CN112898405A - 多肽化合物及其在预防或治疗糖尿病或糖尿病并发症中的应用 - Google Patents
多肽化合物及其在预防或治疗糖尿病或糖尿病并发症中的应用 Download PDFInfo
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- CN112898405A CN112898405A CN202110087877.9A CN202110087877A CN112898405A CN 112898405 A CN112898405 A CN 112898405A CN 202110087877 A CN202110087877 A CN 202110087877A CN 112898405 A CN112898405 A CN 112898405A
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Abstract
本发明公开一种多肽化合物及其在预防或治疗糖尿病或糖尿病并发症中的应用,该多肽化合物显示出了良好的长效降血糖作用和糖尿病肾病的治疗效果;同时具有高酶解稳定性、高生物活性、无不良发应发生等效果,可以用于制备用于治疗摄食过量、肥胖症和超重、胆固醇升高、糖尿病及糖尿病肾病药物。
Description
技术领域
本发明属于生物化学技术领域,具体而言,本发明涉及一类多肽化合物及其在预防或治疗糖尿病或糖尿病并发症中的应用。
背景技术
糖尿病是常见的内分泌代谢疾病,其是一种慢性终身性疾病,由遗传因素、免疫功能紊乱等各种因素作用于机体导致胰岛功能减退、胰岛素抵抗等而引起的体内代谢失衡与高血糖状态(Orfila C,Lepert JC,Modesto A,et al.IgA nephropathy complicatingdiabetic glomerulosclerosis[J].Nephron,1998,79(3):279-287.)。糖尿病主要分为1型糖尿病和2型糖尿病,1型糖尿病约占糖尿病总数的5%~10%,2型糖尿病大约占糖尿病总数的90%~95%,两种类型的糖尿病均可导致糖尿病肾病(Kanauchi M,Kawano T,DohiK.Serum IgA levels in patients with diabetic nephropathy and IgA nephropathysuperimposed on diabetes mellitus[J].Diab Res Clin Pract,2000,48(2):113-118.)。
随着糖尿病发病率的增加,糖尿病肾病(diabetic nephropathy,DN)成为我国最常见的继发性肾脏疾病之一(Hovind P,Rossing P,Tarnow L,et al.Progression ofdiabetic nephropathy[J],Kidney Int,2001,59(2):702.)。糖尿病肾病是一种微血管并发症,临床表现为蛋白尿、渐进性肾功能损害、高血压和水肿,晚期出现严重的肾功能衰竭,是糖尿病患者主要死亡原因之一(Olsen S,Mogensen CE.How often is NIDDMeomplicated with non-diabetic renal disease?An amalysis of renal biopsies andthe literature[J].Diabetolo-gia,1996,39(12):1638-1645.)。糖尿病肾病分为以下五期:肾小球高过滤和肾脏肥大期、正常白蛋白尿期、早期糖尿病肾病期(又称“持续微量白蛋白尿期”)、临床糖尿病肾病期以及终末期肾衰竭(《实用医院临床杂志》200年7月第3卷第4期,汤益忠)。
糖尿病肾病根据病因可分为原发和继发性两大类:原发性患者占绝大多数,病因和发病机理不明;继发性患者占少数,如肢端肥大症中垂体性糖尿病肾病、柯兴综合征中类固醇性糖尿病肾病等(Cooper ME Pathogenesis,prevention,and treatment ofdiabetic nephropathy[J].Lancet,1998,352(9123):213-219.)。糖尿病微血管病变导致肾组织缺血、缺氧,使血液粘度增加,红细胞变形能力减弱,出现肾小球毛细血管内压力增高,肾小球动脉阻力增大,入球动脉阻力增高,超滤压升高;肾小球毛细血管和小动脉的损害形成蛋白尿、水肿(浮肿)、肾功能衰竭和高血压等症状。
目前认为,糖尿病肾病的发生因素是多方面的,包括多种代谢紊乱、内分泌失常、血流动力改变和微血管损害。
由于糖尿病肾病的发生因素复杂,尽管市场上已经存在一些治疗糖尿病肾病的药物,但是这些药物的治疗效果并不理想,糖尿病肾病的治疗仍然存在挑战,实有必要提供一种能够有效治疗糖尿病肾病的药物。
发明内容
本发明的目的在于提供一类新型的多肽化合物。本发明的发明人经过大量的实验研究,证明该类新型的多肽化合物具有更长的半衰期,具有促胰岛素活性,没有不良反应发生,可用于糖尿病及糖尿病肾病等糖尿病并发症的预防或治疗。
本发明的另一个目的在于提供一种上述新型的多肽化合物的应用,该新型的多肽化合物潜在地可作为新一代预防或治疗糖尿病及糖尿病肾病等糖尿病并发症的药物,还可用于降糖或降低体重。
为达上述目的,本发明的技术方案如下:
本发明提供一种多肽化合物,其含有以下氨基酸序列表示的母体肽:
His-Xaa2-Gln-Gly-Thr5-Phe-Thr-Ser-Asp-Lys10-Ser-Lys-Tyr-Leu-Gln15-Ser-Xaa17-Ala-Ala-Gln20-Xaa21-Phe-Leu-Xaa24-Trp25-Leu-Xaa27-Xaa28-Gly-Gly30-Pro-Ser-Ser-Gly-Xaa3535-Pro-Pro-Pro-Ser,
其中:
Xaa2=Aib,Ser或D-Ser;
Xaa17=Lys或Arg;
Xaa21=Aib或Gln;
Xaa24=Glu或Gln;
Xaa27=Ile或Arg;
Xaa28=Asn,Gln;
Xaa35=Iva或Aib。
优选地,在所述母体肽的氨基酸序列中,Xaa2=Aib或D-Ser。
优选地,所述母体肽的氨基酸序列的羧基端不经修饰,或者经氨基修饰形成-CONH2基团。
优选地,所述母体肽的氨基酸序列中第10位或第12位Lys的侧链经由桥接基团与亲脂性取代基连接;所述桥接基团为(PEG)m、(PEG)m-γGlu、(PEG)m-Asp、(Gly)x-(Gly-Ser)y-(Gly)z-、(Gly)x-(Gly-Ser)y-(Gly)z-γGlu和(Gly)x-(Gly-Ser)y-(Gly)z-Asp中的一种;所述连接方式为所述第10位或第12位Lys的侧链氨基与所述桥接基团一端的甘氨酸残基的羧基或(PEG)m末端修饰的羧基形成酰胺键,且所述亲脂性的取代基以其羧基与另一端桥接基团的氨基通过形成酰胺键相连;所述亲脂性取代基为HOOC(CH2)nC(O)-且其酰基与所述桥接基团中的氨基形成酰胺键。
优选地,m为2-10的整数;n为14-20的整数;x为0-5的整数;y为1-5的整数;z为1-5的整数。
优选地,所述母体肽的氨基酸序列中第10位或第12位Lys被HomoLys、Orn、Dap或Dab代替。
优选地,所述母体肽的氨基酸序列中第10位或第12位,最优选第10位Lys经由桥接基团与亲脂性取代基连接形成的结构为:
Lys(PEG2-PEG2-γGlu-CO(CH2)18CO2H):
Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H):
Lys(PEG2-PEG2-CO(CH2)18CO2H):
LyS(Gly-Gly-Ser-Cly-Ser-Gly-γGlu-CO(CH2)18CI2H)
Lys(Gly-Gly-Ser-Gly-Ser-Gly-Ser-Gly-γGlu-CO(CH2)18CO2H)
根据本发明的具体实施方式,本发明的多肽化合物为如下化合物中的任一种:
化合物1:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Lys-Ala-Ala-Gln-Aib-Phe-Leu-Glu-Trp-Leu-Ile-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Iva-Pro-Pro-Pro-Ser-OH
H-(D-Ser)-QGTFTSDK(PEG2-PEG2-γGlu-CO(CH2)18COOH)SKYLQSKAAQ-Aib-FLEWLINGGPSSG-Iva-PPPS-OH
化合物2:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(GGSGSG-γGlu-CO(CH2)18-COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Lys-Ala-Ala-Gln-Aib-Phe-Leu-Glu-Trp-Leu-Ile-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Iva-Pro-Pro-Pro-Ser-OH
H-(D-Ser)-QGTFTSDK(GGSGSG-γGlu-CO(CH2)18-COOH)SKYLQSKAAQ-Aib-FLEWLINGGPSSG-Iva-PPPS-OH
化合物3:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(GGSGSG-γGlu-CO(CH2)18-COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Lys-Ala-Ala-Gln-Aib-Phe-Leu-Glu-Trp-Leu-Ile-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Iva-Pro-Pro-Pro-Ser-NH2
H-(D-Ser)-QGTFTSDK(GGSGSG-γGlu-CO(CH2)18-COOH)SKYLQSKAAQ-Aib-FLEWLINGGPSSG-Iva-PPPS-NH2
化合物4:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Gln-Phe-Leu-Glu-Trp-Leu-Ile-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Iva-Pro-Pro-Pro-Ser-OH
H-(D-Ser)-QGTFTSDK(PEG2-PEG2-γGlu-CO(CH2)18COOH)SKYLQSRAAQQFLEWLINGGPSSG-Iva-PPPS-OH
化合物5:
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Gln-Phe-Leu-Glu-Trp-Leu-Arg-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH
H-Aib-QGTFTSDK(PEG2-PEG2-γGlu-CO(CH2)18COOH)SKYLQSRAAQQFLEWLIRGGPSSG-Aib-PPPS-OH
化合物6:
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH
H-Aib-QGTFTSDK(PEG2-PEG2-γGlu-CO(CH2)18COOH)SKYLQSRAAQ-Aib-FLEWLRQGGPSSG-Aib-PPPS-OH
化合物7:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH
H-(D-Ser)-QGTFTSDK(PEG2-PEG2-γGlu-CO(CH2)18COOH)SKYLQSRAAQ-Aib-FLEWLRQGGPSSG-Aib-PPPS-OH
化合物8:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-NH2
H-(D-Ser)-QGTFTSDK(PEG2-PEG2-γGlu-CO(CH2)18COOH)SKYLQSRAAQ-Aib-FLEWLRQGGPSSG-Aib-PPPS-NH2
化合物9:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(GGSGSG-γGlu-CO(CH2)18-COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH
H-(D-Ser)-QGTFTSDK(GGSGSG-γGlu-CO(CH2)18-COOH)SKYLQSRAAQ-Aib-FLEWLRQGGPSSG-Aib-PPPS-OH
化合物10:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(GGSGSGSG-γGlu-CO(CH2)18-COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH。
H-(D-Ser)-QGTFTSDK(GGSGSGSG-γGlu-CO(CH2)18-COOH)SKYLQSRAAQ-Aib-FLEWLRQGGPSSG-Aib-PPPS-OH。
本发明还提供一种组合物,其包含本发明所述的多肽化合物。
优选地,所述组合物为药物组合物,其任选地还包含药学上可接受的载体或辅料。
本发明再提供一种所述多肽化合物或者所述组合物在制备预防或治疗糖尿病和/或糖尿病并发症的药物中的应用;所述糖尿病并发症为糖尿病肾病。
本发明又提供一种所述多肽化合物或者所述组合物在制备降低体重的保健品或药物中的应用。
本发明的技术方案详细描述如下:
本发明的第一个方面是提供一种新型的多肽化合物,该新型的多肽化合物含有以下氨基酸序列表示的母体肽:
其含有以下氨基酸序列表示的母体肽:
His-Xaa2-Gln-Gly-Thr5-Phe-Thr-Ser-Asp-Lys10-Ser-Lys-Tyr-Leu-Gln15-Ser-Xaa17-Ala-Ala-Gln20-Xaa21-Phe-Leu-Xaa24-Trp25-Leu-Xaa27-Xaa28-Gly-Gly30-Pro-Ser-Ser-Gly-Xaa3535-Pro-Pro-Pro-Ser-COR1,
其中:R1=-NH2或-OH;
Xaa2=Aib,Ser或D-Ser;
Xaa17=Lys或Arg;
Xaa21=Aib或Gln;
Xaa24=Glu或Gln;
Xaa27=Ile或Arg;
Xaa28=Asn,Gln;
Xaa35=Iva或Aib。
所述母体肽的氨基酸序列中,Xaa2=Aib或D-Ser。
所述母体肽的氨基酸序列的羧基端不经修饰,或者经氨基修饰形成-CONH2基团。
所述母体肽的氨基酸序列中第10位或第12位Lys的侧链经由桥接基团与亲脂性取代基连接。
所述桥接基团包含(PEG)m,或者(PEG)m-γGlu或(PEG)m-Asp;也可以包含(Gly)x-(Gly-Ser)y-(Gly)z-,或者(Gly)x-(Gly-Ser)y-(Gly)z-γGlu或(Gly)x-(Gly-Ser)y-(Gly)z-Asp。所述连接方式为:所述第10位或第12位Lys的侧链氨基与所述桥接基团一端的甘氨酸残基的羧基或(PEG)m末端修饰的羧基形成一个酰胺键连接到母体肽上;同时,所述亲脂性的取代基以其羧基与另一端桥接基团的氨基通过形成酰胺键相连。所述亲脂性取代基连接的第10位或12位Lys能够被HomoLys、Orn、Dap或Dab代替。其中m为2-10的整数;x为0-5的整数;y为1-5的整数;z为1-5的整数。所述亲脂性取代基为选自HOOC(CH2)nCO-,其中n是14-20的整数,连接方式详见图5和图6,图5为本发明的化合物的母体肽中Lys侧链的一示例性修饰方式,图6为本发明的化合物的母体肽中Lys侧链的另一示例性修饰方式。
于本发明的说明书全文中,采用常规的三字母代码代表天然氨基酸,并采用公认的三字母代码代表其他氨基酸,如Aib(氨基异丁酸),Orn(鸟氨酸)。本发明化合物基于理论分子内桥可以稳定分子的螺旋结构,从而提高了针对胰高血糖素样肽1(GLP-1R)受体和胰高血糖素(GCGR)受体的效力和/或选择性。
本发明化合物基于理论亲脂性取代基可以结合血液中的白蛋白,从而保护本发明化合物免受酶降解,从而提高化合物的半衰期。
本发明的另一方面是提供含有本发明的新型的激动剂多肽化合物的药物组合物,以所述新型的激动剂多肽化合物作为活性成分添加药学上可接受载体和/或辅料制成药物组合物。
本发明的再一方面是提供本发明的新型的激动剂多肽化合物的医药用途。细胞和动物实验显示,本发明的新型的激动剂多肽化合物具有长效降糖作用,可用作治疗糖尿病的药物。
本发明的还有一个方面是提供本发明的新型的激动剂多肽化合物的其他医药用。细胞和动物实验显示,本发明的新型的激动剂多肽化合物具有治疗糖尿病肾病等糖尿病并发症的药效作用。动物实验显示治疗效果优于上市的GLP-1类似物索玛鲁肽,可用作治疗糖尿病肾病等糖尿病并发症的药物。
本发明的新型的激动剂多肽化合物还可以降低体重,具有作为治疗肥胖症药物的潜在用途。
本发明中提到的新型的激动剂多肽化合物中的母体肽为同源性多肽。本发明中的同源性多肽是指,多肽本来具有胃泌酸调节素(OXM)、胰高血糖素样肽(GLP-1)、艾塞那肽(Exenatide)或胰高血糖素(Glucagon)的氨基酸序列,但其中一个或多个氨基酸残基己被不同的氨基酸残基取代,这些氨基酸残基彼此之间是保守的,并且所得到的多肽可用于实施本发明。
本发明多肽化合物还可用于防止体重增长或促进体重减轻。所述多肽化合物可引起摄食量降低和/或能量消耗升高,使得对体重产生可观察到的作用。因此,本发明多肽化合物可用于直接或间接治疗由体重超重所引起的或者以其为特征的任何病症,例如治疗和/或预防肥胖症、病态肥胖症、肥胖症相关炎症、肥胖症相关的胆囊疾病、肥胖症引起的睡眠呼吸暂停。本发明多肽化合物在这些病症中的作用可以是由多肽化合物对体重的作用所致或与之相关,或者可以独立于其对体重的作用。
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,可将本发明的多肽化合物的药物组合物制成各种合适的剂型,其中包含至少一种有效剂量的本发明的多肽化合物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。
含有本发明多肽化合物的药物组合物可以制成溶液或者冻干粉末以用于胃肠外给药,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置,液体配方一般是缓冲液、等渗溶液和水溶液。
本发明的药物组合物的用量可以在一个较大范围内变动,本领域技术人员可以根据一些客观的因素如根据疾病的种类,病情严重程度,病人体重,剂型,给药途径等因素很容易的加以确定。
相较于现有技术,本发明具有以下优点:
1)在质量数相同时与天然OXM相比,本发明的多肽化合物具有更好的生物学活性;
2)在质量数相同时与GLP-1类似物相比,本发明的多肽化合物具有更好的治疗糖尿病肾病等糖尿病并发症的药效作用;
3)在药物的药代实验中显示出显著延长的半衰期和稳定性;
4)合成产率高,稳定性好,易于放大生产,成本低。
在具体的实施方案中,本发明涉及下述新型的激动剂多肽化合物,其具有的序列与侧链修饰结果如下:
化合物1(SEQ ID NO.1):
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Lys-Ala-Ala-Gln-Aib-Phe-Leu-Glu-Trp-Leu-Ile-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Iva-Pro-Pro-Pro-Ser-OH
H-(D-Ser)-QGTFTSDK(PEG2-PEG2-γGlu-CO(CH2)18COOH)SKYLQSKAAQ-Aib-FLEWLINGGPSSG-Iva-PPPS-OH
化合物2(SEQ ID NO.2):
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(GGSGSG-γGlu-CO(CH2)18-COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Lys-Ala-Ala-Gln-Aib-Phe-Leu-Glu-Trp-Leu-Ile-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Iva-Pro-Pro-Pro-Ser-OH
H-(D-Ser)-QGTFTSDK(GGSGSG-γGlu-CO(CH2)18-COOH)SKYLQSKAAQ-Aib-FLEWLINGGPSSG-Iva-PPPS-OH
化合物3(SEQ ID NO.3):
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(GGSGSG-γGlu-CO(CH2)18-COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Lys-Ala-Ala-Gln-Aib-Phe-Leu-Glu-Trp-Leu-Ile-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Iva-Pro-Pro-Pro-Ser-NH2
H-(D-Ser)-QGTFTSDK(GGSGSG-γGlu-CO(CH2)18-COOH)SKYLQSKAAQ-Aib-FLEWLINGGPSSG-Iva-PPPS-NH2
化合物4(SEQ ID NO.4):
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Gln-Phe-Leu-Glu-Trp-Leu-Ile-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Iva-Pro-Pro-Pro-Ser-OH
H-(D-Ser)-QGTFTSDK(PEG2-PEG2-γGlu-CO(CH2)18COOH)SKYLQSRAAQQFLEWLINGGPSSG-Iva-PPPS-OH
化合物5(SEQ ID NO.5):
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Gln-Phe-Leu-Glu-Trp-Leu-Arg-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH
H-Aib-QGTFTSDK(PEG2-PEG2-γGlu-CO(CH2)18COOH)SKYLQSRAAQQFLEWLIRGGPSSG-Aib-PPPS-OH
化合物6(SEQ ID NO.6):
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH
H-Aib-QGTFTSDK(PEG2-PEG2-γGlu-CO(CH2)18COOH)SKYLQSRAAQ-Aib-FLEWLRQGGPSSG-Aib-PPPS-OH
化合物7(SEQ ID NO.7):
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH
H-(D-Ser)-QGTFTSDK(PEG2-PEG2-γGlu-CO(CH2)18COOH)SKYLQSRAAQ-Aib-FLEWLRQGGPSSG-Aib-PPPS-OH
化合物8(SEQ ID NO.8):
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-NH2
H-(D-Ser)-QGTFTSDK(PEG2-PEG2-γGlu-CO(CH2)18COOH)SKYLQSRAAQ-Aib-FLEWLRQGGPSSG-Aib-PPPS-NH2
化合物9(SEQ ID NO.9):
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(GGSGSG-γGlu-CO(CH2)18-COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH
H-(D-Ser)-QGTFTSDK(GGSGSG-γGlu-CO(CH2)18-COOH)SKYLQSRAAQ-Aib-FLEWLRQGGPSSG-Aib-PPPS-OH
化合物10(SEQ ID NO.10):
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(GGSGSGSG-γGlu-CO(CH2)18-COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH。
H-(D-Ser)-QGTFTSDK(GGSGSGSG-γGlu-CO(CH2)18-COOH)SKYLQSRAAQ-Aib-FLEWLRQGGPSSG-Aib-PPPS-OH。
本发明的母体肽的氨基酸序列中第10位或第12位,最优选第10位Lys经由桥接基团与亲脂性取代基连接形成的结构为:
Lys(PEG2-PEG2-γGlu-CO(CH2)18CO2H):
Lys(PEG2-PEG2-γGlu-CO(CH2)16CO2H):
Lys(PEG2-PEG2-CO(CH2)18CO2H):
Lys(Gly-Gly-Ser-Gly-Ser-Gly-γGlu-CO(CH2)18CO2H)
Lys(Gly-Gly-Ser-Gly-Ser-Gly-Ser-Gly-γGlu-CO(CH2)18CO2H)
本发明的母体肽的氨基酸序列中第10位或第12位Lys可被以下HomoLys、Orn、Dap或Dab代替:
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,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,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,IIe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,Aib为2-氨基异丁酸,Iva为异缬氨酸。
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2中小鼠血糖变化AUC图。
图2A为实施例3中糖尿病肾病小鼠经给药治疗后,小鼠尿糖含量柱状图。
图2B为实施例3中糖尿病肾病小鼠经给药治疗后,小鼠尿液中的尿蛋白含量柱状图。
图3A为实施例3中糖尿病肾病小鼠经给药治疗后,小鼠血清中糖化血红蛋白含量柱状图。
图3B为实施例3中糖尿病肾病小鼠经给药治疗后,小鼠血清中血肌酐含量柱状图。
图3C为实施例3中糖尿病肾病小鼠经给药治疗后,小鼠血清中尿素氮含量柱状图。
图4A为实施例3中糖尿病肾病小鼠肾脏H&E染色切片图。图4B为实施例3中糖尿病肾病小鼠肾脏PAS染色切片图。图5为本发明的化合物的母体肽中Lys侧链的一示例性修饰方式。
图6为本发明的化合物的母体肽中Lys侧链的另一示例性修饰方式。
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。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1多肽化合物的合成
材料:
所有的氨基酸购自吉尔生化(上海)有限公司。如果没有特别说明,其他所有试剂均为分析纯,Sigma品牌。采用Protein Technologies PRELUDE 6通道多肽合成仪。Phenomenex Luna C18制备柱(46mmx250mm)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。
实验方法:
化合物采用Fmoc固相多肽的合成法,由羧基端向氨基端方向合成,按照上述氨基酸序列顺序依次连接。具体步骤如下:首先采用MBHAR(Amide-MBHA-Resin酰胺保护的MBHA树脂)或者王树脂,脱Fmoc保护基合成。用茚检试剂进行检测,其中茚检试剂的使用量为试剂1:试剂2:试剂3=l:2:l(滴),沸水中加热3-10min。处理树脂,称取一定量MBHA树脂于合成仪中,加入DCM搅拌30min,抽干,再用DMF洗4次,每次2min,挑取少量树脂进行茚检,若树脂颜色无改变,表明正常,可使用。脱Fmoc保护:20%哌啶洗4次,在第3次洗之后茚检,如果茚检显蓝紫色说明可接下一个氨基酸。如此重复操作,直至合肽完成为止。最后利用冰乙醚洗涤沉淀切割后的多肽,然后进行高效液相色谱纯化。
基于以上合成步骤,合成本发明的如下表1所示的多肽化合物:
表1.本发明的多肽化合物
实施例2多肽化合物1-10、索玛鲁肽对口服葡萄糖耐量(OGTT)的作用
本实施例的索玛鲁肽(Semaglutide)购自浙江湃肽生物有限公司(CAS No.:910463-68-2)。
将8周龄的雄性C57BL/6J小鼠(南京大学模式动物研究中心)按照相似的血糖(从尾尖获取的血液样品评估)随机分组,每组6只。
禁食(6小时)后对动物给药,本发明中多肽化合物1-10、索玛鲁肽均按照120ug/kg的剂量,皮下进行给药,对照组给予PBS。约4小时后,获取初始血液样品(禁食血液葡萄糖水平)。随后,给予口服剂量的葡萄糖(2g/kg),并将动物放回其饲养笼中(t=0)。在t=15分钟、t=30分钟、t=60分钟和t=120分钟时测量血糖。然后在给药8h,给药12h以及给药24h后,重复给予口服剂量的葡萄糖,并检测血糖变化,跟踪血糖直到24个小时。使用软件GraphPadPrism处理数据作出血糖变化折线图,并计算曲线下面积得到AUC图,结果如图1所示。
与载剂(对照组PBS)相比,索玛鲁肽在四个OGTT曲线时段其AUC均显著降低(P<0.05),说明其具有长效降糖效果。而与载剂(对照组PBS)相比,本发明的多肽化合物均有不同程度地改善小鼠糖耐受的效果,其中多肽化合物1-10在4个OGTT曲线时段(0-22h),展现了更为优秀和显著地改善葡萄糖耐受效果。其中与索玛鲁肽相比,多肽化合物7、8、9、10在4个OGTT曲线时段(0-22h),展现了更为优秀和显著地长效降糖效果。
实施例3多肽化合物7,8,9,10和索玛鲁肽对糖尿病肾病的治疗作用
获得db/db小鼠糖尿病肾病模型(购于南京大学-南京生物医药研究院,12周左右小鼠,并测定血糖和体重保证后续实验顺利进行),对模型小鼠随机分成6组(多肽化合物7、8、9、10、索玛鲁肽和生理盐水组),每组6只,每只小鼠的基础体重和血糖无差异,每组老鼠每天分别皮下注射多肽化合物7、8、9、10(120μg/kg),索玛鲁肽(120μg/kg),和生理盐水(DN组:同窝出生的正常小鼠;DC组:db/db小鼠对照组)。在给药7周之后,使用代谢笼收集小鼠尿液,使用相关试剂盒检测尿液中的蛋白含量。在给药8周之后,取材,血液用于检测血肌酐、尿素氮等血清学指标检测。
3.1多肽化合物对糖尿病肾病小鼠尿液中尿糖和尿蛋白含量的影响
尿蛋白定性有生理性的,也有病理性,其阳性程度与肾损害程度不一定成正比。糖尿病患者尿中持续出现尿蛋白阳性,除外泌尿系感染、原发性肾病外,应考虑糖尿病肾病的诊断。有专家认为,糖尿病肾病早期蛋白尿呈间歇性,只在劳动或运动后为阳性反应。因此,运动后尿蛋白检验对诊断糖尿病肾病的早期发现有一定的意义。
图2A为糖尿病肾病小鼠经给药治疗后,小鼠尿糖含量柱状图;图2B为糖尿病肾病小鼠经给药治疗后,小鼠尿液中的尿蛋白含量柱状图。由图2A和2B的结果可知,与DN组同窝出生的正常小鼠相比,DC组db/db小鼠对照组中小鼠的尿糖含量以及尿蛋白含量均明显增加,说明小鼠的糖尿病肾病已经非常严重。在经索玛鲁肽以及本发明的多肽化合物7、8、9、10给药之后,小鼠的尿糖含量以及尿蛋白含量均有不同程度的改善;同时相比于索玛鲁肽,经本发明多肽化合物7、8、9、10给药治疗之后小鼠的尿糖含量以及尿蛋白含量改善效果更加明显。由此可以说明,本发明的多肽化合物对于糖尿病肾病中尿糖含量以及尿蛋白含量具有良好的改善效果。
3.2多肽化合物对糖尿病肾病小鼠血清中糖化血红蛋白(GHb)、血肌酐(CRE)和尿素氮(BUN)的影响
糖化血红蛋白(GHb)目前用作反映糖尿病患者得到血糖在一段较长时间内(4-10)周的控制指标,血糖长期控制不良的,其糖化血红蛋白就会升高,因此糖化血红蛋白测定有助于控制,对糖尿病肾病的研究有重要作用。
临床上检测血肌酐(CRE)是常用的了解肾功能的主要方法之一。血肌酐的浓度变化主要由肾小球的滤过能力(肾小球滤过率)来决定。滤过能力下降,则血肌酐浓度升高。血肌酐高出正常值多数意味肾脏受损,血肌酐能较准确的反应肾实质受损的情况。
尿素氮(BUN)是血浆中除蛋白质以外的一种含氮化合物,它从肾小球滤过而排出体外。在肾功能不全失代偿时,尿素氮将升高。所以临床以尿素氮作为判断肾小球滤过功能的指标。
图3A为糖尿病肾病小鼠经给药治疗后,小鼠血清中糖化血红蛋白含量柱状图;图3B为糖尿病肾病小鼠经给药治疗后,小鼠血清中血肌酐含量柱状图;图3C为糖尿病肾病小鼠经给药治疗后,小鼠血清中尿素氮含量柱状图。
由图3A至图3C的结果可知,与DN组同窝出生的正常小鼠相比,DC组db/db小鼠对照组中小鼠的糖化血红蛋白、血肌酐和尿素氮均明显增加,经本发明多肽化合物7、8、9、10给药之后,小鼠的糖化血红蛋白、血肌酐和尿素氮均明显降低。由此可以说明,本发明的多肽化合物对于糖尿病肾病中糖化血红蛋白、血肌酐和尿素氮具有良好的改善效果。
3.3病理结果分析
取小鼠肾脏进行石蜡包埋,用于后续的染色及免疫组化研究。
(1)肾脏H&E染色
根据图4A小鼠肾脏H&E染色结果可知,与正常小鼠相比,糖尿病肾病小鼠肾脏组织出现局部的炎症,肾小球黏连等现象,给药之后,能抑制糖尿病肾病小鼠肾脏纤维化病变,并且改善肾脏受损,肾小球黏连现象得到缓解;相比于索玛鲁肽,本发明的多肽化合物7、8、9、10的改善和治疗作用更为显著。由此可以说明,本发明的多肽化合物的对于糖尿病肾病小鼠的肾脏纤维化病变、肾脏受损、肾小球黏连现象等症状具有更良好的治疗效果。
(2)肾脏PAS染色
一般来说,肾脏病变的观察多集中在皮质,主要包括肾小球和肾间质,小球的观察集中在系膜区。PAS染色可以观察肾小球系膜区和基底膜的情况,例如系膜区是否有增宽,系膜细胞和系膜基质是否有增生,基底膜是否有增厚。
根据图4B小鼠肾脏PAS染色结果可知,光镜下,正常小鼠的肾小球用PAS染色以突出基底膜,肾小球血管袢薄而清晰,内皮细胞和系膜细胞数目正常,周围的肾小管也正常。与正常小鼠相比,糖尿病肾病小鼠组肾脏出现明显的肾系膜细胞增生。经给药治疗后,糖尿病肾病小鼠肾脏系膜细胞增生均得到改善,且相比于索玛鲁肽,本发明的多肽化合物7、8、9、10的改善和治疗作用更为显著。由此可以说明,本发明的多肽化合物的对于糖尿病肾病小鼠的治疗效果更加明显。
综上所述,本发明的多肽化合物半衰期更长,且在改善和治疗糖尿病并发症方面优于之前报道的化合物,在临床应用方面更具有优势。
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明所附权利要求的范围。
序列表
<110> 深圳市图微安创科技开发有限公司
<120> 多肽化合物及其在预防或治疗糖尿病或糖尿病并发症中的应用
<130> GD2300-21P125291
<160> 10
<170> PatentIn version 3.5
<210> 1
<211> 39
<212> PRT
<213> 人工序列
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa=D-Ser
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Lys的侧链连接-PEG2-PEG2-γGlu-CO(CH2)18COOH
<220>
<221> MISC_FEATURE
<222> (21)..(21)
<223> Xaa = Aib
<220>
<221> MISC_FEATURE
<222> (35)..(35)
<223> Xaa = Iva
<400> 1
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Gln Ser
1 5 10 15
Lys Ala Ala Gln Xaa Phe Leu Glu Trp Leu Ile Asn Gly Gly Pro Ser
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Ser Gly Xaa Pro Pro Pro Ser
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<213> 人工序列
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<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa =D-Ser
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Lys的侧链连接-GGSGSG-γGlu-CO(CH2)18-COOH
<220>
<221> MISC_FEATURE
<222> (21)..(21)
<223> Xaa= Aib
<220>
<221> MISC_FEATURE
<222> (35)..(35)
<223> Xaa = Iva
<400> 2
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Gln Ser
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Lys Ala Ala Gln Xaa Phe Leu Glu Trp Leu Ile Asn Gly Gly Pro Ser
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Ser Gly Xaa Pro Pro Pro Ser
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<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa=D-Ser
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Lys的侧链连接-GGSGSG-γGlu-CO(CH2)18-COOH
<220>
<221> MISC_FEATURE
<222> (21)..(21)
<223> Xaa = Aib
<220>
<221> MISC_FEATURE
<222> (35)..(35)
<223> Xaa= Iva
<400> 3
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Gln Ser
1 5 10 15
Lys Ala Ala Gln Xaa Phe Leu Glu Trp Leu Ile Asn Gly Gly Pro Ser
20 25 30
Ser Gly Xaa Pro Pro Pro Ser
35
<210> 4
<211> 39
<212> PRT
<213> 人工序列
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa=D-Ser
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Lys的侧链连接-PEG2-PEG2-γGlu-CO(CH2)18COOH
<220>
<221> MISC_FEATURE
<222> (35)..(35)
<223> Xaa= Iva
<400> 4
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Gln Ser
1 5 10 15
Arg Ala Ala Gln Gln Phe Leu Glu Trp Leu Ile Asn Gly Gly Pro Ser
20 25 30
Ser Gly Xaa Pro Pro Pro Ser
35
<210> 5
<211> 39
<212> PRT
<213> 人工序列
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa= Aib
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Lys的侧链连接-PEG2-PEG2-γGlu-CO(CH2)18COOH)
<220>
<221> MISC_FEATURE
<222> (35)..(35)
<223> Xaa= Aib
<400> 5
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Gln Ser
1 5 10 15
Arg Ala Ala Gln Gln Phe Leu Glu Trp Leu Arg Asn Gly Gly Pro Ser
20 25 30
Ser Gly Xaa Pro Pro Pro Ser
35
<210> 6
<211> 39
<212> PRT
<213> 人工序列
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa= Aib
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Lys的侧链连接-PEG2-PEG2-γGlu-CO(CH2)18COOH
<220>
<221> MISC_FEATURE
<222> (21)..(21)
<223> Xaa= Aib
<220>
<221> MISC_FEATURE
<222> (35)..(35)
<223> Xaa= Aib
<400> 6
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Gln Ser
1 5 10 15
Arg Ala Ala Gln Xaa Phe Leu Gln Trp Leu Arg Gln Gly Gly Pro Ser
20 25 30
Ser Gly Xaa Pro Pro Pro Ser
35
<210> 7
<211> 39
<212> PRT
<213> 人工序列
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa= D-Ser
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Lys的侧链连接-PEG2-PEG2-γGlu-CO(CH2)18COOH
<220>
<221> MISC_FEATURE
<222> (21)..(21)
<223> Xaa= Aib
<220>
<221> MISC_FEATURE
<222> (35)..(35)
<223> Xaa= Aib
<400> 7
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Gln Ser
1 5 10 15
Arg Ala Ala Gln Xaa Phe Leu Gln Trp Leu Arg Gln Gly Gly Pro Ser
20 25 30
Ser Gly Xaa Pro Pro Pro Ser
35
<210> 8
<211> 39
<212> PRT
<213> 人工序列
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa= D-Ser
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Lys的侧链连接-PEG2-PEG2-γGlu-CO(CH2)18COOH
<220>
<221> MISC_FEATURE
<222> (21)..(21)
<223> Xaa= Aib
<220>
<221> MISC_FEATURE
<222> (35)..(35)
<223> Xaa= Aib
<400> 8
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Gln Ser
1 5 10 15
Arg Ala Ala Gln Xaa Phe Leu Gln Trp Leu Arg Gln Gly Gly Pro Ser
20 25 30
Ser Gly Xaa Pro Pro Pro Ser
35
<210> 9
<211> 39
<212> PRT
<213> 人工序列
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa= D-Ser
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Lys的侧链连接-GGSGSG-γGlu-CO(CH2)18-COOH
<220>
<221> MISC_FEATURE
<222> (21)..(21)
<223> Xaa= Aib
<220>
<221> MISC_FEATURE
<222> (35)..(35)
<223> Xaa= Aib
<400> 9
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Gln Ser
1 5 10 15
Arg Ala Ala Gln Xaa Phe Leu Gln Trp Leu Arg Gln Gly Gly Pro Ser
20 25 30
Ser Gly Xaa Pro Pro Pro Ser
35
<210> 10
<211> 39
<212> PRT
<213> 人工序列
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa= D-Ser
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Lys的侧链连接-GGSGSGSG-γGlu-CO(CH2)18-COOH
<220>
<221> MISC_FEATURE
<222> (21)..(21)
<223> Xaa= Aib
<220>
<221> MISC_FEATURE
<222> (35)..(35)
<223> Xaa= Aib
<400> 10
His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Gln Ser
1 5 10 15
Arg Ala Ala Gln Xaa Phe Leu Gln Trp Leu Arg Gln Gly Gly Pro Ser
20 25 30
Ser Gly Xaa Pro Pro Pro Ser
35
Claims (13)
1.一种多肽化合物,其含有以下氨基酸序列表示的母体肽:
His-Xaa2-Gln-Gly-Thr5-Phe-Thr-Ser-Asp-Lys10-Ser-Lys-Tyr-Leu-Gln15-Ser-Xaa17-Ala-Ala-Gln20-Xaa21-Phe-Leu-Xaa24-Trp25-Leu-Xaa27-Xaa28-Gly-Gly30-Pro-Ser-Ser-Gly-Xaa3535-Pro-Pro-Pro-Ser,
其中:
Xaa2=Aib,Ser或D-Ser;
Xaa17=Lys或Arg;
Xaa21=Aib或Gln;
Xaa24=Glu或Gln;
Xaa27=Ile或Arg;
Xaa28=Asn,Gln;
Xaa35=Iva或Aib。
2.根据权利要求1所述的多肽化合物,其特征在于,所述Xaa2=Aib或D-Ser。
3.根据权利要求1或2所述的多肽化合物,其特征在于,所述母体肽的氨基酸序列的羧基端不经修饰,或者经氨基修饰形成-CONH2基团。
4.根据权利要求1或2所述的多肽化合物,其特征在于,所述母体肽的氨基酸序列中第10位或第12位Lys的侧链经由桥接基团与亲脂性取代基连接;所述桥接基团为(PEG)m、(PEG)m-γGlu、(PEG)m-Asp、(Gly)x-(Gly-Ser)y-(Gly)z-、(Gly)x-(Gly-Ser)y-(Gly)z-γGlu和(Gly)x-(Gly-Ser)y-(Gly)z-Asp中的一种;所述连接方式为所述第10位或第12位Lys的侧链氨基与所述桥接基团一端的甘氨酸残基的羧基或(PEG)m末端修饰的羧基形成酰胺键,且所述亲脂性的取代基以其羧基与另一端桥接基团的氨基通过形成酰胺键相连;所述亲脂性取代基为HOOC(CH2)nC(O)-且其酰基与所述桥接基团中的氨基形成酰胺键。
5.根据权利要求4所述的多肽化合物,其特征在于,m为2-10的整数;n为14-20的整数;x为0-5的整数;y为1-5的整数;z为1-5的整数。
6.根据权利要求1所述的多肽化合物,其特征在于,所述母体肽的氨基酸序列中第10位或第12位Lys被HomoLys、Orn、Dap或Dab代替。
9.根据权利要求1所述的多肽化合物,其特征在于,所述多肽化合物为如下化合物中的任一种:
化合物1:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-C0(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Lys-Ala-Ala-Gln-Aib-Phe-Leu-Glu-Trp-Leu-Ile-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Iva-Pro-Pro-Pro-Ser-OH
化合物2:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(GGSGSG-γGlu-CO(CH2)18-COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Lys-Ala-Ala-Gln-Aib-Phe-Leu-Glu-Trp-Leu-Ile-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Iva-Pro-Pro-Pro-Ser-OH
化合物3:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(GGSGSG-γGlu-CO(CH2)18-COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Lys-Ala-Ala-Gln-Aib-Phe-Leu-Glu-Trp-Leu-Ile-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Iva-Pro-Pro-Pro-Ser-NH2
化合物4:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Gln-Phe-Leu-Glu-Trp-Leu-Ile-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Iva-Pro-Pro-Pro-Ser-OH
化合物5:
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Gln-Phe-Leu-Glu-Trp-Leu-Arg-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH
化合物6:
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH
化合物7:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH
化合物8:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(PEG2-PEG2-γGlu-CO(CH2)18COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-NH2
化合物9:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(GGSGSG-γGlu-CO(CH2)18-COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH
化合物10:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Lys(GGSGSGSG-γGlu-CO(CH2)18-COOH)-Ser-Lys-Tyr-Leu-Gln-Ser-Arg-Ala-Ala-Gln-Aib-Phe-Leu-Gln-Trp-Leu-Arg-Gln-Gly-Gly-Pro-Ser-Ser-Gly-Aib-Pro-Pro-Pro-Ser-OH。
10.一种组合物,其包含权利要求1至9任一项所述的多肽化合物。
11.根据权利要求10所述的组合物,其特征在于,所述组合物为药物组合物,还包含药学上可接受的载体或辅料。
12.一种权利要求1至9任一项所述的多肽化合物或者权利要求11至12任一项所述的组合物在制备预防或治疗糖尿病和/或糖尿病并发症的药物中的应用;所述糖尿病并发症为糖尿病肾病。
13.一种权利要求1至9任一项所述的多肽化合物或者权利要求11至12任一项所述的组合物在制备降低体重的保健品或药物中的应用。
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