、苦味酸、3-苯基丙酸、特戊酸、衣康酸、2-羟基乙磺酸、氨基磺酸、十二烷基硫酸、三氟甲磺酸、萘二磺酸、2-萘磺酸、柠檬酸、扁桃酸、抗坏血酸、酒硬脂酸、石酸、草酸、乳酸、琥珀酸、丙二酸、半硫酸、苹果酸、马来酸、藻酸、富马酸、D-葡糖酸、甘油磷酸、葡庚酸、天冬氨酸、硫氰酸、磺基水杨酸。
6.含有GLP-1/GCG受体双重激动多肽化合物的药物组合物，其特征在于，包括：权利要求1中所述GLP-1/GCG受体双重激动多肽化合物或权利要求4中所述药学上可接受的盐，以及药学上可接受的载体或稀释剂。
7.含有权利要求1中所述GLP-1/GCG受体双重激动多肽化合物的药剂，其特征在于，包括：GLP-1/GCG受体双重激动多肽化合物及药学上可接受的药用辅料、载体或稀释剂。
8.根据要求7所述的药剂，其特征在于，所述药剂是药剂学上所说的胶囊、片剂、喷雾剂、吸入剂、注射剂、贴剂、乳剂、膜剂、散剂或者复方制剂，药剂由GLP-1/GCG受体双重激动多肽化合物和药学上可接受的药用辅料、载体或稀释剂组成。
9.GLP-1/GCG受体双重激动多肽化合物、其药学上可接受的盐、及其药物组合物或其药剂在制备用于治疗代谢性疾病或病症的药物中的应用。
10.根据权利要求9所述的应用，其特征在于，所述代谢性疾病或病症为糖尿病、NAFLD、NASH、高血脂或肥胖。
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| WO2024012472A1 (zh) * | 2022-07-13 | 2024-01-18 | 杭州中美华东制药有限公司 | Glp-1/gip双激动剂及其制备方法和用途 |
| CN115960258A (zh) * | 2022-09-30 | 2023-04-14 | 广西医科大学附属肿瘤医院 | 一类GLP-1/glucagon/Y2受体三重激动剂及其应用 |
| CN115960258B (zh) * | 2022-09-30 | 2024-01-12 | 广西医科大学附属肿瘤医院 | 一类GLP-1/glucagon/Y2受体三重激动剂及其应用 |
| CN117603364A (zh) * | 2022-09-30 | 2024-02-27 | 广西医科大学附属肿瘤医院 | 一类GLP-1/glucagon/Y2受体三重激动剂及其应用 |
| CN115785249A (zh) * | 2022-10-13 | 2023-03-14 | 江苏师范大学 | 一类glp-1类似物及其应用 |
| WO2024153090A1 (zh) * | 2023-01-17 | 2024-07-25 | 广东众生睿创生物科技有限公司 | 基于glp-1的三重激动剂 |
| WO2024153089A1 (zh) * | 2023-01-17 | 2024-07-25 | 广东众生睿创生物科技有限公司 | 多靶点长效多肽类激动剂 |
| WO2024153091A1 (zh) * | 2023-01-17 | 2024-07-25 | 广东众生睿创生物科技有限公司 | 带有修饰结构的多肽及其应用 |
| CN116712530A (zh) * | 2023-02-03 | 2023-09-08 | 江苏师范大学 | 一类长效GLP-1/glucagon/GIP受体三重激动剂及其应用 |
| CN116712530B (zh) * | 2023-02-03 | 2024-03-08 | 江苏师范大学 | 一类长效GLP-1/glucagon/GIP受体三重激动剂及其应用 |
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| Publication number | Publication date |
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| CN112409460B (zh) | 2022-02-01 |
| CN114349828B (zh) | 2023-12-08 |
| WO2022111370A1 (zh) | 2022-06-02 |
| CN114349828A (zh) | 2022-04-15 |
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