CN1454214A - 具有增高功效的修饰生物肽 - Google Patents
具有增高功效的修饰生物肽 Download PDFInfo
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- CN1454214A CN1454214A CN01813865A CN01813865A CN1454214A CN 1454214 A CN1454214 A CN 1454214A CN 01813865 A CN01813865 A CN 01813865A CN 01813865 A CN01813865 A CN 01813865A CN 1454214 A CN1454214 A CN 1454214A
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Abstract
本发明涉及具有高效价、长效活性和/或长半寿期的修饰生物肽。经偶联通过酰胺键用至少一个刚性构象取代基在肽的N端上、在肽的C端上、在沿肽链的游离氨基或羧基上,或者在多个这些位点上进行修饰。那些肽在例如与病变如II型糖尿病有关的胰岛素耐受性的治疗中表现出临床效果。
Description
发明领域
本发明涉及具有增高的生物功效、长效活性和/或增长的半寿期的修饰肽。通过酰胺键与至少一个位于肽的N端、肽的C端或沿肽链的游离氨基或羧基或位于多个这些位点的刚性构象取代基偶联来完成修饰。
发明背景
大多数肽在血清培养基中迅速降解,因此其代谢物有时以没有剩余生物血活性或剩余生物学活性很低而告终。为了提高肽的活性,人们已经提出了许多技术。其中一种是在肽序列的N端或C端或在沿肽链的其他残基固着一个疏水性链。然而这种技术也存在局限性。譬如,如果肽具有长肽链,事实上固着在N端或C端的小疏水性基团不一定使如此修饰的肽产生增高的活性。
譬如,已知用更加疏水的基团如-Net2取代肽序列的C端的OH可以使比活性明显增高。然而,这些结论却遭到许多文章的反驳,例如Muranichi等在Pharm.Res.,1991,8,649-652中,他们强调月桂酰基作为疏水性基团在N端无法提高活性。所以,目前似乎没有任何有关生物功效、作用时间和/或半寿期的普遍规则,是在N端还是C端上或在沿肽链的某些残基上,可以从肽链上的取代基的添加获得结果。
US 6,020,311公开一种疏水性生长激素释放因子(GRF)类似物,其中刚性疏水性部分经酰胺键偶联在GRF肽的N端。这样的类似物据称具有增高的合成代谢效价、降低的剂量,并且延长的活性。所以按照该专利的教导,刚性疏水性部分总是在一个末端含有一个羰基,这意味着与GRF的酰胺偶联只发生在氨基位点以生成所需的酰胺键。该专利没有提及、建议或暗示如果酰胺偶联是在C端进行通过用氨基置换刚性疏水性部分的羰基可以获得类似的结果。该专利没有进一步提及、建议或暗示酰胺偶联也可以在肽链上发生。
Biochemistry 2001,40,2860-2869页公开了一种疏水性胰高血糖素样肽-1(GLP-1)类似物,其中己烯酸——一种刚性疏水性部分偶联在GLP-1肽的N端。结果证明这种类似物对GLP-1受体具有低亲和力,但体内生物活性类似于或略好于野生型GLP-1,推断这归因于对血清降解的耐受性增高。根据这个研究,酰基链与His1的连接、Ala2的氨基酸取代,以及在分子的N端氨基酸序列的添加将是比固着刚性疏水链更好的提高体内生物活性的战略。然而,大多数的这些战略涉及天然分子的氨基酸组成的修饰,这可能对临床应用产生负面的安全后果,包括免疫原性的危险和副作用。
所以非常需要开发出以提高其活性方式修改的肽,由此提高其功效,即对血清降解作用和/或高激动活性的对抗性更高,和/或延长其半寿期但不改变氨基酸序列,这在临床上安全且可接受。
发明概述
根据本发明,现在提供了式Xn-R1的肽,其中:
-R1是肽序列,当X表示连接在肽序列的N端的反式-3-己烯酰基时它不是GRF序列;
-各X可以相同或彼此独立并且选自下列具有下面组成的刚性构象部分:
a)经酰胺键可以与肽序列在肽序列的N端、肽序列的C端、肽序列链的可利用羧基或氨基位点上及其组合偶联的羧基或氨基;和
b)与肽序列经酯键在该肽序列链上的可利用羟基位点及其组合偶联的羧基;
其中,
n是介于1-5的任意数;
X被定义为:
i)直链、被取代的C1-C10烷基;
ii)支链、被取代的C1-C10烷基;
iii)直链或支链、未被取代的和被取代的C1-C10链烯;
iv)直链或支链、未被取代的和被取代的C1-C10链炔;
v)未被取代的和被取代的、饱和或不饱和C3-C10环烷基或杂环烷基,其中所述的杂原子是O、S或N;
vi)未被取代的和被取代的C5-C14芳基或杂芳基,其中所述的杂原子O、S或N;
其中定义i)-vi)中的取代基包括一个或多个
a)直链或支链C1-C6烷基;
b)直链或支链C1-C6链烯;
c)直链或支链C1-C6链炔;
d)C3-C10环烷基或杂环烷基,其中至少2个碳原子任选地与C1-C10烷基、C1-C10链烯、C1-C10链炔、C3-C10环烷基或杂环烷基、和C5-C14芳基或杂芳基连接;和
e)C5-C14芳基或杂芳基,其中所述芳基或杂芳基的至少2个碳原子任选地与C1-C10烷基、C1-C10链烯、C1-C10链炔、C3-C10环烷基或杂环烷基、和C5-C14芳基或杂芳基连接;
及其任何异构体,包括顺式和反式构型、差向异构体、对映异构体、非对映异构体和消旋混合物。
术语″芳基″包括苯基、萘基等;术语″杂环烷基″包括四氢呋喃基、四氢噻吩基、四氢噻喃基、四氢吡喃基及其部分脱氢衍生物,氮杂环丁烷基、哌啶基、吡咯烷基等;术语″杂芳基″包括吡啶基、吲哚基、呋喃基、咪唑基、四氢噻吩基、吡咯基、喹啉基、异喹啉基、嘧啶基、噁唑基、噻唑基、异噻唑基、异噁唑基、吡唑基等。
术语″刚性构象部分″是指具有受限制构象,即围绕其单键旋转移动的实体。这种运动受到限制,例如,由于双键、叁键或饱和或不饱和环的存在,其具有很小的或没有构象移动性。所以,当与例如相应的直链、未取代和饱和脂肪链比较时,构象异构体或内旋异构体的数量有所减少。刚性构象部分可以是疏水性的,尽管这不是先决条件。
根据本发明的一个优选实施方式,肽序列选自生长激素释放因子(GRF)、促生长素抑制素、胰高血糖素样肽1(7-37)、酰胺人(GLP-1)、hGLP-1(7-36)NH2甲状旁腺素片段如(PTH 1-34)、促肾上腺皮质激素(ACTH)、骨钙蛋白、降钙素、促肾上腺皮质激素释放因子、强啡肽A、β-内啡肽、巨胃泌素-1、GLP-2、黄体激素释放激素、促黑激素(MSH)、心房肽、神经调节肽B、人神经肽Y、人OrexinA、人肽YY、人促胰液素、血管活性肠肽(VIP)、抗菌肽(爪蟾抗菌肽1、爪蟾抗菌肽2、杀菌肽A和杀菌肽B)、P物质(SP)、βCasomorphin-5、内啡素-2、Procolipase、Enterostatin、肠抑肽、嗜铬粒蛋白A、Vasostatin I & II、降钙素原、ProNCT、ProCGRP、IL8(单核细胞衍化的)、GCP-2、PF4、IP-10、MIG、SDF-1α、GRO-α、I-TAC、RANTES、LD78、MIP-1α、MCP-1、MCP-2、MCP-3、MCP-4、Eotaxin、MDC,和它们的官能衍生物或片段。发明详述
在本申请中氨基酸用下列常规的三字母缩写来表示,其通过IUPAC-IUB协会按生物化学命名法推荐被肽领域普遍接受:
丙氨酸 Ala 亮氨酸 Leu
精氨酸 Arg 赖氨酸 Lys
天门冬酰胺 Asn 蛋氨酸 Met
天门冬氨酸 Asp 苯丙氨酸 Phe
半胱氨酸 Cys 脯氨酸 Pro
谷氨酸 Glu 丝氨酸 Ser
谷酰胺 Gln 苏氨酸 Thr
甘氨酸 Gly 色氨酸 Trp
组氨酸 His 酪氨酸 Tyr
异亮氨酸 Ile 缬氨酸 Val
所有在此给出的肽序列按照一般可接受的常规方式按照N端氨基酸位于左方且C端氨基酸位于右方来撰写。
本发明涉及至少一种刚性构象部分在制备一类新的具有增强了的药理学特性的肽家族中的应用。
本发明的修饰肽是按照下面固相合成领域中熟知的通用方法来制备。
含有羧基的刚性构象部分可以用于固着氨基例如存在于赖氨酸侧链上及肽的N端上的那些。含有氨基酸的那些用于固着羧基例如在天门冬氨酸或谷氨酸侧链或肽的C端上发现的那些。对于这样的情况,固着反应适宜在固相载体上(Merrifield R.B.1963,J.Am.Chem.Soc.,
1963,
85,2149和J.Am.Chem.Soc.,
1964,
86,304)用苯并三唑-1-基-氧基-三(二甲基氨基)六氟磷酸鏻通过Castro在文章(B.Castro等,1975,Tetrahedron letters,Vol.14:1219)中所述的方法制备。
对于固着动态,优选的工作温度是20℃-60℃。在更加疏水部分的情况中固着反应时间逆反应温度而变化,并且在0.1-24小时。
合成步骤是通过固相法在手动肽合成仪上用采用Fmoc策略进行。Fmoc氨基酸是由位于芝加哥的Chem Impex International Inc.和其他化学品来源提供。使用BOP作为偶联剂的连续Fmoc化学应用于PL-Wang树脂(Polymer Laboratories,目录号:1463-4799)来制备C端羧酸。
Fmoc脱保护是用哌啶20%的DMF溶液在三个连续步骤中完成。通常在氮气冲洗下,使用1分钟20%的哌啶第一溶液以除去大部分的Fmoc保护基。随后,排出该溶液,并且引入另一新制的哌啶20%溶液,共3分钟,再排出该溶液且最后引入另一20%哌啶溶液,共10分钟。进而肽-树脂连续用50mL的DMF在氮气冲洗下洗涤4次。合成完成之后,树脂用DMF和DCM充分洗涤,随后干燥。
侧链保护基和肽-树脂键的最终裂解是用下列混合物进行:TFA、乙二硫醇、三异丙基硅烷、苯硫基甲烷、苯酚、水(92∶1.66∶1.66∶1.66∶1∶2)。用20mL裂解混合物/克干燥肽-树脂的终浓度裂解下树脂上的肽。该裂解反应是在室温下进行2小时。将现存于TFA混合物中的游离肽在粗玻璃圆盘漏斗上过滤。该树脂随后用纯净TFA洗涤3次。所述的肽/TFA混合物在真空下在旋转转发器上蒸发,沉淀并用醚洗涤,随后将其溶解在水中并冷冻干燥以消除残留的溶剂和清除剂。第一Fmoc-氨基酸偶联于Wang树脂
我们使用4-烷氧基苄醇聚苯乙烯(Wang树脂)和2当量存在于DMF中的预定Fmoc-氨基酸并且在氮气冲洗下使这两者产品在室温下混和15分钟。随后连续加入3.3当量的吡啶和2当量的2,6-二氯苯甲酰氯,该反应在氮气冲洗下进行15-20小时。(Seiber P.,1987,Tetrahedron Letters,Vol.28,No.49,pp 6147-6150)。该反应之后,取出反应容器并连续用DMF在氮气冲洗下洗涤该树脂4次。树脂的所有残留羟基用3当量的苯甲酰氯和吡啶在DCE(二氯乙烷)中苯甲酰化2小时。在伸长的肽上各种残余氨基酸的偶联
对于下列各种Fmoc-氨基酸,我们将3当量的Fmoc-氨基酸溶解在3当量存在于DMF中的BOP(苯并三唑-1-基-氧基-三(二甲基氨基)六氟磷酸鏻)(B.Castro等,1975,Tetrahedron letters,Vol.14:1219),将所得溶液加入到反应容器中的树脂上,开始氮气冲洗并加入6当量的DIPEA(二异丙基乙胺)以开始该偶联反应。反应容器中偶联混合物在氮气下冲洗60分钟;随后从容器中取出,该树脂连续用DMF洗涤3次并进行定量茚三酮试验以检验反应是否完全。
Fmoc-L-Lys(Aloc)-OH(PerSeptive Biosystems,目录号:GEN911209)、Fmoc-L-Glu(OAl)-OH(PerSeptive Biosystems,目录号:GEN911207)和Fmoc-L-Asp(OAl)-OH(PerSeptive Biosystems,目录号:GEN911205)的偶联是按照与上述Fmoc-氨基酸相同的方式进行。烯丙基的脱保护
将肽-树脂(Xmmol)随后引入氮气冲洗下的DCM中并在10分钟之后向该混合物中加入PdCl2(PPh3)2(Xmmol×0.05/0.05当量)(钯(II)双-三苯基膦)(Bürger H.,Kilion W.,J.Organometallics,1969,18:299)。此后使(CH3CH2CH2)3SnH(Xmmol×6/6当量)(tributyltinhydride)在DCM中稀释并用滴液漏斗在30分钟内滴加到肽-树脂混悬液。该反应继续进行10分钟,此后从容器取出裂解混合物且随后肽-树脂用DCM洗涤4次并DMF洗涤4次(Dangles O.,GuibéF.,Balavoine G.,LavielleS.,Marquet A.,1987,J.Org.Chem.,52:4984).刚性构象酸和烷基胺的偶联
刚性构象酸和胺与肽-树脂的侧链的偶联是在如同Fmoc-氨基酸的那些条件下进行,但对于这些侧链修饰我们使用10当量的刚性部分和偶联剂,而不是3当量。
本发明不限于任何具体肽序列。优选的肽序列R1包含具有治疗性质的那些,以及它们的官能衍生物或片段。本发明可以使用的这些肽的治疗性质包括但不限于:骨疾病的治疗,包括骨质疏松症、绝经后骨质疏松症和骨沉积,癌治疗,血糖调控,II型糖尿病,增强肠道疾病患者中粘膜再生的治疗,与炎性反应有关的疾病的治疗,肥胖治疗,孤独癖和倒错恶化症(pervasive development disorder)的治疗,过度增生性皮肤病症,衰老,改变外周血单核细胞的增殖,子宫肌收缩性和前列腺素释放的调节,ACTH释放的刺激,白介素-8生成的抑制,酸释放的刺激,患有肠道疾病的患者中粘膜再生的促进,激素依赖性疾病和涉及激素药理学癌的病症的治疗,黑素细胞信息传递过程的调节,参与压力和容积的内环境稳定,外分泌物和内分泌物分泌、平滑肌收缩、饮食、血压血糖、体温和细胞生长的调控,食物摄取和能力平衡的调节,癌细胞生长的抑制,胰腺分泌的刺激,和促进细胞生长。
生长激素释放因子(GRF):
Xaa1-Xaa2-Asp-Ala-Ile-Phe-Thr-Xaa8-Ser-Tyr-Arg-Lys-Xaa13-Leu-Xaa15-Gln-Leu-Xaa18-Ala-Arg-Lys-Leu-Leu-Xaa24-Xaa25-Ile-Xaa27-Xaa28-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH2
其中,
Xaa1是Tyr或His;
Xaa2是Val或Ala;
Xaa8是Asn或Ser;
Xaa13是Val或Ile;
Xaa15是Ala或Gly;
Xaa18是Ser或Tyr;
Xaa24是Gln或His;
Xaa25是Asp或Glu;
Xaa27是Met、Ile或Nle;和
Xaa28是Ser或Asn。
其中,
Xaa12是Tyr或Ser.
胰高血糖素样肽1(7-37),(酰胺人(hGLP-1)):
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-OH(NH2)
甲状旁腺素片段(PTH 1-34):
Xaa1-Val-Ser-Glu-Xaa5-Gln-Xaa7-Met-His-Asn-Leu-Gly-Xaa13-His-Xaa15-Xaa16-Xaa17-Xaa18-Glu-Arg-Xaa21-Xaa22-Trp-Leu-Xaa25-Xaa26-Lys-Leu-Gln-Asp-Val-His-Xaa33-Xaa34-NH2
其中,
Xaa1是Ser或Ala;
Xaa5是Ile或Met;
Xaa7是Leu或Phe;
Xaa13是Lys或Glu;
Xaa15是Leu或Arg;
Xaa16是Asn或Ala或Ser或His;
Xaa17是Ser of Thr;
Xaa18是Met或Val或Leu;
Xaa21是Val或met或Gln;
Xaa22是Glu或Gln或Asp;
Xaa25是Arg或Gln;
Xaa26是Lys或Met;
Xaa33是Asn或Ser;和
Xaa34是Phe或Ala.
促肾上腺皮质激素(ACTH):
Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Xaa13-Gly-Xaa15-Lys-Arg-Arg-Pro-Xaa20-Lys-Val-Tyr-Pro-Asn-Xaa26-Xaa27-Xaa28-Xaa29-Glu-Xaa31-Xaa32-Glu-Xaa34-Xaa35-Xaa36-Xaa37-Glu-Xaa39-NH2
其中,
Xaa13是Val或Met;
Xaa15是Lys或Arg;
Xaa20是Val或Ile;
Xaa26是Gly或Ser;
Xaa27是Ala或Phe或Val;
Xaa28是Glu或Gln;
Xaa29是Asp或Asn或Glu;
Xaa31是Ser或Thr;
Xaa32是Ala或Val或Ser;
Xaa34是Ala或Asn或Gly;
Xaa35是Phe或Met;
Xaa36是Pro或Gly;
Xaa37是Leu或Val或Pro;和
Xaa39是Phe或Val或Leu.
骨钙蛋白:
Tyr-Leu-Xaa52-Xaa53-Xaa54-Leu-Gly-Ala-Pro-Xaa59-Pro-Tyr-Pro-Asp-Pro-Leu-Glu-Pro-Xaa68-Arg-Glu-Val-Cys-Glu-Leu-Asn-Pro-Xaa77-Cys-Asp-Glu-Leu-Ala-Asp-His-Ile-Gly-Phe-Gln-Xaa89-Ala-Tyr-Xaa92-Arg-Xaa94-Tyr-Gly-Xaa97-Val-NH2
其中,
Xaa52是Tyr或Asp或Asn;
Xaa53是Gln或His或Asn;
Xaa54是Trp或Gly;
Xaa59是Val或Ala;
Xaa68是Arg或Lys或His;
Xaa77是Asp或Asn;
Xaa89是Glu或Asp;
Xaa92是Arg或Lys;
Xaa94是Phe或Ile;和
Xaa97是Pro或Thr.
降钙素:
Cys-Xaa86-Xaa87-Leu-Ser-Thr-Cys-Xaa92-Leu-Gly-Xaa95-Xaa96-Xaa97-Xaa98-Xaa99-Xaa100-Xaa101-Xaa102-Xaa103-Xaa104-Thr-Xaa106-Xaa107-Xaa108-Xaa109-Xaa110-Xaa111-Gly-Xaa113-Xaa114-Xaa115-Pro-NH2
其中,
Xaa86是Gly或Ser或Ala;
Xaa87是Asn或Ser;
Xaa92是Met或Val;
Xaa95是Thr或Lys;
Xaa96是Tyr或Leu;
Xaa97是Thr或Ser;
Xaa98是Gln或Lys;
Xaa99是Asp或Glu;
Xaa100是Phe或Leu;
Xaa101是Asn或His;
Xaa102是Lys或Asn;
Xaa103是Phe或Leu;
Xaa104是His或Gln;
Xaa106是Phe或Tyr;
Xaa107是Pro或Ser;
Xaa108是Gln或Gly或Arg;
Xaa109是Thr或Ile;
Xaa110是Ala或Gly或Ser或Asp或Asn;
Xaa111是Ile或Phe或Val或Thr;
Xaa113是Val或Ala或Ser;
Xaa114是Gly或Glu;和
Xaa115是Ala或Thr.
促肾上腺皮质激素释放因子:
Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Xaa101-Xaa102-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Met-Glu-Ile-Ile-NH2
其中,
Xaa101是Ala或Pro;和
Xaa102是Arg或Gly.
强啡肽A:
H-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-OH
β-内啡肽:
H-Tyr-Gly-Gly-Phe-Met-Thr-Xaa243-Glu-Xaa245-Ser-Gln-Thr-Pro-Leu-Xaa251-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Xaa259-Lys-Asn-Xaa262-Xaa263-Lys-Lys-Gly-Xaa267-OH
其中,
Xaa243是Ser或Pro;
Xaa245是Lys或Arg;
Xaa251是Val或Met;
Xaa259是Ile或Val;
Xaa262是Ala或Thr或Ser或Val;
Xaa263是Tyr或His;和
Xaa267是Glu或Leu或Gln或His.
巨胃泌素-1:
pXaa59-Leu-Gly-Xaa62-Gln-Xaa64-Xaa65-Xaa66-Xaa67-Xaa68-Xaa69-Ala-Asp-Xaa72-Xaa73-Lys-Lys-Xaa76-Xaa77-Pro-Xaa79-Xaa80-Glu-Xaa82-Glu-Glu-Xaa85-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2
其中,
Xaa59是Glu或Gln;
Xaa62是Pro或Leu;
Xaa64是Gly或Asp;
Xaa65是Pro或Ser;
Xaa66是Pro或Gln;
Xaa67是His或Gln;
Xaa68是Leu或Met或Phe或Gln;
Xaa69是Val或Ile;
Xaa72是Pro或Leu;
Xaa73是Ser或Ala;
Xaa76是Gln或Glu;
Xaa77是Gly或Arg;
Xaa79是Trp或Pro或Arg;
Xaa80是Leu或Val或Met;
Xaa82是Glu或Lys;和
Xaa85是Glu或Ala.
GLP-2:
His-Ala-Asp-Gly-Ser-Phe-Xaa152-Xaa153-Xaa154-Xaa155-Xaa156-Xaa157-Xaa158-Leu-Asp-Xaa161-Xaa162-Ala-Xaa164-Xaa165-Xaa166-Phe-Xaa168-Xaa169-Trp-Xaa171-Xaa172-Xaa173-Thr-Xaa175-Xaa176-Xaa177-Xaa178;
其中,
Xaa152是Ser或Thr;
Xaa153是Asp或Ser;
Xaa154是Glu或Asp;
Xaa155是Met或Phe;
Xaa156是Asn或Ser;
Xaa157是Thr或Lys;
Xaa158是Ile或Val或Ala;
Xaa161是Asn或Ile或His或Ser;
Xaa162是Leu或Lys;
Xaa164是Ala或Thr;
Xaa165是Arg或Gln或Lys;
Xaa166是Asp或Glu;
Xaa168是Ile或Leu;
Xaa169是Asn或Asp;
Xaa171是Leu或Ile;
Xaa172是Ile或Leu;
Xaa173是Gln或Asn或His;
Xaa175是Lys或Pro;
Xaa176是Ile或Val;
Xaa177是Thr或Lys;和
Xaa178是Asp或Glu.
黄体激素释放素:
Xaa1-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-OH
其中,
Xaa1是pGlu、5-氧代Pro或Gln.
促黑激素(MSH):
Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2
心房肽:
H-Ser-Leu-Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Xaa135-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Xaa142-Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr-OH
其中,
Xaa135是Met或Ile;和
Xaa142是Gly或Ser.
神经调节肽B:
H-Gly-Asn-Leu-Trp-Ala-Thr-Gly-His-Phe-Met-NH2
人神经肽Y:
H-Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-Ala-Pro-Ala-Glu-asp-Met-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH2
人Orexin A:
pGlu-Pro-Leu-Pro-Asp-Cys-Cys-Arg-Gln-Lys-Thr-Cys-Ser-Cys-Arg-Leu-Tyr-Glu-Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2
人肽YY:
H-Tyr-Pro-Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2
人促胰液素:
H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Glu-Gly-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH2
血管活性肠肽(VIP):
H-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2
抗菌肽例如:
爪蟾抗菌肽1:
Gly-Ile-Gly-Lys-Phe-Leu-His-Ser-Ala-Gly-Lys-Phe-Gly-Lys-Ala-Phe-Val-Gly-Glu-Ile-Met-Lys-Ser
爪蟾抗菌肽2:
Gly-Ile-Gly-Lys-Phe-Leu-His-Ser-Ala-Lys-Lys-Phe-Gly-Lys-Ala-Phe-Val-Gly-Glu-Ile-Met-Asn-Ser
杀菌肽A:
Lys-Trp-Lys-Val-Phe-Lys-Lys-Ile-Glu-Lys-Val-Gly-Gln-Ala-Thr-Gln-Ile-Ala-Lys
杀菌肽B:
Lys-Trp-Lys-Val-Phe-Lys-Lys-Ile-Glu-Lys-Met-Gly-Arg-Asn-Ile-Arg-Asn-Gly-Ile-Val-Lys-Ala-Gly-Pro-Ala-Ile-Ala-Val-Leu-Gly-Glu-Ala-Lys-Ala-Leu.
P物质(SP):
Arg-Pro-Leu-Pro-Gln-Glu-Phe-Phe-Gly-Leu-Met-amide
βCasomorphin-5:
Tyr-Pro-Phe-Pro-Gly
内啡素-2:
Tyr-Pro-Phe-Phe-NH2
Procolipase:
100氨基酸肽(X1-Pro-X2-Pro-Arg....)
Enterostatin:
Val-Pro-Asp-Pro-Arg
胃泌素抑制肽:
Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln
嗜铬粒蛋白A
Vasostatin I
Vasostatin II:
Leu Pro Val Asn Ser Pro Met Asn Lys Gly Asp Thr Glu Val MetLys Cys Ile Val Glu Val Ile Ser Asp Thr Leu Ser Lys Pro Ser Pro MetPro Val Ser Gln Glu Cys Phe Glu Thr Leu Arg Gly Asp Glu Arg Ile LeuSer Ile Leu Arg His Gln Asn Leu Leu Lys Glu Leu Gln Asp Leu Ala LeuGln Gly Ala Lys Glu Arg Ala His Gln Gln Lys Lys His Ser Gly Phe GluAsp Glu Leu Ser Glu Val Leu Glu Asn Gln Ser Ser Gln Ala Glu Leu LysGlu Ala Val Glu Glu Pro Ser Ser Lys Asp Val Met Glu
Pro降钙素
ProNCT
ProCGRP
趋化因子家族:
CXC组:
IL8(单核细胞衍化的):
SerAlaLysGluLeuArgCysGlnCys...
GCP-2:
GlyProValSerAlaValLeuThrGluLeuArgCysThrCys...
PF4:
GluAlaGluGluAspGlyAspLeuGlnCysLeuCys...
IP-10:
ValProLeuSerArgThrValArgCCysThrCys...
MIG:
ThrProValValArgLysGlyArgCysSerCys...
SDF-1α
LysProValSerLeuSerTyrArgCysProCys...
GRO-α
AlaProLeuAlaThrGluLeuArgCysGlnCys...
I-TAC:
PheProMetPheLysLysGlyArgCysLeuCys...
CC-组:
RANTES:
SerProTyrSerSerAspThrThrProCys...
LD78:
AlaProLeuAlaAlaAspThrProThrAlaCys...
MIP-1α
AlaProMetGlySerAspProProThrAlaCys...
MCP-1:
GlnProAspAlaIleAsnAlaProValThrCys...
MCP-2:
GlnProSerAspValSerIleProIleThrCys...
MCP-3:
GlnProValGlyIleTAsnSeerThrThrCys...
MCP-4:
GlnProAspAlaLeuAspValProSerThrCys...
Eotaxin:
GlyProAlaSerValProThrThrCys...
MDC:
GlyProTyrGlyAlaAsnMetGluAspSerValCys...
和它们的官能衍生物或片段。
上述序列的完全定义具体参见Mentlein,R(1999)Regul.Pept.85:9-24和De Meester,I.等(2000)Adv ExpMed Biol.477:67-87。那些文献在此以引用方式并入本专利申请。
在更加优选的一个实施方式中,肽被一个或多个刚性构象部分取代。刚性构象部分的优选结构是含有双键、叁键或饱和或不饱和环的那些结构。
下面是优选刚性构象部分的结构式的简单目录,称作式1-63,它们适合于本发明的目的。
其中,R是H、CH3或CH2CH3。
本发明的一个优选实施方式是由其中肽序列是促生长素抑制素且至少一个刚性构象部分与该促生长素抑制素肽序列经酰胺键在下面不同的位置偶联的那些肽组成:
位置 刚性构象部分
本发明的另一个优选实施方式是由其中所述肽序列是PTH1-34且至少一个刚性构象部分经酰胺键与该PTH1-34肽序列在下列不同位置偶联的那些肽组成:
位置 刚性构象部分
本发明的另一优选实施方式是由其中所述肽序列是GLP-1且至少一个刚性构象部分与该GLP-1肽序列经酰胺键在下列不同位置偶联的那些肽组成:
位置 刚性构象部分
本发明的另外优选的修饰肽是那些肽,其中:
-所述肽序列是GLP-2且至少一个刚性构象部分与该GLP-2肽序列经酰胺或酯键在该肽序列的不同位置偶联;
-所述肽序列是Enterostatin且至少一个刚性构象部分与该Enterostatin肽序列经酰胺键在该肽序列的不同位置偶联;
-所述肽序列是NPY且至少一个刚性构象部分与该NPY肽序列经酰胺或酯键在该肽序列的不同位置偶联;
-所述肽序列是NPYY且至少一个刚性构象部分与该NPYY肽序列经酰胺或酯键在该肽序列的不同位置偶联;
-所述肽序列是促胰液素且至少一个刚性构象部分与该促胰液素肽序列经酰胺或酯键在该肽序列的不同位置偶联;
-所述肽序列是血管活性肠肽且至少一个刚性构象部分与该血管活性肠肽序列经酰胺或酯键在该肽序列的不同位置偶联;
所述肽序列是胃泌素抑制肽且至少一个刚性构象部分与该胃泌素抑制肽序列经酰胺或酯键在该肽序列的不同位置偶联;
所述肽序列是Vasostatin II和至少一个刚性构象部分与该Vasostatin II肽序列经酰胺或酯键在该肽序列的不同位置偶联;
-所述肽序列是RANTES且至少一个刚性构象部分与该RANTES肽序列经酰胺或酯键在该肽序列的不同位置偶联;
-所述肽序列是Eotaxin且至少一个刚性构象部分与该Eotaxin肽序列经酰胺或酯键在该肽序列的不同位置偶联。
在本发明的修饰肽中,刚性构象部分优选与所述肽序列经酰胺键在N端偶联。
特别优选本发明的修饰肽,其中刚性构象部分是说明书中的式60。
本发明的修饰肽可以以多种途径给药,例如静脉内、皮下、真皮内、经皮、腹膜内、口服和局部给药。当是粉末形式或气雾剂形式时,本发明的修饰肽还可以通过吸入给药。此外,运载本发明的修饰肽的药学可接受载体包括但不限于,脂质体、纳米体、贴剂、植入物和任何给药装置。
除了肽的C端和N端上各自存在的羧基和氨基以外,可以在肽链上获得其他羧基和氨基位点。譬如,如果所述肽链含有提供羧酸侧链的氨基酸如天门冬氨酸和谷氨酸,可以在链上获得用于酰胺化的附加羧酸位点。如果肽链含有具有羧酰胺侧链的氨基酸如天门冬酰胺和谷酰胺,这些也为刚性构象部分酰胺化提供附加的羧基,条件是它们在合成上是经过相应天门冬氨酸和谷氨酸实现的。此外,如果肽含有提供碱性侧链的氨基酸如精氨酸、组氨酸或赖氨酸,则可以在链上获得用于刚性构象部分酰胺化的附加氨基位点。肽链还可以同时含有酸性和碱性氨基酸,是指刚性构象取代基可以经N端、C端、肽链上的羧基位点、肽链上的氨基位点或多个此类位点与肽偶联。
本发明参考下列实施例将更容易理解,这些实施例举例说明而不是限制本发明的范围。实施例1GLP-1类似物的合成
按照本发明,下列刚性构象部分的至少一个与GLP-1肽序列经酰胺键在下列不同位置偶联。
在氨基末端用刚性疏水性部分修饰的hGLP-1(7-37)衍生物是采用Fmoc化学法(1)、在Symphony仪(Rainin Instrument Co.,Inc.)上合成。使用Fmoc-Gly-Wang树脂(0.70mmole/g)和5当量的试剂(100μm规模,氨基酸浓度为200mM)且偶联时间为30分钟。通过Kaiser试验监测该反应。引入到hGLP-1(7-37)的N端的三个刚性构象部分是:
肽#1=(O-甲苯乙酸-His7)-hGLP-1(7-37)[O-甲苯乙酸(
13)(10当量/次偶联;偶联时间45分钟)]
肽#2=((+,-)-顺式-2-乙基环丙基乙酸-His7)-hGLP-1(7-37)[(+,-)-顺式-2-乙基环丙基乙酸(
60)(7.5当量/次偶联:偶联时间60分钟)]。
所述的肽用TFA多层混合物(92%TFA,2%乙二硫醇,2%苯硫基甲烷,2%三异丙基硅烷,2%水,2%(w/v)苯酚)裂解2小时。全部类似物已经通过反相HPLC纯化。通过分析HPLC和通过MS(MALDI-TOF)分析它们。
GLP-1类似物的合成是本发明所属领域技术人员熟知的并且在通用参考文献《Fmoc Solid Phase Peptide Synthesis.A Practical Approach(2000)》Chan,W.C.和White,P.D.,Oxford University Press,New York,USA,346p中有详细的描述,其在此以引用方式并入本文。GLP-1类似物的生物学评估材料和方法口服葡萄糖耐受试验(OGTT)
使6周龄CD1小鼠(Charles River)禁食至少16小时。经胃口饲管在t=0时刻口服给予存在于水中的1.5mg葡萄糖/g体重并且在t=0,10,20,30,60,90分钟和120分钟从尾静脉取血,用葡萄糖计(Lifescan)测定血糖。在给予葡萄糖之前5分钟皮下注射所述的肽或载体。数据表示为曲线下面积,由各时刻的血糖的变化(δ)按照梯形规则计算。所以,数据代表在给予葡萄糖之后120分钟内血糖的整合增量。数据表示为每组4-11只动物的平均值±SEM。试验项目
所有的肽,包括野生型GLP-1(7-37)在OGTT试验中在3个不同浓度下测试:1,5和10ug/小鼠。在第一组的试验(研究A)中,肽3与载体和hGLP-1(7-37)比较试验。在第二组的试验(研究B)中,肽1和2与载体和hGLP-1(7-37)比较试验。
wt GLP1:hGLP(7-37)
肽#1:(O-甲苯乙酸-His7)-hGLP-1(7-37)
肽#2:((+,-)-顺式-2-乙基环丙基乙酸-His7)-hGLP-1(7-37)
肽#3:(己烯酰基-反式-3-His7)-hGLP-1(7-37)结果和结论
结果如图I(研究A)和图II(研究B)。
研究A和B中,载体的给予在葡萄糖水平中得到相似的整合反应(研究A:380±57对研究B:309±68mM×120分钟),说明该方法的有效性和再现性。虽然wt GLP-1引起葡糖反应的剂量相关性降低,这种肽不能在任何剂量下完全抑制葡糖反应,这可能解释为其潜在临床有效性的局限性。与此形成对照,肽3(研究A,图1)能够完全消除葡萄糖反应,但只在10ug的剂量(9±26mM×120分钟)下。令人惊奇地,肽2(研究B,图2)比肽3更加有效,能够在5ug和10ug剂量下完全阻止葡糖反应(5ug:-17±67mM×120分钟;10ug:61±64mM×120分钟)。所以,相当于肽2的GLP-1类似物被鉴定为具有比野生型GLP-1(7-37)明显增高的生物学效价,由于这种增高的效价,这种肽可以在与病变如II型糖尿病有关的胰岛素耐受性的治疗中具有临床效果。
按照本发明,下列刚性构象部分的至少一个与PTH1-34肽序列经酰胺键在下列不同位置偶联
按照本发明,下列刚性构象部分与促生长素抑制素肽序列经酰胺键在下列不同位置偶联。
虽然本发明结合具体实施方式进行描述,但应理解其能够进行进一步的改进,并且本申请概括了根据本发明的一般性原理所做的任何本发明的改变方案、应用和调整,而且包括根据本发明所涉及领域的已知或常规实践由本发明的说明、并且可利用上述必要特征、并且按照所附权利要求书的范围做出的偏离。
Claims (25)
1.式Xn-R1的肽,其中:
-R1是肽序列、其官能类似物或其片段;
各X可以相同或彼此独立并选自下列刚性构象部分:
i)直链、被取代的C1-C10烷基;
ii)支链、被取代的C1-C10烷基;
iii)直链或支链、未被取代或被取代的C1-C10链烯;
iv)直链或支链、未被取代或被取代的C1-C10链炔;
v)未被取代或被取代的、饱和或不饱和C3-C10环烷基或杂环烷基其中所述的杂原子是O、S或N;
vi)未被取代或被取代的C5-C14芳基或杂芳基其中所述的杂原子是O、S或N;
其中在定义i)-vi)中的取代基含有一个或多个
a)直链或支链C1-C6烷基;
b)直链或支链C1-C6链烯;
c)直链或支链C1-C6链炔;
d)C3-C10环烷基或杂环烷基其中至少2个碳原子任选地与C1-C10烷基、C1-C10链烯、C1-C10链炔、C3-C10环烷基或杂环烷基、和C5-C14芳基或杂芳基连接;或
e)C5-C14芳基或杂芳基,其中所述芳基或杂芳基的至少2个碳原子任选地与C1-C10烷基、C1-C10链烯、C1-C10链炔、C3-C10环烷基或杂环烷基、和C5-C14芳基或杂芳基连接;所述基团X也含有至少一个选自下列的基团:
α)经酰胺键在肽序列的N端、肽序列的C端、肽序列链的可利用羧基或氨基位点及其组合用于与肽序列偶联的羧基或氨基;和
β)经酯键在该肽序列链上的可利用羟基位点及其组合用于与肽序列偶联的羧基;;
其中,
n是介于1-5的整数;
和其任何异构体,包括顺式和反式构象、差向异构体、对映异构体、非对映异构体和消旋混合物。
不包括美国专利号6,020,311的权利要求1所述的肽。
2.权利要求1所述的肽,其中所述肽序列选自生长激素释放因子(GRF)、促生长素抑制素、胰高血糖素样肽1(7-37)、酰胺人(GLP-1)hGLP-1(7-36)NH2、甲状旁腺素片段(PTH1-34)、促肾上腺皮质激素(ACTH)、骨钙蛋白、降钙素、促肾上腺皮质激素释放因子、强啡肽A、β-内啡肽、巨胃泌素-1、GLP-2、黄体激素释放激素、促黑激素(MSH)、心房肽、神经调节肽B、人神经肽Y、人OrexinA、人肽YY、人促胰液素、血管活性肠肽(VIP)、抗菌肽(爪蟾抗菌肽1,爪蟾抗菌肽2,杀菌肽A,和杀菌肽B)、P物质(SP)、βCasomorphin-5、内啡素-2、Procolipase、Enterostatin、肠抑肽、嗜铬粒蛋白A、Vasostatin I & II,降钙素原、ProNCT、CGRP(降钙素基因相关肽)、IL8(单核细胞衍化的)、GCP-2、PF4、IP-10、MIG、SDF-1、GRO-α、I-TAC、RANTES、LD78、MIP-1α、MCP-1、MCP-2、MCP-3、MCP-4、Eotaxin、MDC,和它们的官能类似物和其衍生物或片段。
3.权利要求1和2所述的肽,其中所述刚性构象部分至少含有双键、叁键或饱和或不饱和环。
4.权利要求1-3任一项所述的肽,其中所述刚性构象部分含有一个或多个说明书中式1-63定义的结构。
5.权利要求1-4任一项所述的肽,其中所述肽序列选自下面成负组成的组:
生长激素释放因子(GRF):
Xaa1-Xaa2-Asp-Ala-Ile-Phe-Thr-Xaa8-Ser-Tyr-Arg-Lys-Xaa13-Leu-Xaa15-Gln-Leu-Xaa18-Ala-Arg-Lys-Leu-Leu-Xaa24-Xaa25-Ile-Xaa27-Xaa28-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH2
其中,
Xaa1是Tyr或His;
Xaa2是Val或Ala;
Xaa8是Asn或Ser;
Xaa13是Val或Ile;
Xaa15是Ala或Gly;
Xaa18是Ser或Tyr;
Xaa24是Gln或His;
Xaa25是Asp或Glu;
Xaa27是Met、Ile或Nle;和
Xaa28是Ser或Asn;
其中,
Xaa12是Tyr或Ser;
胰高血糖素样肽1(7-37),(酰胺人(hGLP-1)):
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-OH(NH2)
甲状旁腺素片段(PTH 1-34):
Xaa1-Val-Ser-Glu-Xaa5-Gln-Xaa7-Met-His-Asn-Leu-Gly-Xaa13-His-Xaa15-Xaa16-Xaa17-Xaa18-Glu-Arg-Xaa21-Xaa22-Trp-Leu-Xaa25-Xaa26-Lys-Leu-Gln-Asp-Val-His-Xaa33-Xaa34-NH2
其中,
Xaa1是Ser或Ala;
Xaa5是Ile或Met;
Xaa7是Leu或Phe;
Xaa13是Lys或Glu;
Xaa15是Leu或Arg;
Xaa16是Asn或Ala或Ser或His;
Xaa17是Thr的Ser;
Xaa18是Met或Val或Leu;
Xaa21是Val或met或Gln;
Xaa22是Glu或Gln或Asp;
Xaa25是Arg或Gln;
Xaa26是Lys或Met;
Xaa33是Asn或Ser;和
Xaa34是Phe或Ala;
促肾上腺皮质激素(ACTH):
Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Xaa13-Gly-Xaa15-Lys-Arg-Arg-Pro-Xaa20-Lys-Val-Tyr-Pro-Asn-Xaa26-Xaa27-Xaa28-Xaa29-Glu-Xaa31-Xaa32-Glu-Xaa34-Xaa35-Xaa36-Xaa37-Glu-Xaa39-NH2
其中,
Xaa13是Val或Met;
Xaa15是Lys或Arg;
Xaa20是Val或Ile;
Xaa26是Gly或Ser;
Xaa27是Ala或Phe或Val;
Xaa28是Glu或Gln;
Xaa29是Asp或Asn或Glu;
Xaa31是Ser或Thr;
Xaa32是Ala或Val或Ser;
Xaa34是Ala或Asn或Gly;
Xaa35是Phe或Met;
Xaa36是Pro或Gly;
Xaa37是Leu或Val或Pro;和
Xaa39是Phe或Val或Leu;
骨钙蛋白:
Tyr-Leu-Xaa52-Xaa53-Xaa54-Leu-Gly-Ala-Pro-Xaa59-Pro-Tyr-Pro-Asp-Pro-Leu-Glu-Pro-Xaa68-Arg-Glu-Val-Cys-Glu-Leu-Asn-Pro-Xaa77-Cys-Asp-Glu-Leu-Ala-Asp-His-Ile-Gly-Phe-Gln-Xaa89-Ala-Tyr-Xaa92-Arg-Xaa94-Tyr-Gly-Xaa97-Val-NH2
其中,
Xaa52是Tyr或Asp或Asn;
Xaa53是Gln或His或Asn;
Xaa54是Trp或Gly;
Xaa59是Val或Ala;
Xaa68是Arg或Lys或His;
Xaa77是Asp或Asn;
Xaa89是Glu或Asp;
Xaa92是Arg或Lys;
Xaa94是Phe或Ile;和
Xaa97是Pro或Thr;
降钙素:
Cys-Xaa86-Xaa87-Leu-Ser-Thr-Cys-Xaa92-Leu-Gly-Xaa95-Xaa96-Xaa97-Xaa98-Xaa99-Xaa100-Xaa101-Xaa102-Xaa103-Xaa104-Thr-Xaa106-Xaa107-Xaa108-Xaa109-Xaa110-Xaa111-Gly-Xaa113-Xaa114-Xaa115-Pro-NH2
其中,
Xaa86是Gly或Ser或Ala;
Xaa87是Asn或Ser;
Xaa92是Met或Val;
Xaa95是Thr或Lys;
Xaa96是Tyr或Leu;
Xaa97是Thr或Ser;
Xaa98是Gln或Lys;
Xaa99是Asp或Glu;
Xaa100是Phe或Leu;
Xaa101是Asn或His;
Xaa102是Lys或Asn;
Xaa103是Phe或Leu;
Xaa104是His或Gln;
Xaa106是Phe或Tyr;
Xaa107是Pro或Ser;
Xaa108是Gln或Gly或Arg;
Xaa109是Thr或Ile;
Xaa110是Ala或Gly或Ser或Asp或Asn;
Xaa111是Ile或Phe或Val或Thr;
Xaa113是Val或Ala或Ser;
Xaa114是Gly或Glu;和
Xaa115是Ala或Thr;
促肾上腺皮质激素释放因子:
Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Xaa101-Xaa102-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Met-Glu-Ile-Ile-NH2
其中,
Xaa101是Ala或Pro;和
Xaa102是Arg或Gly;
强啡肽A:
H-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-OH
β-内啡肽:
H-Tyr-Gly-Gly-Phe-Met-Thr-Xaa243-Glu-Xaa245-Ser-Gln-Thr-Pro-Leu-Xaa251-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Xaa259-Lys-Asn-Xaa262-Xaa263-Lys-Lys-Gly-Xaa267-OH
其中,
Xaa243是Ser或Pro;
Xaa245是Lys或Arg;
Xaa251是Val或Met;
Xaa259是Ile或Val;
Xaa262是Ala或Thr或Ser或Val;
Xaa263是Tyr或His;和
Xaa267是Glu或Leu或Gln或His;
巨胃泌素-1:
pXaa59-Leu-Gly-Xaa62-Gln-Xaa64-Xaa65-Xaa66-Xaa67-Xaa68-Xaa69-Ala-Asp-Xaa72-Xaa73-Lys-Lys-Xaa76-Xaa77-Pro-Xaa79-Xaa80-Glu-Xaa82-Glu-Glu-Xaa85-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2
其中,
Xaa59是Glu或Gln;
Xaa62是Pro或Leu;
Xaa64是Gly或Asp;
Xaa65是Pro或Ser;
Xaa66是Pro或Gln;
Xaa67是His或Gln;
Xaa68是Leu或Met或Phe或Gln;
Xaa69是Val或Ile;
Xaa72是Pro或Leu;
Xaa73是Ser或Ala;
Xaa76是Gln或Glu;
Xaa77是Gly或Arg;
Xaa79是Trp或Pro或Arg;
Xaa80是Leu或Val或Met;
Xaa82是Glu或Lys;和
Xaa85是Glu或Ala;
GLP-2:
His-Ala-Asp-Gly-Ser-Phe-Xaa152-Xaa153-Xaa154-Xaa155-Xaa156-Xaa157-Xaa158-Leu-Asp-Xaa161-Xaa162-Ala-Xaa164-Xaa165-Xaa166-Phe-Xaa168-Xaa169-Trp-Xaa171-Xaa172-Xaa173-Thr-Xaa175-Xaa176-Xaa177-Xaa178;
其中,
Xaa152是Ser或Thr;
Xaa153是Asp或Ser;
Xaa154是Glu或Asp;
Xaa155是Met或Phe;
Xaa156是Asn或Ser;
Xaa157是Thr或Lys;
Xaa158是Ile或Val或Ala;
Xaa161是Asn或Ile或His或Ser;
Xaa162是Leu或Lys;
Xaa164是Ala或Thr;
Xaa165是Arg或Gln或Lys;
Xaa166是Asp或Glu;
Xaa168是Ile或Leu;
Xaa169是Asn或Asp;
Xaa171是Leu或Ile;
Xaa172是Ile或Leu;
Xaa173是Gln或Asn或His;
Xaa175是Lys或Pro;
Xaa176是Ile或Val;
Xaa177是Thr或Lys;和
Xaa178是Asp或Glu;
黄体激素释放激素:
Xaa1-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-OH
其中,
Xaa1是pGlu、5-氧代脯氨酸或Gln,
促黑激素(MSH):
Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2
心房肽:
H-Ser-Leu-Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Xaa135-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Xaa142-Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr-OH
其中,
Xaa135是Met或Ile;和
Xaa142是Gly或Ser;
神经调节肽B:
H-Gly-Asn-Leu-Trp-Ala-Thr-Gly-His-Phe-Met-NH2
人神经肽Y:
H-Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-Ala-Pro-Ala-Glu-asp-Met-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH2
人Orexin A:
pGlu-Pro-Leu-Pro-Asp-Cys-Cys-Arg-Gln-Lys-Thr-Cys-Ser-Cys-Arg-Leu-Tyr-Glu-Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2
人肽YY:
H-Tyr-Pro-Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2
人促胰液素:
H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Glu-Gly-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH2
血管活性肠肽(VIP):
H-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2
抗菌肽例如:
爪蟾抗菌肽1:
Gly-Ile-Gly-Lys-Phe-Leu-His-Ser-Ala-Gly-Lys-Phe-Gly-Lys-Ala-Phe-Val-Gly-Glu-Ile-Met-Lys-Ser
爪蟾抗菌肽2:
Gly-Ile-Gly-Lys-Phe-Leu-His-Ser-Ala-Lys-Lys-Phe-Gly-Lys-Ala-Phe-Val-Gly-Glu-Ile-Met-Asn-Ser
杀菌肽A:
Lys-Trp-Lys-Val-Phe-Lys-Lys-Ile-Glu-Lys-Val-Gly-Gln-Ala-Thr-Gln-Ile-Ala-Lys
杀菌肽B:
Lys-Trp-Lys-Val-Phe-Lys-Lys-Ile-Glu-Lys-Met-Gly-Arg-Asn-Ile-Arg-Asn-Gly-Ile-Val-Lys-Ala-Gly-Pro-Ala-Ile-Ala-Val-Leu-Gly-Glu-Ala-Lys-Ala-Leu
P物质(SP):
Arg-Pro-Leu-Pro-Gln-Glu-Phe-Phe-Gly-Leu-Met-酰按
βCasomorphin-5:
Tyr-Pro-Phe-Pro-Gly
内啡素-2:
Tyr-Pro-Phe-Phe-NH2
Procolipase:
100氨基酸肽(X1-Pro-X2-Pro-Arg....)
Enterostatin:
Val-Pro-Asp-Pro-Arg
胃泌素抑制肽:
Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln
嗜铬粒蛋白A
Vasostatin I
Vasostatin II:
Leu Pro Val Asn Ser Pro Met Asn Lys Gly Asp Thr Glu Val MetLys Cys Ile Val Glu Val Ile Ser Asp Thr Leu Ser Lys Pro Ser Pro MetPro Val Ser Gln Glu Cys Phe Glu Thr Leu Arg Gly Asp Glu Arg Ile LeuSer Ile Leu Arg His Gln Asn Leu Leu Lys Glu Leu Gln Asp Leu Ala LeuGln Gly Ala Lys Glu Arg Ala His Gln Gln Lys Lys His Ser Gly Phe GluAsp Glu Leu Ser Glu Val Leu Glu Asn Gln Ser Ser Gln Ala Glu Leu LysGlu Ala Val Glu Glu Pro Ser Ser Lys Asp Val Met Glu
Pro降钙素
ProNCT
ProCGRP
趋化因子家族:
CXC-组:
IL8(单核细胞衍化的):
SerAlaLysGluLeuArgCysGlnCys...
GCP-2:
GlyProValSerAlaValLeuThrGluLeuArgCysThrCys...
PF4:
GluAlaGluGluAspGlyAspLeuGlnCysLeuCys...
IP-10:
ValProLeuSerArgThrValArgCCysThrCys...
MIG:
ThrProValValArgLysGlyArgCysSerCys...
SDF-1:
LysProValSerLeuSerTyrArgCysProCys...
GRO-α:
AlaProLeuAlaThrGluLeuArgCysGlnCys...
I-TAC:
PheProMetPheLysLysGlyArgCysLeuCys...
CC-组:
RANTES:
SerProTyrSerSerAspThrThrProCys...
LD78:
AlaProLeuAlaAlaAspThrProThrAlaCys...
MIP-1α
AlaProMetGlySerAspProProThrAlaCys...
MCP-1:
GlnProAspAlaIleAsnAlaProValThrCys...
MCP-2:
GlnProSerAspValSerIleProIleThrCys...
MCP-3:
GlnProValGlyIleTAsnSeerThrThrCys...
MCP-4:
GlnProAspAlaLeuAspValProSerThrCys...
Eotaxin:
GlyProAlaSerValProThrThrCys...
MDC:
GlyProTyrGlyAlaAsnMetGluAspSerValCys...
和它们的官能类似物和其衍生物或片段。
6.按照权利要求5所述的肽,其中所述肽序列是天然肽的序列和其官能类似物或片段或其临床安全且可接受的衍生物或类似物。
7.权利要求1所述的肽,其中所述肽序列是促生长素抑制素且至少一个刚性构象部分与该促生长素抑制素肽序列经酰胺键在下列不同位置偶联:
位置 刚性构象部分
8.权利要求1所述的肽,其中所述肽序列是PTH 1-34且至少一个刚性构象部分与该PTH 1-34肽序列经酰胺键在下列不同位置偶联:
位置 刚性构象部分
10.权利要求1所述的肽,其中该肽序列是GLP-2且至少一个刚性构象部分与该GLP-2肽序列经酰胺或酯键在该肽序列的不同位置偶联。
11.权利要求1所述的肽,其中该肽序列是Enterostatin且至少一个刚性构象部分与该Enterostatin肽序列经酰胺键在该肽序列的不同位置偶联。
12.权利要求1所述的肽,其中该肽序列是NPY且至少一个刚性构象部分与该NPY肽序列经酰胺或酯键在该肽序列的不同位置偶联。
13.权利要求1所述的肽,其中该肽序列是NPYY且至少一个刚性构象部分与该NPYY肽序列经酰胺或酯键在该肽序列的不同位置偶联。
14.权利要求1所述的肽,其中所述肽序列是促胰液素且至少一个刚性构象部分与该促胰液素肽序列经酰胺或酯键在该肽序列的不同位置偶联。
15.权利要求1所述的肽,其中所述肽序列是血管活性肠肽且至少一个刚性构象部分与该血管活性肠肽序列经酰胺或酯键在该肽序列的不同位置偶联。
16.权利要求1所述的肽,其中所述肽序列是胃泌素抑制肽且至少一个刚性构象部分与该胃泌素抑制肽序列经酰胺或酯键在该肽序列的不同位置偶联。
17.权利要求1所述的肽,其中所述肽序列是Vasostatin II且至少一个刚性构象部分与该Vasostatin II肽序列经酰胺或酯键在该肽序列的不同位置偶联。
18.权利要求1所述的肽,其中所述肽序列是RANTES且至少一个刚性构象部分与该RANTES肽序列经酰胺或酯键在该肽序列的不同位置上偶联。
19.权利要求1所述的肽,其中所述肽序列是Eotaxin且至少一个刚性构象部分与该Eotaxin肽序列经酰胺或酯键在该肽序列的不同位置偶联。
20.权利要求1-18任一项所述的肽,其中所述刚性构象部分与该肽序列经酰胺或酯键在N端偶联。
21.权利要求8-19任一项所述的肽,其中刚性构象部分具有说明书中所述的式60所示的结构。
22.按照权利要求20的肽,其中所述肽序列是GLP-1。
23.权利要求22所述的肽在与胰岛素耐受性病变有关或无关的葡萄糖不耐受的治疗中的应用。
24.权利要求23所述的在II型糖尿病中的应用。
25.权利要求1所述的肽,其中所述肽序列是CGRP且至少一个刚性构象部分与该CGRP肽序列经酰胺或酯键在该肽序列的不同位置偶联。
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EP (1) | EP1305338A2 (zh) |
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AU (1) | AU2001279526A1 (zh) |
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ATE466028T1 (de) * | 1998-02-27 | 2010-05-15 | Novo Nordisk As | N-terminal veränderte glp-1 abkömmlinge |
KR100458748B1 (ko) * | 1998-12-07 | 2004-12-03 | 더 어드미니스트레이터즈 오브 더 튜래인 어듀케이셔널 훤드 | Glp-1 유사체 |
EP2322545A1 (en) * | 1998-12-07 | 2011-05-18 | Ipsen Pharma | Analogues of GLP-1 |
-
2001
- 2001-08-02 JP JP2002515924A patent/JP2004509079A/ja active Pending
- 2001-08-02 CA CA002417100A patent/CA2417100A1/en not_active Abandoned
- 2001-08-02 CN CN01813865A patent/CN1454214A/zh active Pending
- 2001-08-02 BR BR0113178-8A patent/BR0113178A/pt not_active Application Discontinuation
- 2001-08-02 EP EP01957662A patent/EP1305338A2/en not_active Withdrawn
- 2001-08-02 WO PCT/CA2001/001119 patent/WO2002010195A2/en not_active Application Discontinuation
- 2001-08-02 US US10/343,654 patent/US20030204063A1/en not_active Abandoned
- 2001-08-02 AU AU2001279526A patent/AU2001279526A1/en not_active Abandoned
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108473547A (zh) * | 2015-10-28 | 2018-08-31 | 塔夫茨大学 | 具有改良的蛋白质分解安定性的新颖多肽,以及制备与使用该新颖多肽的方法 |
CN109180800A (zh) * | 2018-08-01 | 2019-01-11 | 广东药科大学 | 新型生长激素释放激素类似肽二聚体及其应用 |
CN109180800B (zh) * | 2018-08-01 | 2019-07-12 | 广东药科大学 | 新型生长激素释放激素类似肽二聚体及其应用 |
CN114450299A (zh) * | 2019-07-24 | 2022-05-06 | 莫尔吉尼有限责任公司 | 受体靶向肽-药物缀合物 |
Also Published As
Publication number | Publication date |
---|---|
WO2002010195A3 (en) | 2002-10-03 |
US20030204063A1 (en) | 2003-10-30 |
CA2417100A1 (en) | 2002-02-07 |
BR0113178A (pt) | 2004-04-06 |
JP2004509079A (ja) | 2004-03-25 |
AU2001279526A1 (en) | 2002-02-13 |
EP1305338A2 (en) | 2003-05-02 |
WO2002010195A2 (en) | 2002-02-07 |
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