CN111171134A - 胰高血糖素衍生肽及其用途 - Google Patents
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- CN111171134A CN111171134A CN201911102453.4A CN201911102453A CN111171134A CN 111171134 A CN111171134 A CN 111171134A CN 201911102453 A CN201911102453 A CN 201911102453A CN 111171134 A CN111171134 A CN 111171134A
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Abstract
本发明提供一种多肽衍生物、其修饰衍生物或其盐，以及所述多肽衍生物、其修饰衍生物或其盐的用途，所述多肽衍生物、其修饰衍生物或其盐包含具有以下通式Ⅰ序列的多肽：通式Ⅰ：HX2QGTFTSDX10SX12YLX15X16X17X18AX20EFX23X24WLX27X28X29X30X31，其中，X2、X10、X12、X15、X16、X17、X18、X20、X23、X24、X27、X28、X29、X30和X31的定义与权利要求书和说明书的定义一致。本发明的多肽衍生物对GC/GLP‑1受体具有双重激动作用，从而对能量代谢产生协同影响，能够有效降低血糖同时减轻体重、改善体脂水平，药效优于单一的GLP‑1受体激动剂。
Description
技术领域
本发明属于医药生物技术领域，具体涉及一种胰高血糖素衍生肽以及其用途。
背景技术
肥胖是引起多种疾病的风险因素，已成为全球性的公众健康问题。尤其是包括2型糖尿病(T2DM)的代谢综合征、心血管病、非酒精性脂肪肝等常见疾病，其发病率与病程进展与肥胖密切相关。多项大样本临床研究发现，与正常体重人群相比，心血管代谢多重疾病的发病率在BMI25.0–29.9kg/m2、30.0–34.9kg/m2和BMI>35.0kg/m2的超重、肥胖或严重肥胖人群分别高出2倍、5倍、15倍(Lancet 2,e277–e285，2017)。研究表明，80～90％的T2DM患者超重或肥胖，适度的减重(4～5kg)有利于预防和控制病情，包括减少患病率、控制血糖和致残(死)率(Curr.Med.Res.Opin.2011,27(7),1431-1438)。
饮食控制和锻炼是最理想的减轻体重手段，但一般收效不佳。肥胖的药物干预疗效有限或存在多种风险，包括严重的心血管影响和因中枢神经作用引起的精神症状等副作用。至目前为止，少有药物单独使用能够达到超过5-10％的体重减轻幅度。T2DM治疗药物中只有SGLT2抑制剂和GLP-1受体激动剂类对体重控制有良性效果。减肥手术效果显著，但手术风险较大，而且长期效应仍不确定。因此，用于控制体重的药物仍存在巨大的临床需求，兼具原发病症治疗作用并能够安全有效地控制体重的药物是理想的选择。
机体的血糖和能量调节信号系统是由多种因子维持精细的平衡，包括不同的多肽类激素。前胰高血糖(pro-glucagon)是一种具有158个氨基酸的前体多肽，其在不同组织中被加工生成胰高血糖素(GC)、胰高血糖素样肽-1、2(GLP-1，2)及胃泌素等多种胰高血糖素原的衍生肽，这些激素参与葡萄糖体内平衡、胰岛素分泌、胃排空、肠道生长以及食物摄取等多种生理功能的调节。因此，基于胰高血糖素原的肠道激素的治疗已成为代谢病领域深受关注的研究方向。
GC是对应于前胰高血糖素的33至61位氨基酸组成的含29个氨基酸的衍生肽，在胰腺α细胞加工生成，在机体饥饿、寒冷等应激状态下作用于肝脏，通过糖分解和糖异生作用使血糖水平升至正常范围。除升血糖作用外，动物和人体试验结果表明GC还具有发热、增加饱腹感、脂解、脂肪氧化、生酮等作用，长期给药可以改善能量代谢，包括减轻体重，但这些对能量代谢的有益作用因其固有的升糖作用未能得以应用。
GLP-1是对应于前胰高血糖素的72至108位氨基酸组成的含37个氨基酸残基的衍生肽，在机体进餐响应中由肠道L细胞分泌，作用于胰腺β-细胞促进胰岛素分泌、同时拮抗GC受体抑制血糖升高。GLP-1受体激动剂被开发为糖尿病患者的高血糖治疗剂，降血糖的同时保护和增殖胰岛细胞，而且减缓胃排空和抑制食物摄入，可有效减轻体重。已经有7个GLP-1受体激动剂上市，包括短效的艾塞那肽、利拉鲁肽、利西拉来(1～2次/日)、以及长效的阿必鲁泰、杜拉鲁肽、Byuderon、以及索玛鲁肽(1次/周)。GLP-1受体激动剂类药物虽具有安全独特的降血糖作用，但用于减轻体重时，一般需要使用大剂量，而这些药物在大剂量下易产生胃肠道副作用，耐受性差，治疗窗较窄。因此，仍然需要更为耐受的，可有效控制血糖和减轻体重的治疗剂。
胃泌酸调节素(Oxintomodulin，OXM)是前胰高血糖素翻译后修饰加工过程中在肠道产生的激素，在进餐反应中从回肠L-细胞与GLP-1等激素同时分泌。OXM的急性影响包括对胃排空、胃和胰腺的外分泌以及摄食的抑制作用、静息能量消耗等，可产生减轻体重作用。OXM特异的受体至今尚未明确，但研究发现OXM是内源性GCGR/GLP-1R双重激动剂，而且对两个受体的活性效力弱于各受体的天然配体。在动物和人体试验中发现，外周给予OXM可减少摄食量和减轻体重，在肥胖对象中增加代谢率以及特别是与活动相关的能量消耗。尤其是在临床试验中大剂量外周给予OXM，减轻体重的同时恶心、呕吐等常见胃肠道副作用发生概率较低。因此，基于OXM或GLP-1/GCGR双重激动剂的治疗对肥胖症和肥胖型糖尿病显示了潜在的应用价值，但至目前为止，尚无有关药物上市。
发明内容
本发明的一个目的是提供一种胰高血糖素多肽衍生物，所述多肽是基于GC天然序列设计的变体，通过GC/GLP-1受体的双重激动作用对能量代谢产生协同影响，可有效降低血糖、减轻体重、改善体脂水平，比单纯的GLP-1受体激动剂在糖尿病、肥胖、代谢综合征以及非酒精性脂肪肝等疾病状态的改善更具优势。
本发明的另一个目的是提供一种包含本发明的胰高血糖素多肽衍生物的药物组合物。
本发明的又一个目的是提供一种本发明的胰高血糖素多肽衍生物的用途。
本发明的目的是通过以下技术方案来实现的。
一方面，本发明提供一种多肽衍生物、其修饰衍生物或其盐，其包含具有以下通式Ⅰ序列的多肽：
HX2QGTFTSDX10SX12YLX15X16X17X18AX20EFX23X24WLX27X28X29X30X31
通式Ⅰ
其中：
X2为Ser、D-Ser或Aib；
X10为Lys或Tyr；
X12为Lys或Arg；
X15为Asp或Glu；
X16为Ser或Glu；
X17为Arg、Glu或Lys；
X18为Lys、Ala或Arg；
X20为Arg或Lys；
X23为Val或Ile；
X24为Ala、Glu或Lys；
X27为Leu、Val或不存在；
X28为Ala、Gly、Lys、Glu、Z或不存在；
X29为Ala、Glu、Arg、Gly、Z；
X30为Glu、Z；
X31为Z或不存在；
Z为片段肽GGPSSG，X28、X29、X30和X31中有且只有一个为Z；C-末端羧基游离或酰胺化；
同时，X10、X17、X20和X24中有且只有一个为侧链被修饰的Lys。
进一步地，本发明提供一种多肽衍生物、其修饰衍生物或其盐，其包含具有以下通式Ⅰa)序列的多肽：
HX2QGTFTSD X10SKYLE X16X17X18A X20EFX23X24WL X27 X28 X29 X30
通式Ⅰa)
其中，
X2为Ser或Aib；
X10为Tyr或Lys；
X16为Ser或Glu；
X17为Arg、Glu或Lys；
X18为Lys、Ala或Arg；
X20为Arg或Lys；
X23为Val或Ile；
X24为Ala、Glu或Lys；
X27为Leu或不存在；
X28为Glu或不存在；
X29为Ala；
X30为Z，Z为片段肽GGPSSG；
X10、X17、X20和X24中有且只有一个为侧链被修饰的Lys；
C-末端羧基游离或酰胺化。
在本发明优选的实施方案中，所述通式Ⅰa)中，
X2为Aib；
X10为Lys或Tyr；
X16为Glu；
X17为Arg或Lys；
X18为Ala、Lys或Arg；
X20为Lys；
X27不存在；
X28为Glu；
X29为Ala；
X30为Z；
X10和X20中有且只有一个为侧链被修饰的Lys；
C-末端羧基游离或酰胺化。
在一些优选的实施方案中，所述通式Ⅰa)中包含以下氨基酸序列的组合：
X17为Arg且X18为Ala；
X17为Arg且X18为Lys；或
X17为Lys且X18为Arg。
在优选实施方案中，所述通式Ⅰa)中包含以下氨基酸序列的组合：
X23为Val且X24为Ala或Glu；或
X23为Ile且X24为Ala或Glu。
本发明优选的实施方案中，所述多肽衍生物包含具有选自SEQ ID NOs.4-15的序列中的任一个的多肽。
本发明的另一些优选的实施方案中提供的具有通式Ⅰ结构的多肽，所述通式Ⅰ中，
X2为Aib；
X10为Lys或Tyr；
X16为Glu；
X17为Arg或Lys；
X18为Ala、Lys或Arg；
X20为Arg或Lys；
X27不存在；
X28不存在；
X29为Glu；
X30为Z；
X31不存在；
X10和X20中有且只有一个为侧链被修饰的Lys；
C-末端羧基游离或酰胺化。
在本发明优选的实施方案中，所述通式Ⅰ中包含以下氨基酸序列的组合：
X17为Arg且X18为Ala；
X17为Arg且X18为Lys；或
X17为Lys且X18为Arg。
在本发明进一步优选的实施方案中，所述通式Ⅰ中包含以下氨基酸序列的组合：X23为Val且X24为Ala或Glu；或
X23为Ile且X24为Ala或Glu。
本发明优选的实施方案中，所述多肽衍生物包含具有选自SEQ ID NOs.16-27中的任一个序列的多肽。
在本发明优选的实施方案中，所述多肽衍生物，其特征在于当X20为侧链被修饰的Lys时，X10为Tyr。
在本发明的一些实施方案中，所述侧链被修饰的Lys是指所述Lys的侧链ε-氨基通过亲水性连接片段偶联脂肪酸而被修饰。
优选地，所述用于修饰Lys的侧链ε-氨基的亲水性连接片段选自由Glu、γGlu、Gly和Ado(8-氨基-3,6二氧辛酸)中的一种或多种组成的片段，优选为γGlu-γGlu-、Glu-γGlu-、Glu-γGlu-、γGlu-Gly-Gly、γGlu-Gly-γGlu-、γGlu-Ado-Ado-；Ado-Ado-γGlu-、或γGlu-Ado-Ado-γGlu-。
在本发明优选的实施方案中，所述脂肪酸为C14-20的脂肪酸，更优选为C16-20脂肪二酸。
另一方面，本发明提供一种药物组合物，其含有本发明所述的多肽衍生物、其修饰衍生物或其盐。
优选地，所述药物组合物进一步包含一种或多种药学上可接受的辅料。所述药学上可接受的辅料包括载体、稀释剂、水溶性填充剂、pH调节剂、稳定剂、注射用水、渗透压调节剂等。
优选地，所述水溶性填充剂包括但不限于甘露醇、低分子右旋糖酐、山梨醇、聚乙二醇、葡萄糖、乳糖、半乳糖等；所述pH调节剂包括但不限于枸橼酸、磷酸、乳酸、酒石酸、盐酸等有机或无机酸以及氢氧化钾、氢氧化钠、氢氧化铵、碳酸钠、碳酸钾、碳酸铵、碳酸氢钾、碳酸氢钠、碳酸氢铵盐等生理上可接受的无机碱或盐；所述稳定剂包括但不限于EDTA-2Na、硫代硫酸钠、焦亚硫酸钠、亚硫酸钠、磷酸氢二钾、碳酸氢钠、碳酸钠、精氨酸、赖氨酸、谷氨酸、天冬氨酸、聚乙二醇、聚乙烯醇、聚乙烯吡咯烷酮、羧基/羟基纤维素或其衍生物如HPC、HPC-SL、HPC-L或HPMC、环糊精、十二烷基硫酸钠或三羟甲基氨基甲烷等；所述渗透压调节剂包括但不限于氯化钠或氯化钾。
优选地，本发明所述的药物组合物可以静脉、肌肉或皮下注射剂形式或口服、直肠、鼻腔给药。剂量范围可以为5μg-10mg/次，这取决于治疗对象、给药方式、适应症以及其他因素等。
又一方面，本发明提供本发明所述的多肽衍生物、其修饰衍生物或其盐在制备用于治疗代谢性疾病的药物中的应用，优选地，所述代谢性疾病为糖尿病、肥胖、脂肪肝、高血脂症和/或代谢综合征；更优选地，所述脂肪肝为非酒精性脂肪肝。
与单纯的GLP-1受体激动剂相比，本发明的多肽衍生物在更为有效地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，与现有药物相比具有意想不到的有益作用。
胰高血糖素衍生肽的结构：内源性GLP-1是对应于前胰高血糖素的72至108位氨基酸组成的含37个氨基酸残基(7-36/37)的衍生肽,其氨基酸序列为HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR(7-36)(SEQ ID NO.1),HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG(7-37)，其C-端游离或酰胺化。内源性GC是对应于前胰高血糖素的33至61位氨基酸组成的含29个氨基酸的衍生肽，氨基酸序列为：HSQGTFTSDYSKYLDSRRAQDFVQWLMNT(SEQ ID NO.2)，C-端羧基游离。天然GLP-1和GC的氨基酸序列有47％的同源性(Andreas Evers等，J.Med.Chem.2017,60,4293-4303)，二者的N-端序列高度保守，GLP-1对其受体具有高度选择性，而GC同时是GLP-1受体的弱激动剂。因此，基于GC序列设计GLP-1/GCGR双重激动剂是可行的。
OXM的氨基酸序列是HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA(SEQ ID NO.3),包含GC的原序列(1-29)和对应于前胰高血糖素原氨基酸序列82-89的插入肽-1(IP-1，30-37)。OXM对GC/GLP-1R具有双重激动活性，提示对GC序列的C-末端序列进行调整有助于实现对GC/GLP-1R的效价平衡。已经公开的专利技术文件中,如CN200980132562.9、CN201080027026.5、CN201680062196.4是将GC原序列(1-29)的变体，以Exendin-4的C-末端10肽(GPSSGAPPPS缩写为Cex)序列延长C-端。而CN201680036771.3是选择将OXM序列的C-末端插入肽段(KRNRNNIA)以GGPSSG肽段替换的设计方案。这些已有的技术均采取了在保留GC全长序列(1-29)的基础上进行若干位点突变，再以不同肽段延长的设计思路。
基于GC序列的多肽C-末端变化对GC/GLP-1受体的识别极为敏感，尤其是对GC受体的活性。因此，一般认为保留GC序列的C-末端对保留GC受体激动活性很重要。现有技术普遍采取保留GC全长序列(1-29)的基础上个别位点突变，基本属于领域公知的合理替换规则：如，21Asp替换为Glu，24Gln保留或替换为Glu，C-末端27-29片段中的敏感氨基酸如27Met替换为Leu，28Asn替换为Glu或Ala。本发明人在研究中发现即便是采取这些保守方法，再延长C-末端和脂肪酰化修饰，也很难预料能够得到效价平衡的GC/GLP-1受体双重受体激动剂。同时也发现这些措施无助于改善多肽的疏水性，尤其是在长链脂肪酰修饰的条件下，合成和制备难度没有改善，增加制备成本，而且终产物的溶解性差，影响制剂的可操作性。
与现有技术方案不同，本发明提供的技术方案中，多肽主链的设计只保留了GC序列的1-26肽段，并对个别位点进行合理突变的基础上再适当延长C末端，后采取脂肪酰修饰措施，得到了活性效价比平衡而且溶解性、稳定性均佳的GC/GLP-1受体双重受体激动剂。
在本发明的一些特定实施方案中，对GC(1-26)序列的位点16-20进行了合理替换，如，将16Ser替换为Glu,18Arg替换为Ala或Lys，20Gln替换为Lys，这些是领域公知的有利于提高GLP-1受体选择性的设计措施。同时在另一些特定实施方案中，位点24Gln被替换为Glu以调节相应肽段的电荷分布。现有公开的技术方案中，对GC序列的27Met一般是以电荷中性或正电荷氨基酸进行替换，如Leu、Lys，而本发明优选技术方案所提供多肽序列的相应位点是Glu残基，再经插入Ala或直接以含有亲水性氨基酸残基的肽段(GGPSSG)延长C-末端，得到主链序列。如，实施例1中化合物1、2；化合物4-7；化合物10-15；化合物21、22；化合物27-39；和化合物41-81的主链序列。
脂肪酰修饰是本技术领域公知的多肽长效化技术。本发明的实施方案中，在活性肽序列中特定位点的Lys侧链上通过亲水性连接臂修饰了脂肪酰基。在某些实施方案中，所述赖氨酸残基位于10位，在某些实施方案中修饰位点为20位。为改善修饰后多肽的溶解性和保持多肽结构的柔性，以亲水性连接臂连接多肽和脂肪酰修饰基团是必要的。在本发明某些实施方案中所述亲水性连接臂是-γ-Glu-γ-Glu-,在另一些实施方案中则为-γ-Glu-Ado-Ado-γ-Glu；或在另一些实施方案中是-Ado-Ado-γ-Glu。所述脂肪酰基优选是C16-20的单脂肪酸或脂肪二酸。在某些实施方案中，所述脂肪酰基是C16或C18酰基；在某些特定实施方案中是C18、C20二酸单酯酰基。
一般的，对天然序列进行尽可能少的改变有利于保持同源性，但内源性胰高血糖素原序列存在较多的成药性难题：N-端二肽易被体内的二肽激肽酶识别而被水解失活，导致血浆半衰期短(≤12min)；物理性质不稳定，即等电点(pI)7.6，呈中性，而且疏水,溶解性差，很容易在溶液中聚集沉淀；序列中有Met、Asp、Asn等易于氧化或消旋的氨基酸，导致化学性质不稳定。
为提高所述多肽的代谢稳定性，本发明优选实施方案中，2Ser通常被替换为Aib或D-Ser，以保证多肽活性的持续发挥。与此同时本发明优选的实施方案中，进一步对GC序列中的敏感氨基酸进行了替换，如15，21Asp替换为Glu，而且调整后的C-末端肽段不含有Met、Gln、Asn等敏感氨基酸残基，从而大幅提高了化学稳定性。因此，上述调整和改进措施对活性平衡和理化性质的改善起到了多重有益作用取得了优于现有技术的明显效果。
本发明提供GLP-1/胰高血糖素双重激动作用的肽，通过本发明前述的结构设计，具有以下活性特点：本发明提供的多肽与GLP-1/GCGR各受体的天然配体相比至少具有1％的受体激动活性。通过一系列的结构优化设计，对GLP-1受体的激动作用强度与内源性天然配体GLP-1(7-36/37)相当或相当于天然配体的150％，200％，300％，500％，1000％或更多。对胰高血糖素受体的激动活性与内源性配体(GC)相当或相当于内源性激动剂作用强度的10～1000％。在某些实施方案中，本发明提供的多肽具有与内源性配体相等或更强的受体激动活性。在另一些实施方案中，对GLP-1受体的激动作用强于对胰高血糖素受体，或对两个受体的激动作用强度相等。对GLP-1和胰高血糖素受体的相对活性强度可以用效价比表示，即本发明提供的包含通式Ⅰ序列的多肽对GLP-1/胰高血糖素受体的效价比包括但不限于10:1,9:1，8:1，7:1，6:1，3:1,1:1至1:10。
本发明提供的具有通式Ⅰ结构的多肽衍生物的基本肽链可以通过本领域公知的方法制备得到：
1)通过常规固相或液相方法逐步或通过片段组装合成；
2)在宿主细胞中表达编码多肽的核酸构建体，并从宿主细胞培养物回收表达产物；
3)影响编码多肽的核酸构建体的无细胞体外表达，并回收表达产物；
或通过方法1)、2)或3)的任意组合来获得肽片段，随后连接这些片段以获得目标肽。
本发明提供的实施方案中优选地，使用Fmoc固相合成方法制备得到目标肽，该技术为本领域技术人员所熟知的。
取代基可以通过上述肽合成步骤逐步合成引入。使用适当保护基的取代基，如，Fmoc-8-氨基-3,6二氧杂辛酸，和Fmoc-γ-Glu-OtBu。脂肪链部分的引入，尤其是脂肪二酸单酯酰基，可以使用但不限于C18、C20烷酸单叔丁酯来实现。在每个偶联步骤后，未反应的中间物可以使用过量的乙酸酐和吡啶进行封闭。可修饰的Lys的ε-氨基可以使用Mtt或Dde保护。
纯化：缀合反应之后，可以通过本领域公知的合适方法将目标产物分离。适用的方法包括但不限于超滤法、透析法或色谱法等。本发明实施方案中优选采用制备型高效液相色谱法纯化。
受体活性测定：本发明的实施方案中通过GLP-1/GC受体介导的体外cAMP产生的影响评价了所述多肽对GLP-1/GC受体的作用。
对体重和血糖的调节作用：本发明的实施方案中采用高脂饮食肥胖型糖尿病小鼠(Dio)模型评价了本发明提供多肽的对体重和血糖的影响，结果表明本发明提供的多肽衍生物具有显著的减轻体重和降血糖作用，体重减轻作用显著优于阳性对照药，提示在制备肥胖等代谢性疾病的控制和糖尿病的治疗药物方面具有潜在优势。
附图说明
以下，结合附图来详细说明本发明的实施方案，其中：
图1为实施例3中化合物1、4、6、22对Dio小鼠体重的影响，图中样品号1#-4#分别为化合物1、化合物4、化合物6和化合物22。
具体实施方式
下面结合具体实施例对本发明作进一步的说明。本实施例仅为解释本发明，不意味以任何方式限制本发明内容。
氨基酸缩写的说明：
Gly:甘氨酸(G)
Ala:丙氨酸(A)
Val:缬氨酸(V)
Leu:亮氨酸(L)
Phe:苯丙氨酸(F)
Trp:色氨酸(W)
Ser:丝氨酸(S)
Thr:苏氨酸(T)
Glu:谷氨酸(E)
Gln:谷氨酰胺(Q)
Asp:天冬氨酸(D)
Asn:天冬酰胺(N)
Tyr:苯丙氨酸(Y)
Arg:精氨酸(R)
Lys:赖氨酸(K)
His:组氨酸(H)
Aib:aα-氨基异丁酸
Ado:8-氨基-3,6-二氧杂辛酸
试剂缩写的说明
Boc:叔丁氧基羰基
Tert-Bu:叔丁基
DCM:二氯甲烷
DIC：二异丙基碳二亚胺
Fmoc:9-芴甲氧基羰基
HoBt:1-羟基苯并三唑
HBTU:2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基-脲鎓六氟磷酸酯
HATU:O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基-脲鎓六氟磷酸酯
Mtt:4-甲基三苯甲基
NMP:N-甲基吡咯烷酮
DMF:二甲基甲酰胺
Pbf:2，2，4，6，7-五甲基二氢苯并呋喃
Dde:1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基-丁基
Trt:三苯基甲基
EDT:乙二硫醇
TFA:三氟乙酸
TIS:三异丙基硅烷
FBS:胎牛血清
实施例1
本发明提供的多肽基本线性序列以及侧链修饰衍生肽按照以下通用方法制备：
1)合成：采用Fmoc策略，用PSI200型多肽合成仪，按照如下步骤逐步合成：
a)在活化剂系统存在下由树脂固相载体和Fmoc保护的C-端氨基酸偶联得到Fmoc-氨基酸-树脂；其中，合成C-端酰胺化多肽采用氨基树脂，如Rink Amide AM，Rink Amide，Rink MBHA等；Fmoc-氨基酸和树脂比(mol/mol)为3～5:1,偶联活化剂为HOBT/DIC或HOBT/HBTU/DIEA。
b)肽链的延长：通过固相合成法按照肽序列氨基酸顺序连接氨基酸，得到N-端和侧链保护的肽－树脂偶联物；带侧链氨基酸采取如下保护措施：色氨酸用Boc，谷氨酸用OtBu，赖氨酸用Boc，谷氨酰胺用Trt，酪氨酸用tBu，丝氨酸用Trt或tBu，天冬氨酸用OtBu，苏氨酸用tBu，半胱氨酸用Trt，精氨酸用Pbf保护,组氨酸(Trt)的α-氨基用Boc保护，可修饰的赖氨酸的ε-氨基用Dde保护。使用的偶联活化剂为HOBT/DIC、HOBT/HBTU/DIEA和HOBT/HATU/DIEA，茚三酮法检测反应终点，脱保护剂为含20％哌啶的NMP(DMF)溶液。
c)赖氨酸的ε-氨基脱保护：
上述步骤中合成完成的全保护多肽-树脂以NMP-DCM(1：1V/V)洗涤3次，加入新鲜制备的2.0％水合肼的NMP溶液，在室温下搅拌12.0分钟，过滤，重复两次，用DCM和NMP各洗涤树脂三次。
d)赖氨酸侧链的修饰:
赖氨酸的ε-氨基脱保护完成后，按比例(树脂：连接基1:4-5(mol/mol))加入Fmoc-Ado或Fmoc-γ-Glu(tBu)以及HOBt/HBTU,DIEA,搅拌反应2.0-4.0小时，脱Fmoc保护，同法继续连接所需链长的连接臂和脂肪酰基。重复两次后反应仍未完全，加过量的乙酸酐/吡啶封闭，继续下一步反应。
e)多肽的裂解：全保护肽-树脂先用NMP洗涤，后用DCM洗涤3-6次去除NMP,加入TFA/EDT/TIS/H2O(92.5:2.5:2.5:2.5v/v)溶液，置室温氮气保护下搅拌90min,脱保护和脱树脂。抽滤得滤液，用过量冰乙醚沉淀粗多肽，离心，收集沉淀，再用少量乙醚洗涤沉淀，真空下干燥，得到多肽粗品。
2)纯化：将多肽粗品溶解于水或10-15％乙腈(10-50mg/ml)，采用制备型HPLC法，C8或C18色谱柱，乙腈－水－三氟乙酸系统分离纯化，浓缩，冻干，得多肽纯品(纯度≥97％)。
以上述方法制备得到以下结构多肽衍生物。
表1合成的化合物
*：-γE-γE-OC16H31
**:-Ado-Ado-γE-OC17H32COOH
***:-Ado-Ado-γE-OC19H36COOH
实施例2对GLP-1/GC受体的作用
通过对GLP-1/GC受体介导的体外cAMP产生的影响评价所述多肽对GLP-1/GC受体的作用。
将转染有人GLP-1受体的中国豚鼠非细胞和转染GC受体的HEK293细胞接种到96孔培养板，(200000个/孔)，以Hanks’平衡盐缓冲液洗涤后，与不同浓度的受试多肽样品(10-5～10-12mol/L),在200mmol/L 3-异丁基-1-甲基茜草黄素存在下于37℃共孵20min。去除介质，溶解细胞，测定cAMP值,测定方法参照分析试剂盒说明。用Origin软件计算50％有效浓度(EC50)。结果见表2。
表2多肽对GLP-1/GC受体的激动作用
表2显示的体外受体激动活性结果表明，具有本发明的氨基酸序列的多肽衍生物具有GLP-1/GC受体的双重激动活性，其中，在相同条件下，具有C-端27位到末端序列为EAGGPSSG或EGGPSSG的多肽衍生物，尤其是前者，其活性强度和效价比更优于具有其他末端序列的多肽衍生物。优选多肽衍生物的效价比在10：1～1：10的均衡范围内，实现了较好的GLP-1/GC受体的双重激动活性。
实施例3
实施例1代表性化合物1、4、6、22对Dio小鼠体重和血糖的影响
1)对体重的影响
C57BL/6J小鼠，35只，模型组(n＝30)用H10060高脂饲料饲养饮食诱导肥胖(DIO)，空白对照组(n＝5)采用标准饲料饲养，均饲养34周。首次给药前一天，模型组按照体重随机分组(平均体重范围45.0-52.0g)，每组5只，分别为模型对照组、阳性对照组(索玛鲁肽)、受试样品组(1#-4#分别为化合物1、化合物4、化合物6和化合物22)。空白对照组、模型对照组每天皮下给予生理盐水，阳性对照组、受试样品组每天皮下注射给药，共给药14天。每天称量记录动物体重，末次给药日与起始体重比较，计算体重变化率(％)。结果见表3和图1。
计算公式：(起始体重-末次体重)/起始体重＝体重变化率(％)
计算结果正值表示降低，负值表示升高。
表3化合物给药14天对DIO鼠体重的影响(％)
| 空白对照组 | 模型对照组 | 阳性对照组 | 1# | 2# | 3# | 4# |
| 2.51 | 2.13 | 13.20 | 28.3 | 22.0 | 22.0 | 26.0 |
2)对糖负荷模型动物的降血糖作用：
DIO鼠禁食16h，皮下注射给药1小时后，腹腔给予葡萄糖溶液(1g/kg)进行糖耐量试验，于给糖后0.5、1、1.5h分别测定血糖值，计算血糖浓度曲线下面积(AUC)与模型对照组比较，计算血糖抑制率(％)。结果见表4。
表4化合物对DIO鼠糖负荷血糖水平的影响
**：与模型对照组相比P＜0.01；*：与模型对照组相比P＜0.05
结论：如表3和表4所示，与模型组相比，阳性药和本发明的受试化合物显示了显著的体重降低作用并能明显改善糖耐量。本发明的受试化合物具有与阳性对照药相当的降血糖作用，并且与单纯的GLP-1受体激动剂(阳性对照药)相比，能够更为显著地降低体重。
实施例4
实施例1中化合物27、35、54、57和66对Dio小鼠体重和血糖的影响
方法同实施例3，对体重的影响试验结果见表5，对血糖的影响见表6。表中5#-9#分别为化合物27、化合物35、化合物54、化合物57和化合物66。
表5.化合物给药14天对DIO鼠体重的影响
| 空白对照组 | 模型对照组 | 阳性对照组 | 5# | 6# | 7# | 8# | 9# |
| -1.43 | 9.52 | 16.29 | 27.74 | 28.32 | 21.45 | 24.1 | 19.9 |
表6化合物对DIO鼠糖负荷血糖水平的影响
**：与模型对照组相比P＜0.01；*：与模型对照组相比P＜0.05
结论：如表5、表6所示，化合物27、化合物35、化合物54、化合物57和化合物66与未经治疗的模型对照组相比，糖耐量显著改善(P＜0.01)，体重明显减轻；受试给药组均显示了与阳性药相当的降血糖活性，同时与阳性药相比具有更显著的减轻体重的作用。
实施例5
实施例1化合物短期给药对模型动物摄食量和体重的影响
方法：饮食诱导的肥胖小鼠(DIO)，平均体重52.5g，每组5只，分为模型对照、受试组。受试样品以pH7.4的10mMPBS溶解，以30nmol/kg剂量每隔24小时注射1次，给药2次，模型组注射溶剂，测定48小时的摄食量和体重变化，计算相对于给药前一天的变化率。结果见表7。
表7受试化合物短期给药对DIO鼠摄食量和体重的影响
注：+：增加；-：减少或降低
表7中的结果显示，与模型组相比，受试化合物给药期间摄食量明显减少，体重显著降低，说明受试化合物的降体重作用部分与摄食量减少有关。
实施例6
实施例1中化合物的溶解性考察
称取2mg化合物，分别以1ml不同浓度(10、20mM)、不同pH值(7.5、8.0)的磷酸盐缓冲液溶解，离心，取上清液，HPLC法(色谱柱：Aeris widepore XB-C18 3.6mm,4.6×150mm；流动相：A:0.05％TFA,B:95％乙腈；检测波长：214nm)测定峰面积，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。结果见表8。
表8.实施例1中化合物在磷酸盐缓冲液中的溶解性
注：-：未测
结论：如表8所示，与胰高血糖素相比，本发明的化合物在生理pH可接受条件下的溶解度得到提高，其中，本发明优选的技术方案，即缩短GC(1-26)序列的延长肽衍生物与保守原序列突变延长肽方案相比(化合物3、化合物16,化合物25,化合物26)相比，溶解性大幅增加。即使是在长链脂肪酰修饰的情况下，化合物在生理pH可接受条件下的水溶性也得到提高，更有利于制成药物制剂。
实施例7
实施例1化合物的化学稳定性
通过加速稳定性试验评价了本发明的化合物在注射溶液体系中的化学稳定性。
方法：称取适量实施例1化合物，以10mM浓度的pH8.5磷酸氢钠缓冲液溶解，以0.1N盐酸调节溶液最终pH值至7.3，加入适量吐温80以及苯酚，于10、37℃放置14天，HPLC-UV检测，以峰面积归一化法得出主峰面积，考察与0日比较的变化情况。结果见表9。
HPLC检测方法同实施例6，根据色谱峰分离情况适当调整流动相梯度。
表9化合物在注射溶剂体系下10、37℃放置14天的纯度变化
结论：表9的结果表明，在初步注射剂制剂处方体系中，受试化合物的化学稳定性在制剂学可接受的范围内，具有可优化实施的潜力。
序列表
<110> 天津药物研究院有限公司
<120> 胰高血糖素衍生肽及其用途
<130> DIC19110098
<150> 2018113382182
<151> 2018-11-12
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His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Xaa Glu
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Ser Gly
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His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu
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Ser Gly
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<222> (15)..(15)
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His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu
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Ser Gly
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<222> (15)..(15)
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Ser Gly
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<222> (15)..(15)
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<222> (24)..(24)
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His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu
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Ser Gly
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<213> 人工序列(Artificial Sequence)
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<222> (2)..(2)
<223> Xaa为Ser或Aib
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<222> (10)..(10)
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<222> (24)..(24)
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<221> UNSURE
<222> (15)..(15)
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<221> UNSURE
<222> (24)..(24)
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His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Xaa Glu
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Ser Gly
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<222> (15)..(15)
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His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Xaa Glu
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Ser Gly
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<222> (2)..(2)
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<222> (10)..(10)
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<222> (24)..(24)
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<222> (15)..(15)
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His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Xaa Glu
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Ser Gly
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<213> 人工序列(Artificial Sequence)
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<221> MUTAGEN
<222> (2)..(2)
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<221> UNSURE
<222> (15)..(15)
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<221> UNSURE
<222> (24)..(24)
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His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Xaa Glu
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20 25 30
Ser Gly
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<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
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<222> (10)..(10)
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<222> (24)..(24)
<223> Xaa为Ala或Glu
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<222> (2)..(2)
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<221> UNSURE
<222> (15)..(15)
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<221> UNSURE
<222> (24)..(24)
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<400> 15
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Xaa Trp Leu Glu Ala Gly Gly Pro Ser
20 25 30
Ser Gly
<210> 16
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
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<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
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<221> BINDING
<222> (10)..(10)
<223> 赖氨酸氨基被修饰
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<222> (15)..(15)
<223> Xaa为Asp或Glu
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<221> MUTAGEN
<222> (24)..(24)
<223> Xaa为Ala或Glu
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (15)..(15)
<223> The 'Xaa' at location 15 stands for Gln, Arg, Pro, or Leu.
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<221> UNSURE
<222> (24)..(24)
<223> The 'Xaa' at location 24 stands for Gln, Arg, Pro, or Leu.
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His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Arg Ala Ala Lys Glu Phe Ile Xaa Trp Leu Glu Gly Gly Pro Ser Ser
20 25 30
Gly
<210> 17
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
<220>
<221> MUTAGEN
<222> (15)..(15)
<223> Xaa为Asp或Glu
<220>
<221> BINDING
<222> (20)..(20)
<223> 赖氨酸氨基被修饰
<220>
<221> MUTAGEN
<222> (24)..(24)
<223> Xaa为Ala或Glu
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (15)..(15)
<223> The 'Xaa' at location 15 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (24)..(24)
<223> The 'Xaa' at location 24 stands for Gln, Arg, Pro, or Leu.
<400> 17
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Arg Ala Ala Lys Glu Phe Ile Xaa Trp Leu Glu Gly Gly Pro Ser Ser
20 25 30
Gly
<210> 18
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
<220>
<221> MUTAGEN
<222> (15)..(15)
<223> Xaa为Asp或Glu
<220>
<221> BINDING
<222> (20)..(20)
<223> 赖氨酸氨基被修饰
<220>
<221> MUTAGEN
<222> (24)..(24)
<223> Xaa为Ala或Glu
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (15)..(15)
<223> The 'Xaa' at location 15 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (24)..(24)
<223> The 'Xaa' at location 24 stands for Gln, Arg, Pro, or Leu.
<400> 18
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Arg Ala Ala Lys Glu Phe Val Xaa Trp Leu Glu Gly Gly Pro Ser Ser
20 25 30
Gly
<210> 19
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
<220>
<221> MUTAGEN
<222> (15)..(15)
<223> Xaa为Asp或Glu
<220>
<221> BINDING
<222> (20)..(20)
<223> 赖氨酸氨基被修饰
<220>
<221> BINDING
<222> (24)..(24)
<223> Xaa为Ala或Glu
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (15)..(15)
<223> The 'Xaa' at location 15 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (24)..(24)
<223> The 'Xaa' at location 24 stands for Gln, Arg, Pro, or Leu.
<400> 19
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Arg Lys Ala Lys Glu Phe Val Xaa Trp Leu Glu Gly Gly Pro Ser Ser
20 25 30
Gly
<210> 20
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
<220>
<221> MUTAGEN
<222> (15)..(15)
<223> Xaa为Asp或Glu
<220>
<221> BINDING
<222> (20)..(20)
<223> 赖氨酸氨基被修饰
<220>
<221> MUTAGEN
<222> (24)..(24)
<223> Xaa为Ala或Glu
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (15)..(15)
<223> The 'Xaa' at location 15 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (24)..(24)
<223> The 'Xaa' at location 24 stands for Gln, Arg, Pro, or Leu.
<400> 20
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Arg Lys Ala Lys Glu Phe Ile Xaa Trp Leu Glu Gly Gly Pro Ser Ser
20 25 30
Gly
<210> 21
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
<220>
<221> MUTAGEN
<222> (15)..(15)
<223> Xaa为Asp或Glu
<220>
<221> BINDING
<222> (20)..(20)
<223> 赖氨酸氨基被修饰
<220>
<221> MUTAGEN
<222> (24)..(24)
<223> Xaa为Ala或Glu
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (15)..(15)
<223> The 'Xaa' at location 15 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (24)..(24)
<223> The 'Xaa' at location 24 stands for Gln, Arg, Pro, or Leu.
<400> 21
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Ile Xaa Trp Leu Glu Gly Gly Pro Ser Ser
20 25 30
Gly
<210> 22
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
<220>
<221> MUTAGEN
<222> (15)..(15)
<223> Xaa为Asp或Glu
<220>
<221> BINDING
<222> (20)..(20)
<223> 赖氨酸氨基被修饰
<220>
<221> MUTAGEN
<222> (24)..(24)
<223> Xaa为Ala或Glu
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (15)..(15)
<223> The 'Xaa' at location 15 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (24)..(24)
<223> The 'Xaa' at location 24 stands for Gln, Arg, Pro, or Leu.
<400> 22
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Xaa Trp Leu Glu Gly Gly Pro Ser Ser
20 25 30
Gly
<210> 23
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
<220>
<221> BINDING
<222> (10)..(10)
<223> 赖氨酸氨基被修饰
<220>
<221> MUTAGEN
<222> (15)..(15)
<223> Xaa为Asp或Glu
<220>
<221> MUTAGEN
<222> (24)..(24)
<223> Xaa为Ala或Glu
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (15)..(15)
<223> The 'Xaa' at location 15 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (24)..(24)
<223> The 'Xaa' at location 24 stands for Gln, Arg, Pro, or Leu.
<400> 23
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Arg Ala Ala Lys Glu Phe Val Xaa Trp Leu Glu Gly Gly Pro Ser Ser
20 25 30
Gly
<210> 24
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
<220>
<221> BINDING
<222> (10)..(10)
<223> 赖氨酸氨基被修饰
<220>
<221> MUTAGEN
<222> (15)..(15)
<223> Xaa为Asp或Glu
<220>
<221> MUTAGEN
<222> (24)..(24)
<223> Xaa为Ala或Glu
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (15)..(15)
<223> The 'Xaa' at location 15 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (24)..(24)
<223> The 'Xaa' at location 24 stands for Gln, Arg, Pro, or Leu.
<400> 24
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Arg Lys Ala Lys Glu Phe Val Xaa Trp Leu Glu Gly Gly Pro Ser Ser
20 25 30
Gly
<210> 25
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
<220>
<221> BINDING
<222> (10)..(10)
<223> 赖氨酸氨基被修饰
<220>
<221> MUTAGEN
<222> (15)..(15)
<223> Xaa为Asp或Glu
<220>
<221> MUTAGEN
<222> (24)..(24)
<223> Xaa为Ala或Glu
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (15)..(15)
<223> The 'Xaa' at location 15 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (24)..(24)
<223> The 'Xaa' at location 24 stands for Gln, Arg, Pro, or Leu.
<400> 25
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Arg Lys Ala Lys Glu Phe Ile Xaa Trp Leu Glu Gly Gly Pro Ser Ser
20 25 30
Gly
<210> 26
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
<220>
<221> BINDING
<222> (10)..(10)
<223> 赖氨酸氨基被修饰
<220>
<221> MUTAGEN
<222> (15)..(15)
<223> Xaa为Asp或Glu
<220>
<221> MUTAGEN
<222> (24)..(24)
<223> Xaa为Ala或Glu
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (15)..(15)
<223> The 'Xaa' at location 15 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (24)..(24)
<223> The 'Xaa' at location 24 stands for Gln, Arg, Pro, or Leu.
<400> 26
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Ile Xaa Trp Leu Glu Gly Gly Pro Ser Ser
20 25 30
Gly
<210> 27
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Ser或Aib
<220>
<221> BINDING
<222> (10)..(10)
<223> 赖氨酸氨基被修饰
<220>
<221> MUTAGEN
<222> (15)..(15)
<223> Xaa为Asp或Glu
<220>
<221> MUTAGEN
<222> (24)..(24)
<223> Xaa为Ala或Glu
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (15)..(15)
<223> The 'Xaa' at location 15 stands for Gln, Arg, Pro, or Leu.
<220>
<221> UNSURE
<222> (24)..(24)
<223> The 'Xaa' at location 24 stands for Gln, Arg, Pro, or Leu.
<400> 27
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Xaa Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Xaa Trp Leu Glu Gly Gly Pro Ser Ser
20 25 30
Gly
<210> 28
<211> 34
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Aib
<220>
<221> BINDING
<222> (17)..(17)
<223> 赖氨酸氨基被修饰
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<400> 28
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu
1 5 10 15
Lys Arg Ala Arg Glu Phe Val Ala Trp Leu Leu Glu Gly Gly Pro Ser
20 25 30
Ser Gly
<210> 29
<211> 34
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Aib
<220>
<221> BINDING
<222> (10)..(10)
<223> 赖氨酸氨基被修饰
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<400> 29
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Glu Glu
1 5 10 15
Arg Ala Ala Lys Glu Phe Val Ala Trp Leu Lys Glu Gly Gly Pro Ser
20 25 30
Ser Gly
<210> 30
<211> 36
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Aib
<220>
<221> BINDING
<222> (10)..(10)
<223> 赖氨酸氨基被修饰
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<400> 30
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Glu Glu
1 5 10 15
Arg Ala Ala Lys Glu Phe Val Glu Trp Leu Val Lys Gly Glu Gly Gly
20 25 30
Pro Ser Ser Gly
35
<210> 31
<211> 35
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Aib
<220>
<221> BINDING
<222> (10)..(10)
<223> 赖氨酸氨基被修饰
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<400> 31
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Glu Ser
1 5 10 15
Glu Arg Ala Lys Glu Phe Val Glu Trp Leu Val Lys Glu Gly Gly Pro
20 25 30
Ser Ser Gly
35
<210> 32
<211> 35
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Aib
<220>
<221> BINDING
<222> (17)..(17)
<223> 赖氨酸氨基被修饰
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<400> 32
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu
1 5 10 15
Lys Arg Ala Arg Glu Phe Val Glu Trp Leu Leu Glu Ala Gly Gly Pro
20 25 30
Ser Ser Gly
35
<210> 33
<211> 34
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Aib
<220>
<221> BINDING
<222> (10)..(10)
<223> 赖氨酸氨基被修饰
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<400> 33
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Glu Glu
1 5 10 15
Arg Ala Ala Lys Glu Phe Ile Ala Trp Leu Leu Glu Gly Gly Pro Ser
20 25 30
Ser Gly
<210> 34
<211> 35
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Aib
<220>
<221> BINDING
<222> (10)..(10)
<223> 赖氨酸氨基被修饰
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<400> 34
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Glu Glu
1 5 10 15
Arg Ala Ala Lys Glu Phe Val Glu Trp Leu Leu Glu Ala Gly Gly Pro
20 25 30
Ser Ser Gly
35
<210> 35
<211> 35
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为Aib
<220>
<221> BINDING
<222> (20)..(20)
<223> 赖氨酸氨基被修饰
<220>
<221> UNSURE
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for Gln, Arg, Pro, or Leu.
<400> 35
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Glu Trp Leu Leu Glu Ala Gly Gly Pro
20 25 30
Ser Ser Gly
35
Claims (15)
1.一种多肽衍生物、其修饰衍生物或其盐，其特征在于，包含具有以下通式Ⅰ序列的多肽：
HX2QGTFTSDX10SX12YLX15X16X17X18AX20EFX23X24WLX27X28X29X30X31
通式Ⅰ
其中：
X2为Ser、D-Ser或Aib；
X10为Lys或Tyr；
X12为Lys或Arg；
X15为Asp或Glu；
X16为Ser或Glu；
X17为Arg、Glu或Lys；
X18为Lys、Ala或Arg；
X20为Arg或Lys；
X23为Val或Ile；
X24为Ala、Glu或Lys；
X27为Leu、Val或不存在；
X28为Ala、Gly、Lys、Glu、Z或不存在；
X29为Ala、Glu、Arg、Gly或Z；
X30为Glu或Z；
X31为Z或不存在；
Z为片段肽GGPSSG，X28、X29、X30和X31中有且只有一个为Z；
C-末端羧基游离或酰胺化；
同时，X10、X17、X20和X24中有且只有一个为侧链被修饰的Lys。
2.如权利要求1所述的多肽衍生物、其修饰衍生物或其盐，其包含具有以下通式Ⅰa)序列的多肽：
HX2QGTFTSD X10SKYLE X16X17X18A X20EFX23X24WL X27 X28 X29 X30
通式Ⅰa)
其中，
X2为Ser或Aib；
X10为Tyr或Lys；
X16为Ser或Glu；
X17为Arg、Glu或Lys；
X18为Lys、Ala或Arg；
X20为Arg或Lys；
X23为Val或Ile；
X24为Ala、Glu或Lys；
X27为Leu或不存在；
X28为Glu或不存在；
X29为Ala；
X30为Z，Z为片段肽GGPSSG；
X10、X17、X20和X24中有且只有一个为侧链被修饰的Lys；
C-末端羧基游离或酰胺化。
3.如权利要求2所述的多肽衍生物、其修饰衍生物或其盐，其特征在于，所述通式Ⅰa)中，
X2为Aib；
X16为Glu；
X17为Arg或Lys；
X20为Lys；
X27不存在；
X28为Glu；
X30为Z；
X10和X20中有且只有一个为侧链被修饰的Lys。
4.如权利要求2或3所述的多肽衍生物、其修饰衍生物或其盐，其特征在于，所述通式Ⅰa)中包含以下氨基酸序列的组合：
X17为Arg且X18为Ala；
X17为Arg且X18为Lys；或
X17为Lys且X18为Arg。
5.如权利要求2-4中任一项所述的多肽衍生物、其修饰衍生物或其盐，其特征在于，所述通式Ⅰa)中包含以下氨基酸序列的组合：
X23为Val且X24为Ala或Glu；或
X23为Ile且X24为Ala或Glu。
6.如权利要求1所述的多肽衍生物、其修饰衍生物或其盐，其特征在于，所述通式Ⅰ中，
X2为Aib；
X16为Glu；
X17为Arg或Lys；
X27不存在；
X28不存在；
X29为Glu；
X30为Z；
X31不存在；
X10和X20中有且只有一个为侧链被修饰的Lys。
7.如权利要求6所述的多肽衍生物、其修饰衍生物或其盐，其特征在于，所述通式Ⅰ中包含以下氨基酸序列的组合：
X17为Arg且X18为Ala；
X17为Arg且X18为Lys；或
X17为Lys且X18为Arg。
8.如权利要求6或7所述的多肽衍生物、其修饰衍生物或其盐，其特征在于，所述通式Ⅰ中包含以下氨基酸序列的组合：
X23为Val且X24为Ala或Glu；或
X23为Ile且X24为Ala或Glu。
9.如权利要求1-8中任一项所述的多肽衍生物、其修饰衍生物或其盐，其特征在于，当X20为侧链被修饰的Lys时，X10为Tyr。
10.如权利要求1-9中任一项所述的多肽衍生物、其修饰衍生物或其盐，其特征在于，所述侧链被修饰的Lys是指所述Lys的侧链ε-氨基通过亲水性连接片段偶联脂肪酸而被修饰。
11.如权利要求10所述的多肽衍生物、其修饰衍生物或其盐，其特征在于，所述亲水性连接片段选自由Glu、γGlu、Gly和Ado(8-氨基-3,6二氧辛酸)中的一种或多种组成的片段；所述的亲水性连接片段优选为γGlu-γGlu-、Glu-γGlu-、Glu-γGlu-、γGlu-Gly-Gly、γGlu-Gly-γGlu-、γGlu-Ado-Ado-；Ado-Ado-γGlu-、或γGlu-Ado-Ado-γGlu-。
12.如权利要求10所述的多肽衍生物、其修饰衍生物或其盐，其特征在于，所述脂肪酸为C14-20的脂肪酸；更优选为C16-20脂肪二酸。
13.如权利要求1所述的多肽衍生物、其修饰衍生物或其盐，所述多肽的序列选自SEQID NOs.4-34中的任一个。
14.一种药物组合物，其含有权利要求1-13中任一项所述的多肽衍生物、其修饰衍生物或其盐和任选的药学上可接受的辅料。
15.如权利要求1-13中任一项所述的多肽衍生物、其修饰衍生物或其盐在制备用于治疗代谢性疾病的药物中的应用，优选地，所述代谢性疾病为糖尿病、肥胖、脂肪肝、高血脂症和/或代谢综合征；更优选地，所述脂肪肝为非酒精性脂肪肝。
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| CN116891522B (zh) * | 2022-04-01 | 2024-05-14 | 南京知和医药科技有限公司 | 一种长效胰高血糖素样肽-1衍生物及其制备方法和用途 |
| CN116970064A (zh) * | 2022-04-29 | 2023-10-31 | 苏州星洲生物科技有限公司 | Glp-1/gcg受体共激动剂、包含其的药物组合物及其用途 |
| CN115536739B (zh) * | 2022-07-04 | 2023-04-14 | 北京惠之衡生物科技有限公司 | 一种glp-1受体和gcg受体共激动多肽衍生物的制备方法 |
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| CN107735100A (zh) * | 2015-06-22 | 2018-02-23 | 伊莱利利公司 | 胰高血糖素和glp‑1协同激动剂化合物 |
| CN107987152A (zh) * | 2017-11-24 | 2018-05-04 | 江苏师范大学 | 霉酚酸-非洲爪蟾胰高血糖素样肽-1缀合肽及其用途 |
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| TR200100079T2 (tr) * | 1998-06-12 | 2001-06-21 | Bionebraska, Inc. | Glikoza karşı ß-hücre tepkisini arttıran glukagon benzeri peptid-1 |
| CL2009001424A1 (es) * | 2008-06-17 | 2010-04-30 | Univ Indiana Res & Tech Corp | Peptido tipo glucagon; dimero que comprende dos de dichos peptidos; composicion farmaceutica que lo comprende; y su uso para tratar diabetes o inducir perdida de peso. |
| IN2012DN00377A (zh) * | 2009-06-16 | 2015-08-21 | Univ Indiana Res & Tech Corp | |
| KR20150023013A (ko) * | 2012-06-21 | 2015-03-04 | 인디애나 유니버시티 리서치 앤드 테크놀로지 코퍼레이션 | 수용체 활성을 나타내는 글루카곤 유사체 |
| TWI674270B (zh) * | 2012-12-11 | 2019-10-11 | 英商梅迪繆思有限公司 | 用於治療肥胖之升糖素與glp-1共促效劑 |
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| EP3882263A4 (en) | 2022-08-31 |
| JP2022507239A (ja) | 2022-01-18 |
| CN111171134B (zh) | 2023-08-15 |
| WO2020103729A1 (zh) | 2020-05-28 |
| EP3882263A1 (en) | 2021-09-22 |
| KR20210091230A (ko) | 2021-07-21 |
| US20240252592A1 (en) | 2024-08-01 |
| JP7350851B2 (ja) | 2023-09-26 |
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