CN107854691A - 治疗高脂血症的包含泌酸调节肽衍生物的组合物 - Google Patents
治疗高脂血症的包含泌酸调节肽衍生物的组合物 Download PDFInfo
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- CN107854691A CN107854691A CN201710990018.4A CN201710990018A CN107854691A CN 107854691 A CN107854691 A CN 107854691A CN 201710990018 A CN201710990018 A CN 201710990018A CN 107854691 A CN107854691 A CN 107854691A
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Abstract
本发明涉及预防或治疗高脂血症、脂肪肝病或动脉硬化的组合物,其包含泌酸调节肽衍生物作为活性成分。与天然泌酸调节肽相比,泌酸调节肽衍生物具有高的激活GLP‑1受体和胰高血糖素受体的能力,并具有降低通过高脂肪膳食而升高的血液总胆固醇、低密度胆固醇和三酰甘油水平,和提高高密度胆固醇水平以及高密度胆固醇/低密度胆固醇之比的作用。因此,泌酸调节肽衍生物可有效用于治疗高脂血症和相关疾病。
Description
本申请是分案申请,原申请的申请日为2013年7月25日,中国申请号为201380039596.X,国际申请号为PCT/KR2013/006668,发明名称为“治疗高脂血症的包含泌酸调节肽衍生物的组合物”。
技术领域
本发明涉及预防或治疗高脂血症、脂肪肝病或动脉硬化的组合物,其包含泌酸调节肽衍生物作为活性成分,并涉及使用所述组合物治疗高脂血症、脂肪肝病或动脉硬化的方法。
发明背景
近年来在韩国,由于经济增长和膳食习惯的西化,从食物中脂肪的摄入增加,且由于缺乏运动而引起的代谢疾病如高脂血症、糖尿病、高血压、动脉硬化和脂肪肝病也增加。
高脂血症是指与血液中升高水平的脂质如游离胆固醇、胆固醇酯、磷脂和三酰甘油有关的状况。高脂血症可以以三种形式存在:(1)高胆固醇血症,(2)高甘油三酯血症,和(3)混合性高脂血症(高胆固醇血症和高甘油三酯血症)。高脂血症通常划分为原发性高脂血症和继发性高脂血症。原发性高脂血症通常由遗传缺陷引起,而继发性高脂血症由各种疾病状况、药物和膳食***和150mg/dl或更高的三酰甘油水平作为高脂血症的诊断标准。
在哺乳动物中自然存在各种形式的胆固醇。已知低密度(LDL)胆固醇对健康有害,并已知LDL胆固醇的升高增加心脏病的风险(Assman et al.,Am.J.Card,1996)。此外,高密度(HDL)胆固醇被视为好的胆固醇并且对健康至关重要,因为其预防动脉粥样硬化等。
尽管高脂血症独自不显示具体症状,但血液中过多的脂质附着于血管壁,减小血管尺寸并通过炎症反应引起动脉粥样硬化。由于这个原因,可出现冠心病、脑血管疾病、外周血管阻塞等(E.Falk et al.,Circulation,1995)。此外,过多的血脂在肝组织中累积,因此可引起脂肪肝病。脂肪肝是指其中肝重量中脂肪的比例大于5%的状况。脂肪肝不仅可由过多的脂肪摄入引起,而且可由酒精的摄入引起。
当前用于降低血脂水平的方法包括膳食疗法、运动疗法和药物疗法。然而,膳食疗法或运动疗法难以严格控制和进行,并且其治疗效果也受到限制。
发展至目前,用于降低脂质水平的药物包括胆汁酸结合树脂、降胆固醇药如在胆固醇生物合成中重要的HMG-CoA还原酶抑制剂、降三酰甘油药如苯氧酸衍生物和烟酸等。然而,据报道这些药物具有副作用,如肝毒性、胃肠紊乱和致癌作用。因此,迫切需要开发可用于治疗高脂血症和相关疾病(例如,动脉粥样硬化和脂肪肝病)同时具有较少副作用的药物。
作为这类药物的候选物,泌酸调节肽最近已经受到关注。泌酸调节肽由胰高血糖素原产生,并且是可与胰高血糖素样肽-1(GLP-1)和胰高血糖素受体结合以执行双功能的肽。由于这些特征,已经以各种目的研究了泌酸调节肽,包括治疗肥胖、高脂血症和脂肪肝病。然而,泌酸调节肽有其需要在高剂量下施用的问题,因为其在体内具有短的半衰期,且其活性不足以用于治疗肥胖、高脂血症和脂肪肝病。
因此,本发明人已经开发了与天然泌酸调节肽相比具有升高的活性的泌酸调节肽衍生物,并且已经发现该泌酸调节肽衍生物降低高脂血症诱导的仓鼠模型的血液中脂质的含量和比例,表明该衍生物可有效用于治疗高脂血症疾病,由此完成本发明。
发明内容
技术问题
本发明的一个目的是提供预防或治疗高脂血症、脂肪肝病或动脉粥样硬化的组合物,其含有泌酸调节肽衍生物作为活性成分。
本发明的另一个目的是提供治疗高脂血症、脂肪肝病或动脉粥样硬化的方法,该方法包括将泌酸调节肽衍生物施用于对象的步骤。
本发明的另一个目的是提供泌酸调节肽衍生物在制备用于预防或治疗高脂血症、脂肪肝病或动脉粥样硬化的药物中的应用。
解决问题的方案
为了实现上述目的,一方面,本发明提供预防或治疗高脂血症、脂肪肝病或动脉粥样硬化的组合物,其包含泌酸调节肽衍生物作为活性成分。
如本文中使用的,术语“泌酸调节肽”是指由胰高血糖素原产生的肽,所述胰高血糖素原为胰高血糖素的前体。在本发明中,泌酸调节肽是指包括天然泌酸调节肽和其前体,类似物(衍生物)、片段和变体。优选地,泌酸调节肽具有氨基酸序列SEQ ID NO:1(HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA)。
如本文中使用的,术语“泌酸调节肽变体”是这样的一种肽,所述肽具有一个或多个与天然泌酸调节肽氨基酸序列的氨基酸残基不同的氨基酸残基并具有激活GLP-1和胰高血糖素受体的功能。泌酸调节肽变体可通过天然泌酸调节肽一些氨基酸的置换、添加、缺失、修饰或其组合的任意一种来制备。
如本文中使用的,术语“泌酸调节肽衍生物”是指肽、肽衍生物或肽模拟物,所述肽、肽衍生物或肽模拟物通过天然泌酸调节肽一些氨基酸的添加、缺失或置换来制备,并且可以以与由天然泌酸调节肽激活的水平相比高水平地激活GLP-1受体和胰高血糖素受体。
如本文中使用的,术语“泌酸调节肽片段”是指具有天然泌酸调节肽氨基或羧基端一个或多个氨基酸的添加或缺失的片段,其中添加的氨基酸也可以是非天然存在的氨基酸(例如,D型氨基酸)。这类氨基酸具有调节体内血糖水平的功能。
制备泌酸调节肽变体、衍生物和片段的方法可单独或组合使用。例如,本发明包括这样的肽,所述肽具有一个或多个与天然肽氨基酸不同的氨基酸以及N端氨基酸残基的脱氨基作用,并具有激活GLP-1受体和胰高血糖素受体的功能。
根据IUPAC-IUB的命名规则,本文中提到的氨基酸缩写如下:
在本发明中,泌酸调节肽衍生物包括任何这样的肽,所述肽通过SEQ ID NO:1的氨基酸序列中氨基酸的置换、添加、缺失或翻译后修饰(例如,甲基化、酰化、泛素化或分子内共价键联)来制备,并可激活胰高血糖素和GLP-1受体。凭借氨基酸的置换或添加,不仅可使用人蛋白中常见的20种氨基酸,而且可使用非典型或非天然存在的氨基酸。非典型氨基酸的商业来源包括Sigma-Aldrich、ChemPep Inc.和Genzyme Pharmaceuticals。包含这些氨基酸和非典型肽序列的肽可合成和购买自商业供应商,例如,American Peptide Company或Bachem(USA)或Anygen(Korea)。
在本发明的具体实施方式中,本发明的泌酸调节肽衍生物是新型肽,其包括以下式1的氨基酸序列:
[式1]
R1-X1-X2-GTFTSD-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-R2
其中
R1为组氨酸、脱氨-组氨酰基、二甲基-组氨酰基(N-二甲基-组氨酰基)、β-羟基咪唑丙酰基、4-咪唑乙酰基、β-羧基咪唑丙酰基或酪氨酸;
X1为Aib(氨基异丁酸)、d-丙氨酸、甘氨酸、Sar(N-甲基甘氨酸)、丝氨酸、或d-丝氨酸;
X2为谷氨酸或谷氨酰胺;
X3为亮氨酸或酪氨酸;
X4为丝氨酸或丙氨酸;
X5为赖氨酸或精氨酸;
X6为谷氨酰胺或酪氨酸;
X7为亮氨酸或甲硫氨酸;
X8为天冬氨酸或谷氨酸;
X9为谷氨酸、丝氨酸、α-甲基-谷氨酸或缺失;
X10为谷氨酰胺、谷氨酸、赖氨酸、精氨酸或丝氨酸或缺失;
X11为丙氨酸、精氨酸或缬氨酸或缺失;
X12为丙氨酸、精氨酸、丝氨酸或缬氨酸或缺失;
X13为赖氨酸、谷氨酰胺、精氨酸或α-甲基-谷氨酸或缺失;
X14为天冬氨酸、谷氨酸或亮氨酸或缺失;
X15为苯丙氨酸或缺失;
X16为异亮氨酸或缬氨酸或缺失;
X17为丙氨酸、半胱氨酸、谷氨酸、赖氨酸、谷氨酰胺或α-甲基-谷氨酸或缺失;
X18为色氨酸或缺失;
X19为丙氨酸、异亮氨酸、亮氨酸、丝氨酸或缬氨酸或缺失;
X20为丙氨酸、赖氨酸、甲硫氨酸、谷氨酰胺或精氨酸或缺失;
X21为天冬酰胺或缺失;
X22为丙氨酸、甘氨酸或苏氨酸或缺失;
X23为半胱氨酸或赖氨酸或缺失;
X24为具有2至10个由丙氨酸、甘氨酸和丝氨酸或缺失的组合组成的氨基酸的肽;且
R2为KRNRNNIA(SEQ ID NO:35),GPSSGAPPPS(SEQ ID NO:36),GPSSGAPPPSK(SEQID NO:37),HSQGTFTSDYSKYLD(SEQ ID NO:38),HSQGTFTSDYSRYLDK(SEQ ID NO:39),HGEGTFTSDLSKQMEEEAVK(SEQ ID NO:40)或缺失(如果式1的氨基酸序列与SEQ ID NO:1的氨基酸序列相同,则不包括在内)。
为了提高用于胰高血糖素受体和GLP-1受体的野生型泌酸调节肽的活性,本发明的泌酸调节肽衍生物可用通过SEQ ID NO:1氨基酸序列第1位的组氨酸α碳的缺失获得的4-咪唑乙酰基、通过N-端氨基的缺失获得的脱氨-组氨酰基,通过用两个甲基修饰N-端氨基获得的二甲基-组氨酰基(N-二甲基-组氨酰基)、通过用羟基置换N-端氨基获得的β-羟基咪唑丙酰基、或通过用羧基置换N-端氨基获得的β-羧基咪唑丙酰基置换。此外,GLP-1受体结合区可用增强疏水键和离子键或其组合的氨基酸置换。泌酸调节肽序列的部分可用GLP-1或毒蜥外泌肽(艾塞那肽,Exendin)-4的氨基酸序列置换,以提高GLP-1受体的活性。
进一步,泌酸调节肽序列的部分可用增强α螺旋的序列置换。优选地,式1氨基酸序列第10、14、16、20、24和28位的氨基酸可用氨基酸或氨基酸衍生物置换,所述氨基酸或氨基酸衍生物由已知稳定α螺旋的Tyr(4-Me)、Phe、Phe(4-Me)、Phe(4-Cl)、Phe(4-CN)、Phe(4-NO2)、Phe(4-NH2)、Phg、Pal、Nal、Ala(2-噻吩基)和Ala(苯并噻吩基)组成,将要***的稳定α螺旋的氨基酸或氨基酸衍生物的类型和数量不受限制。
优选地,该氨基酸序列第10与14位、第12与16位、第16与20位、第20与24位、以及第24与28位的氨基酸也可用谷氨酸或赖氨酸置换,以便形成环,并且将要***的环的数量不受限制。最优选地,泌酸调节肽衍生物可具有从以下式1至式6中选择的氨基酸序列。
在具体实施方式中,本发明的泌酸调节肽衍生物为新型肽,所述新型肽包括以下式2的氨基酸序列,其通过用毒蜥外泌肽或GLP-1的氨基酸序列置换泌酸调节肽的氨基酸序列而获得:
[式2]
R1-A-R3
在另一种具体实施方式中,本发明的泌酸调节肽衍生物为新型肽,所述新型肽包括以下式3的氨基酸序列,其通过凭借合适的氨基酸连接体连接泌酸调节肽氨基酸序列的部分与毒蜥外泌肽或GLP-1氨基酸序列的部分而制备:
[式3]
R1-B-C-R4
在又一种具体实施方式中,本发明的泌酸调节肽衍生物为新型肽,所述新型肽包括以下式4的氨基酸序列,其中泌酸调节肽氨基酸序列的部分用能够增强对GLP-1受体的结合亲和力的氨基酸置换,例如,通过疏水相互作用与GLP-1受体结合的第26位的Leu用疏水残基Ile或Val置换。
[式4]
R1-SQGTFTSDYSKYLD-D1-D2-D3-D4-D5-LFVQW-D6-D7-N-D8-R3
在又一种具体实施方式中,本发明的泌酸调节肽衍生物为新型肽,所述新型肽包括以下式5的氨基酸序列,其中天然泌酸调节肽氨基酸序列的部分缺失、添加、或用其他氨基酸置换,从而提高天然泌酸调节肽激活GLP-1受体和胰高血糖素受体的能力:
[式5]
R1-E1-QGTFTSDYSKYLD-E2-E3-RA-E4-E5-FV-E6-WLMNT-E7-R5
在式2至5中,R1与式1中所述的相同;
A选自:
SQGTFTSDYSKYLDSRRAQDFVQWLMNT(SEQ ID NO:41)、
SQGTFTSDYSKYLDEEAVRLFIEWLMNT(SEQ ID NO:42)、
SQGTFTSDYSKYLDERRAQDFVAWLKNT(SEQ ID NO:43)、
GQGTFTSDYSRYLEEEAVRLFIEWLKNG(SEQ ID NO:44)、
GQGTFTSDYSRQMEEEAVRLFIEWLKNG(SEQ ID NO:45)、
GEGTFTSDLSRQMEEEAVRLFIEWAA(SEQ ID NO:46)和
SQGTFTSDYSRQMEEEAVRLFIEWLMNG(SEQ ID NO:47);
B选自:
SQGTFTSDYSKYLDSRRAQDFVQWLMNT(SEQ ID NO:41)、
SQGTFTSDYSKYLDEEAVRLFIEWLMNT(SEQ ID NO:42)、
SQGTFTSDYSKYLDERRAQDFVAWLKNT(SEQ ID NO:43)、
GQGTFTSDYSRYLEEEAVRLFIEWLKNG(SEQ ID NO:44)、
GQGTFTSDYSRQMEEEAVRLFIEWLKNG(SEQ ID NO:45)、
GEGTFTSDLSRQMEEEAVRLFIEWAA(SEQ ID NO:46)、
SQGTFTSDYSRQMEEEAVRLFIEWLMNG(SEQ ID NO:47)、
GEGTFTSDLSRQMEEEAVRLFIEW(SEQ ID NO:48)和SQGTFTSDYSRYLD(SEQ ID NO:49);
C为具有2至10个由丙氨酸、甘氨酸和丝氨酸的组合组成的氨基酸的肽;
D1为丝氨酸、谷氨酸或精氨酸;
D2为精氨酸、谷氨酸或丝氨酸;
D3为精氨酸、丙氨酸或缬氨酸;
D4为精氨酸、缬氨酸或丝氨酸;
D5为谷氨酰胺、精氨酸或赖氨酸;
D6为异亮氨酸、缬氨酸或丝氨酸;
D7为甲硫氨酸、精氨酸或谷氨酰胺;
D8为苏氨酸、甘氨酸或丙氨酸;
E1为丝氨酸、Aib、Sar、d-丙氨酸或d-丝氨酸;
E2为丝氨酸或谷氨酸;
E3为精氨酸或赖氨酸;
E4为谷氨酰胺或赖氨酸;
E5为天冬氨酸或谷氨酸;
E6为谷氨酰胺、半胱氨酸或赖氨酸;
E7为半胱氨酸或赖氨酸或缺失;
R3为KRNRNNIA(SEQ ID NO:35)、GPSSGAPPPS(SEQ ID NO:36)或GPSSGAPPPSK(SEQID NO:37);
R4为HSQGTFTSDYSKYLD(SEQ ID NO:38)、HSQGTFTSDYSRYLDK(SEQ ID NO:39)或HGEGTFTSDLSKQMEEEAVK(SEQ ID NO:40);且
R5为KRNRNNIA(SEQ ID NO:35)、GPSSGAPPPS(SEQ ID NO:36)或GPSSGAPPPSK(SEQID NO:37)或缺失(如果式2至5的氨基酸序列与SEQ ID NO:1的氨基酸序列相同,则不包括在内)。
优选地,本发明的泌酸调节肽衍生物可以为以下式6的新型肽:
[式6]
R1-X1-X2-GTFTSD-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-R2
其中R1为组氨酸、脱氨-组氨酰基、4-咪唑乙酰基或酪氨酸;
X1为Aib(氨基异丁酸)、甘氨酸、丝氨酸或d-丝氨酸;
X2为谷氨酸或谷氨酰胺;
X3为亮氨酸或酪氨酸;
X4为丝氨酸或丙氨酸;
X5为赖氨酸或精氨酸;
X6为谷氨酰胺或酪氨酸;
X7为亮氨酸或甲硫氨酸;
X8为天冬氨酸或谷氨酸;
X9为谷氨酸或α-甲基-谷氨酸或缺失;
X10为谷氨酰胺、谷氨酸、赖氨酸或精氨酸或缺失;
X11为丙氨酸或精氨酸或缺失;
X12为丙氨酸或缬氨酸或缺失;
X13为赖氨酸、谷氨酰胺、精氨酸或α-甲基-谷氨酸或缺失;
X14为天冬氨酸、谷氨酸或亮氨酸或缺失;
X15为苯丙氨酸或缺失;
X16为异亮氨酸或缬氨酸或缺失;
X17为丙氨酸、半胱氨酸、谷氨酸、谷氨酰胺或α-甲基-谷氨酸或缺失;
X18为色氨酸或缺失;
X19为丙氨酸、异亮氨酸、亮氨酸或缬氨酸或缺失;
X20为丙氨酸、赖氨酸、甲硫氨酸或精氨酸或缺失;
X21为天冬酰胺或缺失;
X22为苏氨酸或缺失;
X23为半胱氨酸、赖氨酸或缺失;
X24为具有2至10个由甘氨酸组成的氨基酸的肽或缺失;且
R2为KRNRNNIA(SEQ ID NO:35)、GPSSGAPPPS(SEQ ID NO:36)、GPSSGAPPPSK(SEQID NO:37)、HSQGTFTSDYSKYLD(SEQ ID NO:38)、HSQGTFTSDYSRYLDK(SEQ ID NO:39)或HGEGTFTSDLSKQMEEEAVK(SEQ ID NO:40)或缺失(如果式6的氨基酸序列与SEQ ID NO:1的氨基酸序列相同,则不包括在内)。
更优选地,本发明的泌酸调节肽衍生物可选自SEQ ID NOs:2至34的肽。甚至更优选地,本发明的泌酸调节肽衍生物可以是实施例2-1的表1中所述的泌酸调节肽衍生物。
在本发明的实施例中,制备分别具有SEQ ID NOs:2至34的氨基酸序列的泌酸调节肽衍生物,并且发现泌酸调节肽衍生物与天然泌酸调节肽(实施例2)相比显示出优异的GLP-1受体和胰高血糖素受体活性。换言之,由以上结果可看出,本发明的泌酸调节肽衍生物通过激活GLP-1受体和胰高血糖素受体,表现出对高脂血症、脂肪肝病或动脉粥样硬化优异的治疗效果。
本发明的泌酸调节肽衍生物以包括各种聚合物的缀合物的形式存在,从而提高衍生物的治疗效果和体内半衰期。
与天然泌酸调节肽相比,本发明的缀合物显示作用的持续时间增加,长效缀合物包括通过天然泌酸调节肽氨基酸的修饰、置换、添加或缺失而制备的泌酸调节肽,缀合至可生物降解的聚合物如聚乙二醇(PEG)的泌酸调节肽,缀合至多糖诸如白蛋白、抗体、弹性蛋白、纤连蛋白或壳多糖或缀合至长效蛋白如免疫球蛋白片段的泌酸调节肽,缀合至具有在体内连接至白蛋白能力的脂肪酸的泌酸调节肽,或包封在可生物降解的纳米颗粒中的泌酸调节肽,并且本发明中使用的长效缀合物的类型不受限制。
优选地,缀合物为这样的缀合物,在该缀合物中具有选自SEQ ID NOs:2至34的氨基酸序列的泌酸调节肽衍生物通过非肽基聚合物连接至免疫球蛋白的Fc区。
免疫球蛋白Fc区为在体内被代谢的可生物降解多肽,因此作为药物的载体而使用是安全的。与整个免疫球蛋白分子相比,免疫球蛋白的Fc区具有低分子量,因此在缀合物的制备、纯化和生产方面是有利的。此外,由于抗体之间的氨基酸序列不同,Fab部分显示高的非同质性,因此可大幅提高材料的同质性,且也可降低诱导血液抗原性的可能性。
如本文中使用的,术语“免疫球蛋白的Fc区”是指包含免疫球蛋白重链恒定区2(CH2)和重链恒定区3(CH3)的蛋白质,其不包括免疫球蛋白重链和轻链可变区、重链恒定区1(CH1)和轻链恒定区1(CL1)。其可进一步包括处于重链恒定区的铰链区。并且,本发明的免疫球蛋白Fc区可以是扩展的Fc区,其除了重链和轻链可变区之外,包括重链恒定区1(CH1)和/或轻链恒定区1(CL1)的部分或全部,只要其具有与天然蛋白质基本上相等或比其更好的作用。并且,免疫球蛋白Fc区可以是这样的区域,该区域具有对应于CH2和/或CH3的部分相对长的氨基酸序列的缺失。具体地,本发明的免疫球蛋白Fc区可包括1)CH1结构域、CH2结构域、CH3结构域和CH4结构域,2)CH1结构域和CH2结构域,3)CH1结构域和CH3结构域,4)CH2结构域和CH3结构域,5)一个或多个结构域与免疫球蛋白铰链区(或铰链区的部分)的组合,或6)重链恒定区和轻链恒定区的每个结构域的二聚体。
本发明的免疫球蛋白Fc区包括天然氨基酸序列及其序列衍生物(突变体)。如本文中使用的,术语“氨基酸序列衍生物”是指由于天然氨基酸序列的一个或多个氨基酸残基的缺失、***、非保守或保守置换或其组合而与天然氨基酸序列不同的序列。例如,在IgG Fc的实例中,在结合中已知重要的第214至238位、第297至299位、第318至322位、或第327至331位的氨基酸残基可用作修饰的合适部位。
此外,其他各种衍生物是可能的,包括具有能够形成二硫键的区域的缺失、或在天然Fc的N-端一些氨基酸残基的缺失或在天然Fc的N-端甲硫氨酸残基的添加的衍生物。另外,为了去除效应子功能,缺失可发生于补体结合部位如C1q结合部位和ADCC(依赖抗体的细胞毒性)部位中。制备这类免疫球蛋白Fc区序列衍生物的技术公开于国际专利申请号WO97/34631和WO 96/32478中。
蛋白质和肽中的氨基酸交换是本领域公知的,其一般不改变蛋白质或肽的活性(H.Neurath,R.L.Hill,The Proteins,Academic Press,New York,1979)。最常发生的交换为在两个方向上的Ala/Ser、Val/Ile、Asp/Glu、Thr/Ser、Ala/Gly、Ala/Thr、Ser/Asn、Ala/Val、Ser/Gly、Thy/Phe、Ala/Pro、Lys/Arg、Asp/Asn、Leu/Ile、Leu/Val、Ala/Glu和Asp/Gly。此外,如果有必要可通过磷酸化、硫酸盐化、丙烯酰化、糖基化、甲基化、法呢基化、乙酰化、酰胺化等修饰Fc区。
上述Fc衍生物显示与本发明的Fc区的生物活性相等的生物活性或具有对热、pH等的提高的结构稳定性。
此外,该Fc区可获自从人和其他动物包括牛、山羊、猪、小鼠、兔、仓鼠、大鼠和豚鼠分离的天然形式,或可以是获自转化的动物细胞或微生物的其重组体或衍生物。本文中,通过从活的人或动物体分离整个免疫球蛋白并用蛋白酶将其处理,Fc区可获自天然免疫球蛋白。当整个免疫球蛋白用木瓜蛋白酶处理时,其消化成Fab和Fc区,当整个免疫球蛋白用胃蛋白酶处理时,其消化成pF'c和F(ab)2片段。Fc或pF'c可使用尺寸排阻层析等分离。优选地,人源Fc区为获自微生物的重组免疫球蛋白Fc区。
此外,本发明的免疫球蛋白Fc区可以是具有天然糖链或与天然形式相比增加的或减少的糖链的形式,或可以是去糖基化的形式。通过常规方法如化学法、酶促法和使用微生物的基因工程法,可实现免疫球蛋白Fc糖链的增加、减少或去除。通过从Fc去除糖链而获得的Fc区显示对第一补体成分C1的C1q部分的结合亲和力显著降低以及依赖抗体的细胞毒性或依赖补体的细胞毒性的降低或丧失,因此不诱导体内不必要的免疫应答。对此,去糖基化或无糖基化形式的免疫球蛋白Fc区作为药物载体可更适合于本发明的对象。
如本文中使用的,术语“去糖基化”是指酶促地从Fc区去除糖部分,和术语“无糖基化”是指在原核生物、优选地为大肠杆菌中产生的未糖基化的Fc区。
同时,免疫球蛋白Fc区可源自人或包括牛、山羊、猪、小鼠、兔、仓鼠、大鼠和豚鼠的其他动物,并且优选地源自人。
此外,免疫球蛋白Fc区可源自IgG、IgA、IgD、IgE、IgM或其组合或杂合。优选地,其源自人血液中最丰富的蛋白质中的IgG或IgM,且最优选地源自IgG,已知其增强配体结合蛋白的半衰期。
如本文中使用的,术语“组合”是指编码同源单链免疫球蛋白Fc区的多肽被连接至不同源的单链多肽以形成二聚体或多聚体。具体地,二聚体或多聚体可由选自IgG Fc、IgAFc、IgM Fc、IgD Fc和IgE Fc片段的两个或多个片段形成。
如本文中使用的,术语“杂合”是指对应于两个或多个不同源免疫球蛋白Fc片段的序列存在于单链免疫球蛋白Fc区中。在本发明中,各种形式的杂合是可能的。换言之,由1至4个选自IgG Fc、IgM Fc、IgA Fc、IgE Fc和IgD Fc的CH1、CH2、CH3和CH4的结构域组成的杂合是可能的,且其可包含铰链。
同时,IgG也可再分为IgG1、IgG2、IgG3和IgG4,且在本发明中,这些亚类的组合或杂合也是可能的。优选地,IgG为IgG2和IgG4亚类,最优选地,其为基本上缺乏效应子功能如依赖补体的细胞毒性(CDC)的IgG4的Fc区。
换言之,本发明中最优选的用作药物载体的免疫球蛋白Fc区为源自人IgG4的Fc区。人源Fc区比非人源Fc区更优选,非人源Fc区可在人体内充当抗原并引起不期望的免疫应答如产生针对该抗原的新抗体。
如本文中使用的,术语“非肽基聚合物”是指生物相容性聚合物,其包括两个或多个通过任何取代肽键的共价键相互连接的重复单位。在本发明中,非肽基聚合物可与非肽基连接体可互换地使用。
可在本发明中使用的非肽基聚合物可选自聚乙二醇、聚丙二醇、乙二醇/丙二醇共聚物、聚氧乙基化多元醇、聚乙烯醇、多糖、葡聚糖、聚乙烯***、可生物降解的聚合物如PLA(聚乳酸)和PLGA(聚乳酸-乙醇酸)、脂质聚合物、壳多糖、透明质酸和其组合。优选地,非肽基聚合物为聚乙二醇。此外,本领域公知的其衍生物和通过本领域公知的方法可容易制备的衍生物包括在本发明的范围内。
在通过常规框内融合(inframe fusion)方法获得的融合蛋白中使用的肽连接体具有在体内容易被蛋白酶剪切的缺点,因此通过载体增加有效药血清半衰期的充分作用不能够如所期望的那样获得。然而,在本发明中,与载体类似,对蛋白酶具有抗性的聚合物可用于维持肽的血清半衰期。因此,在本发明中可使用任何非肽基聚合物而不受限制,只要其为具有前述功能的聚合物,即在体内对蛋白酶具有抗性的聚合物。非肽基聚合物的分子量范围为1至100kDa,且优选地为1至20kDa。本发明的连接至免疫球蛋白Fc区的非肽基聚合物,可为聚合物的一种聚合物或不同聚合物的组合。
在本发明中使用的非肽基聚合物可具有能够连接至免疫球蛋白Fc区和蛋白药物的反应基。非肽基聚合物两端的反应基优选地选自反应性醛基、丙醛基、丁醛基、马来酰亚胺基和琥珀酰亚胺衍生物。
琥珀酰亚胺衍生物可以是琥珀酰亚胺基丙酸酯、羟基琥珀酰亚胺基、琥珀酰亚胺基羧甲基、或琥珀酰亚胺基碳酸酯。特别地,当非肽基聚合物在其两端均具有反应性醛基时,非特异性反应可最小化,并且生理活性多肽和免疫球蛋白可分别有效结合至非肽基聚合物的一端和另一端。通过使用醛键的还原烷基化而生成的最终产物比通过酰胺键连接的最终产物更稳定。醛反应基在低pH下选择性地结合N-端,并可在高pH如pH 9.0下与赖氨酸残基形成共价键。
非肽基聚合物两端的反应基可相同或不同。例如,非肽基聚合物可在一端具有马来酰亚胺基,在另一端具有醛基、丙醛基或丁醛基。当在其两端均具有反应性羟基的聚乙二醇被用作非肽基聚合物时,羟基可通过公知的化学反应被激活成各种反应基,或可使用具有商业上可获得的经修饰的反应基的聚乙二醇,以便制备本发明的长效缀合物。
本发明的缀合物可以是其中非肽基聚合物的一端和另一端分别连接至免疫球蛋白Fc区和泌酸调节肽衍生物的胺基或硫醇基的缀合物。
本发明的非肽基聚合物在两端均具有官能团,该官能团可连接至免疫球蛋白Fc区或蛋白药物。官能团可以是醛基、丙醛基、丁醛基、马来酰亚胺基和琥珀酰亚胺衍生物(即,琥珀酰亚胺基丙酸酯、羟基琥珀酰亚胺基、琥珀酰亚胺基羧甲基、或琥珀酰亚胺基碳酸酯),但不限于此。
在非肽基聚合物的连接体两端的反应基可相同或不同。例如,非肽基聚合物可在一端具有马来酰亚胺基,且在另一端具有醛基、丙醛基或丁醛基。例如,当非肽基聚合物在一端具有反应性醛基并在另一端具有反应性马来酰亚胺基时,非特异性反应可最小化,且生理活性多肽和免疫球蛋白可有效结合至非肽基聚合物的两端。根据本发明的实施方式,缀合物通过使用非肽基聚合物PEG经共价键将泌酸调节肽或其衍生物连接至免疫球蛋白Fc区而被合成,该非肽基聚合物PEG只包含丙醛基或同时包含马来酰亚胺基和醛基。
本发明的药物组合物可用于预防或治疗高脂血症、脂肪肝病或动脉粥样硬化。
如本文中使用的,术语“预防”是指所有抑制或延迟目标疾病发展的作用。如本文中使用的,术语“预防”意思是施用本发明的泌酸调节肽衍生物以抑制或延迟高脂血症、脂肪肝病或动脉粥样硬化的发展,高脂血症、脂肪肝病或动脉粥样硬化显示血液总胆固醇与低密度胆固醇水平的升高以及高密度胆固醇水平的降低。
如本文中使用的,术语“治疗”是指所有缓解、减轻或缓和发展的疾病症状的作用。如本文中使用的,术语“治疗”是指施用本发明的泌酸调节肽衍生物以缓解、减轻或缓和高脂血症、脂肪肝病或动脉粥样硬化,高脂血症、脂肪肝病或动脉粥样硬化显示血液总胆固醇与低密度胆固醇水平的升高以及高密度胆固醇水平的降低。
如本文中使用的,术语“高脂血症”是指与血液中脂质如游离胆固醇、胆固醇酯、磷脂和三酰甘油的水平异常升高有关的状况。虽然高脂血症自身不显示具体的症状,但血液中过多的脂质附着于血管壁,以降低血管尺寸并通过炎症反应引起动脉粥样硬化。由于这个原因,可发生冠心病、脑血管疾病、外周血管阻塞等。
因此,本发明的药物组合物不仅可用于治疗高脂血症、脂肪肝病或动脉粥样硬化,而且可用于治疗冠心病、脑血管疾病、或外周血管阻塞。
如本文中使用的,术语“脂肪肝病”是指在其中肝的重量中脂肪的比例大于5%的状况。在本发明中,脂肪肝病包括非酒精性脂肪肝病(NAFLD)、酒精性脂肪肝病、营养性脂肪肝病、饥饿性脂肪肝病、肥胖性脂肪肝病、糖尿病性脂肪肝病或脂肪性肝炎。非酒精性脂肪肝病是指包括原发性和继发性非酒精性脂肪肝病,但可优选地为由原发性高脂血症、糖尿病或肥胖引起的非酒精性脂肪肝病。
此外,在本发明中,非酒精性脂肪肝病是指包括由这类疾病的发展引起的单纯性脂肪变性、非酒精性脂肪性肝炎、以及肝纤维化和肝硬化。
动脉粥样硬化是指这样的血管病,在该血管病中由于胆固醇在血管内皮中的沉积和内皮细胞的增殖而形成动脉粥样化。
在本发明的实施例中,通过使用聚乙二醇由共价键将泌酸调节肽衍生物连接至免疫球蛋白Fc区,制备长效泌酸调节肽衍生物缀合物,所制备的缀合物被施加至具有由高脂肪膳食的摄入引起的高脂血症的仓鼠动物模型。结果显示,与高脂血症诱导的动物模型相比,施用根据本发明的长效泌酸调节肽衍生物缀合物的组显示出血液三酰甘油水平(图1)的显著降低,血液总胆固醇水平的显著降低(图2),以及血液低密度(LDL)胆固醇水平的显著降低。此外,观察到与高脂血症诱导的动物模型相比,施用根据本发明的长效泌酸调节肽衍生物缀合物的组显示出血液高密度(HDL)胆固醇水平的显著升高(图4)和血液HDL-胆固醇/LDL-胆固醇比的显著升高(图5)。
另外,可见根据本发明的长效泌酸调节肽衍生物缀合物与商业的长效GLP-1类似物相比,显示出血液总胆固醇水平(图6)的降低和血液LDL-胆固醇和三酰甘油水平的降低(图7)。此外,可见与施用(FIGS.8和9)相比,施用本发明的长效泌酸调节肽衍生物缀合物显示血液HDL-胆固醇水平以及HDL/LDL-胆固醇之比的升高。具体地,与相比,具有Fc的SEQ ID NO:25肽的长效缀合物显示出血液HDL水平以及HDL/LDL-胆固醇之比的显著升高。
换言之,根据本发明的泌酸调节肽衍生物降低血脂水平,因此可用作用于治疗高脂血症、脂肪肝病或动脉硬化的剂。此外,本发明的缀合物具有与天然泌酸调节肽相比极佳的激活GLP-1受体和胰高血糖素受体的能力,并显示在体内升高的血液半衰期,因此其活性在体内可保持以延长的时间。
本发明的泌酸调节肽衍生物可提高调节涉及脂肪脂解的酶活性的因子(蛋白激酶C-ζ或PKC-ζ)的活性,并提高涉及脂肪脂解的因子(Glut2)的表达,从而治疗高脂血症、脂肪肝病或动脉硬化,但本发明的范围不限于以上作用机制。
本发明的药物组合物可进一步包括表现出对高脂血症、脂肪肝病或动脉硬化的预防或治疗效果的药剂。具体地,本发明的组合物可进一步包括已知作为用于治疗高脂血症、脂肪肝病或动脉硬化的剂的药剂,从而组合本发明的衍生物施用药剂。
因此,本发明的组合物可单独或组合其他药物施用,从而预防或治疗高脂血症、脂肪肝病或动脉硬化。
如本文中使用的,术语“施用”意思是通过任何适当的方法将给定的物质引入患者。本发明衍生物可通过任何一般的途径施用,只要其可到达目标组织。具体地,本发明的衍生物可腹膜内、静脉内、肌内、皮下、皮內、经口、局部、鼻内、肺内或直肠内施用,但不限于此。然而,由于经口给药时肽被消化,优选地配制经口组合物以便活性成分被包被或避免在胃中降解。优选地,本发明的组合物可以注射型形式施用。此外,可使用任何能够将活性成分递送至靶细胞的***来施用本发明的药物组合物。
包含本发明的泌酸调节肽衍生物的药物组合物可进一步包括药学上可接受的载体。对于经口施用,药学上可接受的载体包括黏合剂、润滑剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、悬浮剂、着色剂和调味剂。对于注射型制剂,药学上可接受的载体包括缓冲剂、防腐剂、镇痛剂、增溶剂、等渗剂和稳定剂。对于局部施用,药学上可接受的载体包括主剂、赋形剂、润滑剂和防腐剂。
本发明的药物组合物可使用前述药学上可接受的载体配制为各种剂型。例如,对于经口施用,药物组合物可配制成片剂、含片、胶囊、酏剂、悬浮液、糖浆、糯米纸囊剂等。对于注射型制剂,药物组合物可以以单位剂量安瓿或多剂量容器的形式提供。药物组合物也可配制成溶液、悬浮液、片剂、丸剂、胶囊和缓释制剂。
同时,适合于制剂的载体、赋形剂和稀释剂的示例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、金合欢胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油。此外,本发明的药物组合物可进一步包括充填剂、抗凝剂、润滑剂、润湿剂、香料、防腐剂等。
本发明的药物组合物的剂量根据活性成分的种类,以及各种因素如待治疗的疾病,施用途径,患者的年龄、性别和重量,和疾病的严重性来确定。
本发明的药物组合物具有长的体内半衰期和优异的效力,因此药物组合物施用的数量和频率可显著减少。
在另一种实施方式中,本发明提供治疗高脂血症、脂肪肝病或动脉硬化的方法,该方法包括将本发明的泌酸调节肽衍生物施用于对象的步骤。
以上泌酸调节肽、高脂血症、脂肪肝病和动脉硬化如上所述。
如本文中使用的,术语“对象”是指被怀疑具有高脂血症、脂肪肝病或动脉硬化的对象。具体的,该术语意为具有或受到患上述疾病的风险的哺乳动物,包括人、大鼠和家畜。此外,该对象可以是任何可由本发明的泌酸调节肽衍生物治疗的对象。
本发明治疗方法可包括施用包含缀合物的药学上有效量的药物组合物。组合物的日总剂量可通过医师适当的医学判断确定,且组合物可施用一次或几次。然而,鉴于本发明的目的,针对每个具体患者的组合物的具体治疗有效剂量可根据医学领域公知的各种因素而不同,该因素包括所实现的反应的种类和程度,根据其他剂是否伴随其使用的具体组合物,患者的年龄、体重、健康状况、性别和日常膳食,施用时间和途径,组合物的分泌率,治疗的持续时间,与本发明的组合物组合或同时使用的其他药物,以及医学领域公知的其他因素。
在又一个方面,本发明提供制备泌酸调节肽衍生物缀合物的方法。
该制备方法可包括步骤:(1)将具有反应性醛、马来酰亚胺或琥珀酰亚胺基的非肽基聚合物共价连接至泌酸调节肽衍生物肽的胺或硫醇基;(2)从步骤(1)的反应混合物分离泌酸调节肽衍生物肽,该泌酸调节肽衍生物肽具有在氨基端以外的位置与其共价结合的非肽基聚合物;和(3)将免疫球蛋白Fc区共价连接至所连接的非肽基聚合物的另一端,从而产生包含分别连接至非肽基聚合物的一端和另一端的免疫球蛋白Fc区和泌酸调节肽衍生物肽的肽缀合物。
更具体地,该制备方法可包括步骤:1)将分别在其一端和另一端具有反应性醛基和反应性马来酰亚胺基的非肽基聚合物共价连接至泌酸调节肽衍生物的半胱氨酸残基;(2)从步骤(1)的反应混合物分离具有共价连接至半胱氨酸残基的非肽基聚合物的泌酸调节肽衍生物;和(3)将免疫球蛋白Fc区共价连接至所连接的非肽基聚合物的另一端,从而产生包括分别连接至非肽基聚合物一端和另一端的免疫球蛋白Fc区和泌酸调节肽衍生物肽的肽缀合物。
在又一个方面,本发明提供泌酸调节肽衍生物在制备用于预防或治疗高脂血症、脂肪肝病或动脉硬化的药物中的应用。
发明的有利效果
本发明的泌酸调节肽衍生物与天然泌酸调节肽相比具有高的激活GLP-1受体和胰高血糖素受体的能力,且表现降低通过高脂肪膳食而升高的血液总胆固醇、低密度胆固醇和三酰甘油水平,并升高高密度胆固醇水平以及高密度胆固醇/低密度胆固醇之比的作用。因此,本发明的泌酸调节肽衍生物可有效由于治疗高脂血症和相关疾病。
附图说明
图1为显示通过将长效泌酸调节肽衍生物施用于高脂肪膳食诱导的高脂血症仓鼠而引起血液三酰甘油水平变化的图(#:表示与普通膳食组相比在99.9%的置信度内(p<0.001)显著升高;*:表示与高脂肪膳食组相比在99.9%的置信度内(p<0.001)显著降低)。
图2为显示通过将长效泌酸调节肽衍生物施用于高脂肪膳食诱导的高脂血症仓鼠而引起血液总胆固醇水平的变化图(#:表示与普通膳食组相比在99.9%的置信度内(p<0.001)显著升高;*:表示与高脂肪膳食组相比在99.9%的置信度内(p<0.001)显著降低)。
图3为显示通过将长效泌酸调节肽衍生物施用于高脂肪膳食诱导的高脂血症仓鼠而引起血液LDL-胆固醇水平变化的图(#:表示与普通膳食组相比在99.9%的置信度内(p<0.001)显著升高;*:表示与高脂肪膳食组相比在99.9%的置信度内(p<0.001)显著降低)。
图4为显示通过将长效泌酸调节肽衍生物施用于高脂肪膳食诱导的高脂血症仓鼠而引起血液HDL-胆固醇水平变化的图(*:表示与高脂肪膳食组相比在99%的置信度内(p<0.01)显著降低)。
图5为显示通过将长效泌酸调节肽衍生物施用于高脂肪膳食诱导的高脂血症仓鼠而引起血液HDL/LDL-胆固醇水平变化的图(*:显示与高脂肪膳食组相比在95%的置信度内(p<0.05)显著降低)。
图6为显示通过将或长效泌酸调节肽衍生物施用于高脂肪膳食诱导的高脂血症仓鼠而引起血液总胆固醇水平变化的图(***:表示与高脂肪膳食组相比在99.9%的置信度内(p<0.001)显著降低)。
图7为显示通过施用将或长效泌酸调节肽衍生物适用于高脂肪膳食诱导的高脂血症仓鼠而引起血液LDL-胆固醇水平变化的图(***:表示与高脂肪膳食组相比在99.9%的置信度内(p<0.001)显著降低)。
图8为显示通过将或长效泌酸调节肽衍生物施用于高脂肪膳食诱导的高脂血症仓鼠而引起血液HDL-胆固醇水平变化的图(*:表示与高脂肪膳食组相比在95%的置信度内(p<0.05)显著降低。
图9为显示通过将或长效泌酸调节肽衍生物施用于高脂肪膳食诱导的高脂血症仓鼠而引起血液HDL/LDL-胆固醇水平降低的图(**:表示与高脂肪膳食组相比在99%的置信度内(p<0.01)显著降低)。
图10为显示通过将或长效泌酸调节肽衍生物施用于高脂肪膳食诱导的高脂血症仓鼠而引起血液三酰甘油水平变化的图(***:表示与高脂肪膳食组相比在99.9%的置信度内(p<0.001)显著降低)。
具体实施方式
在下文中,将引用实施例进一步详细描述本发明。然而要理解的是,这些实施例仅仅是为了说明的目的,而不旨在限制本发明的范围。
实施例1:产生用于体内激活的细胞系
实施例1-1:产生对GLP-1显示cAMP应答的细胞系
使用对应于人GLP-1受体基因cDNA(OriGene Technologies,Inc.USA)ORF(可读框)的部分作为模板,利用分别包含HindIII切割位点和EcoRI切割位点的反向和正向引物进行PCR,从而获得PCR产物。
正向引物:5'-CCCGGCCCCCGCGGCCGCTATTCGAAATAC-3'(SEQ ID NO:50)
反向引物:5'-GAACGGTCCGGAGGACGTCGACTCTTAAGATAG-3'(SEQ ID NO:51)
PCR产物被克隆至已知的动物细胞表达载体x0GC/dhfr中,从而构建重组载体x0GC/GLP-1R。
重组载体x0GC/GLP-1R被引入CHO DG44细胞系,在DMEM/F12(10%FBS)培养基中培养,使用脂质转染胺(Invitrogene,USA),以获得转化体。在含有1mg/mL G418和10nM氨甲蝶呤的选择性培养基中温育该转化体,从中选择单克隆细胞系。然后,最终从单克隆细胞系中选择对GLP-1显示良好浓度依赖性cAMP应答的细胞系。
实施例1-2:产生对胰高血糖素显示cAMP应答的细胞系
使用对应于人胰高血糖素受体基因的cDNA(OriGene Technologies,Inc.USA)ORF(可读框)的部分作为模板,利用分别包含EcoRI切割位点和XhoI切割位点的反向和正向引物进行PCR,从而获得PCR产物。
正向引物:5'-CAGCGACACCGACCGTCCCCCCGTACTTAAGGCC-3'(SEQ ID NO:52)
反向引物:5'-CTAACCGACTCTCGGGGAAGACTGAGCTCGCC-3'(SEQ ID NO:53)
PCR产物被克隆至已知的动物细胞表达载体x0GC/dhfr,从而构建重组载体x0GC/GCGR。
重组载体x0GC/GCGR被引入CHO DG44细胞系,在DMEM/F12(10%FBS)培养基中培养,使用脂质转染胺(Invitrogene,USA),以获得转化体。在含有1mg/mL G418和10nM氨甲蝶呤的选择性培养基中温育该转化体,从中选择单克隆细胞系。然后,最终从单克隆细胞系中选择对胰高血糖素显示良好浓度依赖性cAMP应答的细胞系。
实施例2:泌酸调节肽衍生物的体内活性
实施例2-1:泌酸调节肽衍生物的合成
为了测量泌酸调节肽衍生物的体内活性,具有以下表1中显示氨基酸序列的泌酸调节肽衍生物。
【表1】
泌酸调节肽和泌酸调节肽衍生物
在以上表1中,黑体字母表示的氨基酸意为环形成,和X表示的氨基酸意为非天然氨基酸α-甲基-谷氨酸。此外,CA表示4-咪唑乙酰基,DA表示脱氨-组氨酰基,Aib表示氨基异丁酸,(d)S表示d-丝氨酸。
实施例2-2:测量泌酸调节肽衍生物的体内活性
为了测量抗肥胖肽的作用,使用实施例1-1和1-2中制备的转化体测量细胞的体内活性。
转化体的每一个得到转化以便在CHO(中国仓鼠卵巢)中表达人GLP-1受体和胰高血糖素受体基因的每一个,且适合于测量GLP-1和胰高血糖素的活性。因此,使用转化体的每一个测量泌酸调节肽衍生物每一个的活性。
具体地,转化体的每一个一周传代培养两次或三次,并将细胞分配至96孔板的每一孔中,密度为1×105细胞/孔,培养24小时。
用KRB缓冲液洗涤经培养的细胞,悬浮于40ml含1mM IBMX的KRB缓冲液中,然后允许在室温下静立5分钟。泌酸调节肽和泌酸调节肽衍生物(SEQ ID NOs:2-6、8、10-13、17、18、23-25、27、28和32-34)的每一个从1000nM至0.02nM连续五倍稀释,将40Ml每一个稀释物添加至细胞,然后在CO2培养箱中37℃下温育1小时。然后,添加20ml细胞裂解缓冲液以裂解细胞,并使用cAMP检测试剂盒(Molecular Device,USA)测量细胞裂解物的每一个中cAMP的浓度。由测量结果,计算EC50值,并相互比较(表2)。
【表2】
泌酸调节肽衍生物之间GLP-1受体和胰高血糖素受体的体内活性比较
由以上表2可见,与SEQ ID NO:1的泌酸调节肽相比,泌酸调节肽衍生物显示优异的体内GLP-1和胰高血糖素活性。
已知泌酸调节肽具有通过激活GLP-1受体和胰高血糖素受体来治疗高脂血症、脂肪肝病或动脉硬化的作用。与天然泌酸调节肽相比,根据本发明的泌酸调节肽衍生物具有优异的激活GLP-1受体和胰高血糖素受体的活性,因此可用于代替天然泌酸调节肽来治疗高脂血症以及与高脂血症有关的脂肪肝病和动脉硬化。
实施例3:制备包含泌酸调节肽衍生物(SEQ ID NO:23)与免疫球蛋白Fc的缀合物
(免疫球蛋白Fc连接的泌酸调节肽衍生物23)
为了用MAL-10K-ALD PEG(NOF.,Japan)聚乙二醇化SEQ ID NO:24泌酸调节肽衍生物第24位的半胱氨酸残基,允许泌酸调节肽衍生物(SEQ ID NO:23)和MAL-10K-ALD PEG在室温下以3㎎/Ml的蛋白浓度以1:3的摩尔比相互反应3小时。该反应在50mM含有1M胍的Tris缓冲液(pH 8.0)中进行。在反应完成之后,使用SOURCE S在以下条件下纯化反应溶液,从而获得单聚乙二醇化至半胱氨酸的泌酸调节肽:柱:SOURCE S,流速:2.0Ml/min,梯度:A 0→100%50min B(A:20mM柠檬酸钠,pH 3.0+45%乙醇,B:A+1M KCl)。
然后,允许经纯化的单聚乙二醇化泌酸调节肽衍生物(SEQ ID NO:23)和免疫球蛋白Fc在4℃下以20㎎/Ml的蛋白浓度以1:5的摩尔比相互反应16小时。该反应在100mM含有20mM SCB作为还原剂的磷酸钾缓冲液(pH 6.0)中进行。在反应完成之后,在以下条件下纯化反应溶液,从而获得含有泌酸调节肽衍生物(SEQ ID NO:23)和免疫球蛋白的缀合物:柱:SOURCE 15Q,流速:2.0Ml/min,梯度:A 0→4%1min,B→20%80min B(A:20mM Tris-HCl,pH7.5,B:A+1M NaCl);源ISO柱:SOURCE ISO,流速:2.0Ml/min,梯度:B 0→100%100min A,(A:20mM Tris-HCl,pH 7.5,B:A+1.1M AS)。
实施例4:制备包含泌酸调节肽衍生物(SEQ ID NO:25)与免疫球蛋白Fc的缀合物
(免疫球蛋白Fc连接的泌酸调节肽衍生物25)
为了用MAL-10K-ALD PEG聚乙二醇化SEQ ID NO:25泌酸调节肽衍生物第30位的半胱氨酸残基,允许泌酸调节肽衍生物(SEQ ID NO:25)和MAL-10K-ALD PEG在室温下以3㎎/ml的蛋白浓度以1:3的摩尔比相互反应3小时。该反应在50mM含有1M胍的Tris缓冲液(pH8.0)中进行。在反应完成之后,使用SOURCE S在以下条件下纯化反应溶液,从而获得单聚乙二醇化至半胱氨酸中的泌酸调节肽:柱:SOURCE S,流速:2.0ml/min,流速:A0→100%50minB(A:20mM柠檬酸钠,pH 3.0+45%乙醇,B:A+1M KCl)。
然后,允许经纯化的单聚乙二醇化泌酸调节肽衍生物(SEQ ID NO:25)和免疫球蛋白Fc在4℃下以20㎎/Ml的蛋白浓度以1:5的摩尔比相互反应16小时。该反应在100mM含有20mM SCB作为还原剂的磷酸钾缓冲液(pH 6.0)中进行。在反应完成之后,在以下条件下纯化反应溶液,从而获得含有泌酸调节肽衍生物(SEQ ID NO:25)和免疫球蛋白的缀合物:SOURCE 15Q柱:SOURCE 15Q,流速:2.0Ml/min,流速:A0→4%1min B→20%80min B(A:20mMTris-HCl,pH 7.5,B:A+1M NaCl);和Source ISO柱:SOURCE ISO,流速:2.0Ml/min,流速:B0→100%100min A(A:20mM Tris-HCl,pH 7.5,B:A+1.1M AS)。
实施例5:长效泌酸调节肽在高脂血症模型仓鼠中降低脂质的作用
实施例5-1:试验动物组
8周龄的雄性仓鼠(Golden Syrian仓鼠,120-130g)购买自Vital River China。已知仓鼠显示与人相似而与其他啮齿类动物不同的血脂谱,并对高脂肪膳食敏感。
允许动物获得灭菌的高脂肪膳食(含有11.5%玉米油、11.5%椰子油、0.5%胆固醇和0.25%脱氧胆酸的Purina 5001;Dyets,Bethlehem,PA)或标准啮齿类动物膳食(低脂肪,2018;Harlan Teklad,Madison,WI)。允许正常膳食组获得过滤和UV灭菌的自来水,并允许高脂肪膳食组获得含有10%果糖的水。将动物关在满足GLP标准的饲养室中,处于12小时照明/12小时避光循环(照明:am 6至pm 6)下,所有的实验过程根据动物实验标准指南进行。在3周的高脂血症诱导之后开始药物施用,如以下表3中所示,动物被分为四组(n=6)。
【表3】
具体地,组1(正常组)被喂以正常食物,并皮下施用5ml/kg的Dulbecco磷酸盐缓冲盐水(DPBS,Sigma)每周一次或多次。
组2(高脂血症诱导的组)被喂以高脂肪膳食以诱导高脂血症,然后皮下施用5ml/kg的Dulbecco磷酸盐缓冲盐水(DPBS,Sigma)每周一次或多次。
组3(高脂血症诱导组+施用3.25nmol/kg的SEQ ID NO:25-Fc缀合物的组)被喂以高脂肪膳食以诱导高脂血症,然后以5ml/kg的注射剂量施用3.25nmol/kg的SEQ ID NO:25-Fc缀合物(在实施例4中制备)每周一次。
组4(高脂血症诱导的组+施用8.96nmol/kg的SEQ ID NO:23-Fc缀合物的组)被喂以高脂肪膳食以诱导高脂血症,然后以5ml/kg的注射剂量施用8.96nmol/kg的SEQ ID NO:23-Fc缀合物(在实施例3中制备)每周一次。
将盐水或药物施加至每个组(n=6)中达2周,然后分析其降低脂质水平的作用。
实施例5-2:分析长效泌酸调节肽衍生物缀合物降低脂质水平的作用
为了检验长效泌酸调节肽衍生物缀合物降低仓鼠中脂质水平的作用,进行以下试验。
从如实施例5-1所述的施用或未施用长效泌酸调节肽衍生物的仓鼠中收集血液,并使用HITACHI 7020分析血液的脂质水平。图1至5显示了分析的结果。
图1至5显示血液三酰甘油水平的变化(图1),血液总胆固醇水平的变化(图2),LDL-胆固醇水平的变化(图3),血液HDL-胆固醇水平(图4),以及血液HDL/LDL-胆固醇之比的变化(图5)。统计学处理获得的结果,并计算平均值和平均值的标准差。在组(n=6)间显著性的证明中,使用单因素ANOVA的Dunnett检验(Dunnett's test)统计学处理数据,p<0.05的值被视为统计学上显著的。
具体地,血液三酰甘油水平的测量结果中,观察到在喂以高脂肪膳食的仓鼠的实例中,三酰甘油水平显著升高,但当长效泌酸调节肽衍生物(SEQ ID NO:25-Fc缀合物或SEQID NO:23-Fc缀合物)施用于仓鼠中时,三酰甘油水平显著降低(图1)。
在血液总胆固醇水平的测量结果中,观察到在喂以高脂肪膳食的仓鼠的实例中,血液总胆固醇水平显著升高,但当长效泌酸调节肽衍生物(SEQ ID NO:25-Fc缀合物或SEQID NO:23-Fc缀合物)施用于仓鼠中时,血液总胆固醇水平显著降低(图2)。
在血液LDL-胆固醇水平的测量结果中,观察到在喂以高脂肪膳食的仓鼠的实例中,血液LDL-胆固醇水平显著升高,但当长效泌酸调节肽衍生物(SEQ ID NO:25-Fc缀合物或SEQ ID NO:23-Fc缀合物)施用于仓鼠中时,血液LDL-胆固醇胆固醇水平显著降低(图3)。
在血液HDL-胆固醇水平的测量结果中,与高脂肪膳食仓鼠组相比,施用SEQ IDNO:25-Fc缀合物或SEQ ID NO:23-Fc缀合物的组显示血液HDL-胆固醇水平显著升高(图4)。
在血液HDL/LDL-胆固醇水平的测量结果中,与高脂肪膳食仓鼠组相比,施用SEQID NO:25-Fc缀合物或SEQ ID NO:23-Fc缀合物的组显示血液HDL/LDL-胆固醇之比显著升高(图5)。
从以上结果可以看出,包含通过PEG共价连接至泌酸调节肽衍生物的免疫球蛋白Fc区的创造性泌酸调节肽衍生物缀合物预防了血液三酰甘油和低密度(LDL)胆固醇的积累,因此可有效用于治疗高脂血症或相关的脂肪肝病或动脉硬化。
实施例6:分析已知的长效GLP-1类似物和长效泌酸调节肽衍生物缀合物的作用
为长效胰高血糖素样肽-1,为目前投入市场作为用于治疗糖尿病的剂并已知具有治疗肥胖和提高HDL胆固醇水平的作用的GLP-1类似物。
在泌酸调节肽衍生物缀合物与已知的之间比较降低脂质水平的作用。
如实施例5中所述,仓鼠被分为正常仓鼠组和喂以高脂肪膳食的仓鼠组。正常仓鼠组皮下施用5ml/kg的DPBS,每周一次或多次。喂以高脂肪膳食的仓鼠组被分为皮下施用5ml/kg的DPBS每周一次或多次的组、皮下施用35.5nmol/kg的每周一次或多次的组、皮下施用3.25nmol/kg的SEQ ID NO:25-Fc缀合物的组、和皮下施用8.96nmol/kg的SEQ ID NO:23-Fc缀合物的组,这些组的血脂水平得到分析。
结果,可见与施用商业的相比,施用创造性长效泌酸调节肽衍生物缀合物(SEQ ID NO:25-Fc缀合物或SEQ ID NO:23-Fc缀合物)显示血液总胆固醇水平的降低(图6)和血液LDL-胆固醇水平的降低(图7)。
此外,可见与施用相比,施用创造性长效泌酸调节肽衍生物缀合物(SEQ ID NO:25-Fc缀合物或SEQ ID NO:23-Fc缀合物)显示血液HDL-胆固醇水平和HDL/LDL-胆固醇之比的升高(图8和9)。具体地,与相比,长效SEQ ID NO:25-Fc缀合物显示血液HDL-胆固醇水平和HDL/LDL-胆固醇之比的显著升高。
此外,与施用相比,施用创造性长效泌酸调节肽衍生物缀合物(SEQID NO:25-Fc缀合物或SEQ ID NO:23-Fc缀合物)显示血液三酰甘油水平的降低。
从以上结果可以看出,本发明的长效泌酸调节肽衍生物缀合物表现与已知的相等或比其高的脂质降低作用,因此缀合物可有效用作治疗高脂血症、脂肪肝病或动脉硬化的剂。
序列表
<110> 韩美药品株式会社
<120> 治疗高脂血症的包含泌酸调节肽衍生物的组合物
<130> OPA13100
<150> KR10-2012-0081475
<151> 2012-07-25
<160> 53
<170> KopatentIn 2.0
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<211> 37
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His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
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Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn
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Arg Asn Asn Ile Ala
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<210> 2
<211> 37
<212> PRT
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<220>
<221> 变体
<222> (1)
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His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
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Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn
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Arg Asn Asn Ile Ala
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His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
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His Gly Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Gln Met Glu Glu
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His Ser Gln Gly Thr Phe Thr Ser Asp Leu Ser Arg Gln Leu Glu Glu
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<223> 该"H"指组氨酸、4-咪唑乙酰基的衍生物。
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His Gly Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Glu
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20 25 30
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<213> 泌酸调节肽衍生物
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<221> 变体
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His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Gln Met Glu Glu
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<213> 泌酸调节肽衍生物
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<221> 变体
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1 5 10 15
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20 25 30
Glu Glu Glu Ala Val Lys
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<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
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<220>
<221> 变体
<222> (16)
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<220>
<221> 变体
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His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Xaa
1 5 10 15
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20 25 30
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<211> 37
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
<223> 该"H"指组氨酸、4-咪唑乙酰基的衍生物。
<220>
<221> 变体
<222> (20)
<223> Xaa = α-甲基-谷氨酸
<220>
<221> 变体
<222> (24)
<223> Xaa = α-甲基-谷氨酸
<400> 14
His Gly Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Glu
1 5 10 15
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20 25 30
Arg Asn Asn Ile Ala
35
<210> 15
<211> 37
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
<223> 该"H"指组氨酸、4-咪唑乙酰基的衍生物。
<220>
<221> 变体
<222> (24)
<223> Xaa = α-甲基-谷氨酸
<400> 15
His Gly Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Xaa Trp Leu Met Asn Thr Lys Arg Asn
20 25 30
Arg Asn Asn Ile Ala
35
<210> 16
<211> 34
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
<223> 该"H"指组氨酸、4-咪唑乙酰基的衍生物。
<400> 16
His Ser Gln Gly Thr Phe Thr Ser Asp Leu Ser Arg Gln Leu Glu Gly
1 5 10 15
Gly Gly His Ser Gln Gly Thr Phe Thr Ser Asp Leu Ser Arg Gln Leu
20 25 30
Glu Lys
<210> 17
<211> 37
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
<223> 该"H"指组氨酸、4-咪唑乙酰基的衍生物。
<400> 17
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Ile Arg Asn Thr Lys Arg Asn
20 25 30
Arg Asn Asn Ile Ala
35
<210> 18
<211> 40
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
<223> 该"H"指组氨酸、4-咪唑乙酰基的衍生物。
<400> 18
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Ile Arg Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Lys
35 40
<210> 19
<211> 37
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
<223> 该"H"指组氨酸、4-咪唑乙酰基的衍生物。
<400> 19
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Glu
1 5 10 15
Glu Ala Val Lys Leu Phe Ile Glu Trp Ile Arg Asn Thr Lys Arg Asn
20 25 30
Arg Asn Asn Ile Ala
35
<210> 20
<211> 40
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
<223> 该"H"指组氨酸、4-咪唑乙酰基的衍生物。
<400> 20
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Glu
1 5 10 15
Glu Ala Val Lys Leu Phe Ile Glu Trp Ile Arg Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Lys
35 40
<210> 21
<211> 37
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
<223> 该"H"指组氨酸、4-咪唑乙酰基的衍生物。
<400> 21
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Gln Leu Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Val Arg Asn Thr Lys Arg Asn
20 25 30
Arg Asn Asn Ile Ala
35
<210> 22
<211> 30
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
<223> 该"H"指组氨酸、脱氨基-组氨酰基的衍生物。
<400> 22
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Gln Trp Leu Met Asn Thr Lys
20 25 30
<210> 23
<211> 29
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (2)
<223> Xaa =氨基异丁酸
<400> 23
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Cys Trp Leu Met Asn Thr
20 25
<210> 24
<211> 30
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (2)
<223> Xaa =氨基异丁酸
<400> 24
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Gln Trp Leu Met Asn Thr Cys
20 25 30
<210> 25
<211> 30
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (2)
<223> Xaa =氨基异丁酸
<400> 25
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Gln Trp Leu Met Asn Thr Cys
20 25 30
<210> 26
<211> 30
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (2)
<223> Xaa =氨基异丁酸
<400> 26
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Gln Trp Leu Met Asn Thr Cys
20 25 30
<210> 27
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (2)
<223> Xaa =氨基异丁酸
<400> 27
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr
20 25
<210> 28
<211> 29
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (2)
<223> Xaa =氨基异丁酸
<400> 28
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Gln Trp Leu Met Asn Thr
20 25
<210> 29
<211> 37
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (2)
<223> 该"S"指丝氨酸或d-丝氨酸的变体
<400> 29
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn
20 25 30
Arg Asn Asn Ile Ala
35
<210> 30
<211> 37
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
<223> 该"H"指组氨酸、4-咪唑乙酰基的衍生物。
<400> 30
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn
20 25 30
Arg Asn Asn Ile Ala
35
<210> 31
<211> 37
<212> PRT
<213> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
<223> 该"H"指组氨酸、4-咪唑乙酰基的衍生物。
<220>
<221> 变体
<222> (2)
<223> 该"S"指丝氨酸或d-丝氨酸的变体
<400> 31
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn
20 25 30
Arg Asn Asn Ile Ala
35
<210> 32
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (1)
<223> 该"H"指组氨酸、4-咪唑乙酰基的衍生物。
<220>
<221> 变体
<222> (2)
<223> Xaa =氨基异丁酸
<400> 32
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Gln Trp Leu Met Asn Thr Cys
20 25 30
<210> 33
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (2)
<223> Xaa =氨基异丁酸
<400> 33
His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ala Lys Tyr Leu Asp Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Gln Trp Leu Met Asn Thr Cys
20 25 30
<210> 34
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 泌酸调节肽衍生物
<220>
<221> 变体
<222> (2)
<223> Xaa =氨基异丁酸
<400> 34
Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Lys Arg Ala Lys Glu Phe Val Gln Trp Leu Met Asn Thr Cys
20 25 30
<210> 35
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 基团 R2
<400> 35
Lys Arg Asn Arg Asn Asn Ile Ala
1 5
<210> 36
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 基团 R2
<400> 36
Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser
1 5 10
<210> 37
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 基团 R2
<400> 37
Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lys
1 5 10
<210> 38
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 基团 R2
<400> 38
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp
1 5 10 15
<210> 39
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 基团 R2
<400> 39
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Lys
1 5 10 15
<210> 40
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 基团 R2
<400> 40
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Lys
20
<210> 41
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 基团 A 或 B
<400> 41
Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg
1 5 10 15
Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr
20 25
<210> 42
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 基团 A 或 B
<400> 42
Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Glu
1 5 10 15
Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr
20 25
<210> 43
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 基团 A 或 B
<400> 43
Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg
1 5 10 15
Arg Ala Gln Asp Phe Val Ala Trp Leu Lys Asn Thr
20 25
<210> 44
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 基团 A 或 B
<400> 44
Gly Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Glu Glu Glu
1 5 10 15
Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly
20 25
<210> 45
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 基团 A 或 B
<400> 45
Gly Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Gln Met Glu Glu Glu
1 5 10 15
Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly
20 25
<210> 46
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> 基团 A 或 B
<400> 46
Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Arg Gln Met Glu Glu Glu
1 5 10 15
Ala Val Arg Leu Phe Ile Glu Trp Ala Ala
20 25
<210> 47
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 基团 A 或 B
<400> 47
Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Gln Met Glu Glu Glu
1 5 10 15
Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Gly
20 25
<210> 48
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 基团 B
<400> 48
Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Arg Gln Met Glu Glu Glu
1 5 10 15
Ala Val Arg Leu Phe Ile Glu Trp
20
<210> 49
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 基团 B
<400> 49
Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp
1 5 10
<210> 50
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 50
cccggccccc gcggccgcta ttcgaaatac 30
<210> 51
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 51
gaacggtccg gaggacgtcg actcttaaga tag 33
<210> 52
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 52
cagcgacacc gaccgtcccc ccgtacttaa ggcc 34
<210> 53
<211> 32
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 53
ctaaccgact ctcggggaag actgagctcg cc 32
Claims (12)
1.预防或治疗高脂血症、脂肪肝病或动脉硬化的组合物,其包含泌酸调节肽衍生物作为活性成分。
2.根据权利要求1所述的组合物,其中所述泌酸调节肽衍生物具有选自SEQ ID NOs:2至34的氨基酸序列。
3.根据权利要求1所述的组合物,其中所述泌酸调节肽衍生物的形式为连接至选自免疫球蛋白片段、抗体、弹性蛋白、白蛋白和纤连蛋白的一种的缀合物。
4.根据权利要求3所述的组合物,其中所述缀合物为这样的缀合物,在其中具有选自SEQ ID NOs:2至34的氨基酸序列的所述泌酸调节肽衍生物通过非肽基聚合物连接至免疫球蛋白Fc区。
5.根据权利要求4所述的组合物,其中所述非肽基聚合物选自聚乙二醇、聚丙二醇、乙二醇/丙二醇共聚物、聚氧乙基化多元醇、聚乙烯醇、多糖、葡聚糖、聚乙烯***、PLA(聚乳酸)、PLGA(聚乳酸-乙醇酸)、脂质聚合物、壳多糖、透明质酸和其组合。
6.根据权利要求4所述的组合物,其中所述非肽基聚合物的一端和另一端分别连接至所述免疫球蛋白Fc区和所述泌酸调节肽衍生物的胺基或硫醇基。
7.根据权利要求1所述的组合物,其进一步包括显示对高脂血症、脂肪肝病或动脉硬化的预防或治疗效果的药剂。
8.根据权利要求1所述的组合物,其中所述脂肪肝病为非酒精性脂肪肝病、酒精性脂肪肝病、营养性脂肪肝病、饥饿性脂肪肝病、肥胖性脂肪肝病、糖尿病性脂肪肝病或脂肪性肝炎。
9.根据权利要求8所述的组合物,其中所述非酒精性脂肪肝病由高脂血症、糖尿病或肥胖所导致。
10.根据权利要求8所述的组合物,其中所述非酒精性脂肪肝病选自单纯性脂肪变性、非酒精性脂肪性肝炎、肝纤维化和肝硬化。
11.预防或治疗高脂血症、脂肪肝病或动脉硬化的方法,其包括将泌酸调节肽衍生物施用于对象的步骤。
12.泌酸调节肽衍生物在制备用于预防或治疗高脂血症、脂肪肝病或动脉硬化的药物中的应用。
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CN103732616A (zh) * | 2011-06-17 | 2014-04-16 | 韩美科学株式会社 | 包括泌酸调节肽和免疫球蛋白片段的结合物以及其应用 |
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