CN1124927A - Yy肽类似物及其应用 - Google Patents
Yy肽类似物及其应用 Download PDFInfo
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- CN1124927A CN1124927A CN94192277A CN94192277A CN1124927A CN 1124927 A CN1124927 A CN 1124927A CN 94192277 A CN94192277 A CN 94192277A CN 94192277 A CN94192277 A CN 94192277A CN 1124927 A CN1124927 A CN 1124927A
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/57545—Neuropeptide Y
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
本发明提供了PYY的类似物。本发明还提供了可用于控制诸如细胞增生、养分运输、脂解及肠水和电解质分泌等生物学活动的组合物和方法。
Description
本发明部分地是用政府的拨款进行的,因此政府在本发明中享有一定的权利。
本发明涉及在胃肠病的治疗中可用作治疗剂的肽衍生物。
YY肽(PYY)是一种含36个残基的肽酰胺,最初是从猪肠中分离而得,它位于胃肠道和胰腺的内分泌细胞中(Tatemoto et al.Proc.Natl.Acad.Sci.79:2514,1982)。YY肽有氨基末端(N-termi-nal)和羧基末端(C-terminal)酪氨酸酰胺;因此,此两个酪氨酸给出了PYY本身的名称(在肽的命名法中,Y代表酪氨酸)。此外,PYY与其同系肽-神经肽Y(NPY)一样,具有许多中枢及周边神经调节功能,后者最初是从猪脑中分离而得(Tatemoto,Proc.Natl.Acad.Sci.79:5485,1982),但与PYY位于细胞内相反,NPY存在于粘膜下及肠肌神经元中(分别支配粘膜层及平滑肌层)(Ekblad et al.Neuroscience 20:169,1987)。PYY及NPY均被认为可抑制肠的活动性和血流(Laburthe,Trends Endocrinol.Metab.1:168,1990),并且也被认为既可刺激净吸收(MacFadyen et al.Neuropeptides7:219,1986),又可减弱小鼠中(Lundberg et al.Proc.Natl.Acad.Sci.USA79:4471,1982;Playford et al.Lancet 335:1555,1990)及人类中(Playford et al.文献同上)基础的肠分泌(Cox.etal.Br.J.Pharmacol.101:247,1990;Cox et al.J.Physiol.398:65,1988;Cox et al.Peptides 12:323,1991;Friel et al.Br.J.Pharmacol.88:425,1986)及促分泌素所致的肠分泌。此外,已有报道,在一些可引起腹泻的疾病中,血浆PYY水平被升高(Adrianet al.Gastroenterology89:1070,1985)。总而言之,这些观察结果提示,PYY和NPY在饭后被释放到循环系统中去(Adrian et al.Gastroenterology 89:1070,1985;Balasubramaniam et al.Neu-ropeptides 14:209,1989),因而在调节肠分泌和吸收中可能起一种生理学功能,作为腹泻的天然抑制剂。
已在鼠肠上皮中鉴定出一种高亲和力的PYY受体系统,该受体系统表现出对PYY的亲和力略高于对NPY的亲和力(Laburthe et al.Endocrinology 118:1910,1986; Laburthe,Trends Endocrinol.Metab.文献同上),并表现出负偶联(negatively coupled)到腺苷酸环化酶(Servin et al.Endocrinology124:692,1989)。在鼠小肠的电压钳(Votage Clamped)制备物中,PYY始终显示出比NPY更大的抗分泌效力(Cox et al.J.Physiol.文献同上),并发现NPY的C-末端片段较PYY的抗分泌效力低(Cox et al.Br.J.Pharmacol.文献同上)。利用几个局部序列进行了“结构-活性”的研究,从而已鉴定出PYY(22-36)是与肠PYY受体相互作用的活性位点(Balsubrama-niam et al.Pept.Res.1:32,1988)。
此外,PYY参与许多生理活动,包括营养吸收(如见:Bilcheiket al.Digestive Disease Week506:623,1993)、细胞增殖(如见:Laburthe,Trends Endocrinol.Metab.1:168,1990;Voisinet al.J.Biol.Chem,1993)、脂解(如见:Valet et al.,J.Clin.Invest.85:291,1990)、以及血管收缩(如见:Lundberg et al.,Proc.Natl.Acad.Sci.,USA79:4471,1982)。
猪和人PYY的氨基酸序列如下:猪PYY:YPAKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY(SEQ.ID.NO.(序列编号)1)人PW:YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY(SEQ.ID.NO.2)狗和鼠PYY的氨基酸序列与猪PYY相同。
一方面,本发明用公式描述了新的YY肽类似物或其药用可接受的盐:其中:
X为一条有0-5个氨基酸的链,包括,其N-末端氨基酸与R1和R2相连;
Y为一条有0-4个氨基酸的链,包括,其C-末端氨基酸与R3和R4相连;
R1为H、C1-C12烷基(如甲基)、C6-C18芳基(如苯基、萘乙酰基)、
C1-C12酰基(如甲酰基、乙酰基、及十四烷酰基)、C7-C18芳
烷基(如苯甲基)、或C7-C18烷芳基(如对-甲苯基);
R2为H、C1-C12烷基(如甲基)、C6-C18芳基(如苯基、萘乙酰基)、
C1-C12酰基(如甲酰基、乙酰基、及十四烷酰基)、C7-C18芳
烷基(如苯甲基)、或C7-C18烷芳基(如对-甲苯基);
A22为一个芳香族氨基酸、Ala、Aib、Anb、N-Me-Ala、或被删
去;
A23为Ser、Thr、Ala、Aib、N-Me(甲基)-Ser、N-Me-Thr、N-Me
-Ala、或被删去;
A24为Leu、Ile、Val、Trp、Gly、Aib、Anb、N-Me-Leu、或被
删去;
A25为Arg、Lys、homo-Arg(高精氨酸)、二乙基-homo-Arg、Lys
-ε-NH-R(其中R为H、一个分支或直链的C1-C10烷基、或一
个芳基)、Orn、或被删去;
A26为Ala、His、Thr、3-Me-His、1-Me-His、β-吡唑基丙氨酸、
N-Me-His、Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-
ε-NH-R(其中R为H、一个分支或直链的C1-C10烷基、或一个
芳基)、Orn、或被删去;
A27为一个除Tyr外的芳香族氨基酸;
A28为Leu、Ile、Val、Trp、Aib、Anb、或N-Me-Leu;
A29为Asn、Ala、Gln、Gly、Trp、或N-Me-Asn;
A30为Leu、Ile、Val、Trp、Aib、Anb、或N-Me-Leu;
A31为Val、Ile、Trp、Aib、Anb、或N-Me-Val;
A32为Thr、Ser、N-Me-Ser、N-Me-Thr、或D-Trp;
R3为H、C1-C12烷基(如甲基)、C6-C18芳基(如苯基、萘乙酰基)、
C1-C12酰基(如甲酰基、乙酰基、及十四烷酰基)、C7-C18芳
烷基(如苯甲基)、或C7-C18烷芳基(如对-甲苯基);以及
R4为H、C1-C12烷基(如甲基)、C6-C18芳基(如苯基、萘乙酰基)、
C1-C12酰基(如甲酰基、乙酰基、及十四烷酰基)、C7-C18芳
烷基(如苯甲基)、或C7-C18烷芳基(如对-甲苯基)。
在优选的实施方案中,A27为Phe、Nal、Bip、Pcp、Tic、Trp、Bth、Thi、或Dip。
在优选的实施方案中,X为A17-A18-A19-A20-A21或其药用可接受的盐,其中:
A17为Cys、Leu、Ile、Val、Aib、Anb或N-Me-Leu;
A18为Cys、Ser、Thr、N-Me-Ser、或N-Me-Thr;
A19为Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-ε-NH-R
(其中R为H、一个分支或直链的C1-C10烷基、或C6-C18芳基)、Cys、或Orn;
A20为一个芳香族氨基酸、或Cys;以及
A21为一个芳香族氨基酸、Cys。在另一些优选的实施方案中,Y为A33-A34-A35-A36或其药用可接受的盐,其中:
A33为Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-ε-NH-R
(其中R为H、一个分支或直链的C1-C10烷基、或一个芳基)、
Cys、或Orn;
A34为Cys、Gln、Asn、Ala、Gly、N-Me-Gln、Aib、或Anb;
A35为Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-ε-NH-R
(其中R为H、一个分支或直链的C1-C10烷基、或一个芳基)、
Cys、或Orn;以及
A36为一个芳香族氨基酸、Cys。
优选地,该化合物有公式:N-α-Ac(乙酰基)-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ.ID.NO.3),H-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ.ID.NO.4),N-α-Ac-Ala-Ser-Leu-Arg-His-Trp-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ.ID.NO.5),N-α-Ac-Ala-Ser-Leu-Arg-His-Thi-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ.ID.NO.6),N-α-Ac-Tyr-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ.ID.NO.7)或其药用可接受的盐。
N-末端氨基酸与R1和R2相连;
Y为一条有0-4个氨基酸的链,包括,其C-末端氨基酸与R3和R4相连;
R1为H、C1-C12烷基(如甲基)、C6-C18芳基(如苯基、萘乙酰基)、
C1-C12酰基(如甲酰基、乙酰基、和十四烷酰基)、C7-C18芳
烷基(如苯甲基)、或C7-C18烷芳基(如对-甲苯基);
R2为H、C1-C12烷基(如甲基)、C6-C18芳基(如苯基、萘乙酰基)、
C1-C12酰基(如甲酰基、乙酰基、和十四烷酰基)、C7-C18芳
烷基(如苯甲基)、或C7-C18烷芳基(如对-甲苯基);
A25为Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-ε-NH-R
(其中R为H、一个分支或直链的C1-C10烷基或一个芳基)、
Orn、或被删去;
A26为Ala、His、Thr、3-Me-His、1-Me-His、β-吡唑基丙氨酸、
N-Me-His、Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-
ε-NH-R(其中R为H、一个分支或直链的C1-C10烷基、或一个
芳基)、Orn、或被删去;
A27为一个芳香族氨基酸;
A28为Leu、Ile、Val、Trp、Aib、Anb、或N-Me-Leu;
A29为Asn、Ala、Gln、Gly、Trp、或N-Me-Asn;
A30为Leu、Ile、Val、Trp、Aib、Anb、或N-Me-Leu;
A31为Val、Ile、Trp、Aib、Anb、或N-Me-Val;
A32为Thr、Ser、N-Me-Ser、N-Me-Thr、或D-Trp;
R3为H、C1-C12烷基(如甲基)、C6-C18芳基(如苯基、萘乙酰基)、
C1-C12酰基(如甲酰基、乙酰基、和十四烷酰基)、C7-C18芳
烷基(如苯甲基)、或C7-C18烷芳基(如对-甲苯基);以及
R4为H、C1-C12烷基(如甲基)、C6-C18芳基(如苯基、萘乙酰基)、
C1-C12酰基(如甲酰基、乙酰基、及十四烷酰基)、C7-C18芳
烷基(如苯甲基)、或C7-C18烷芳基(如对-甲苯基)。
在优选的实施方案中,A27为Phe、Nal、Bip、Pcp、Tic、Trp、Bth、Thi、或Dip。
在优选的实施方案中,Y为A33-A34-A35-A36或其药用可接受的盐,其中:
A33为Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-ε-NH-R
(其中R为H、一个分支或直链的C1-C10烷基、或C6-C18芳基)、
Cys、或Orn;
A34为Gln、Asn、Ala、Gly、N-Me-Gln、Aib、Cys或Anb;
A35为Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-ε-NH-R
(其中R为H、一个分支或直链的C1-C10烷基、或C6-C18芳基)、
Cys、或Orn;以及
A36为一个芳香族氨基酸、Cys。优选地,该化合物有公式:N-α-Ac-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ.ID.NO.8)。
另一方面,本发明描述了新的YY肽二聚类似物的特征。此二聚体可由公式I的两条肽、公式II的两条肽、或公式I的一条肽和公式II的一条肽组成。在一实施方案中,该二聚体是通过使用一个二羧酸偶联剂(linker)而形成的,该二羧酸偶联剂能连接位于每个肽内的一个自由胺(一级或二级)(如见:R.Vavrek and J.Stewart,Peptides:Structure and Function381-384(Pierce ChemicalCo.1983))。合适的二羧酸偶联剂的例子为:琥珀酸、谷氨酸、和苯二甲酸。在其它的实施方案中,二聚体是利用一个氨基酸偶联剂而生成的,氨基酸偶联剂能连接一条肽的自由胺基和另一条肽的自由羧基。优选地,该氨基酸偶联剂是一种非α-氨基酸。合适的氨基酸偶联剂的例子有:氨基-己酸及氨基-戊酸。而在另一实施方案中,该二聚体是通过位于每条肽链内的半胱氨酸之间的二硫键而形成的(如见:M.Berngtowicz and G.Piatsueda,Peptides:Structure and Function233-244(Pierce Chemical Co.1985);F.Albericio,et al.,Peptides 1990,535(ESCOM1991))。
在本文的肽序列中所见到的符号:X、Y、Z、A22、A23、A24、等等,以及Ser、Leu、或其相似符号,代表一个氨基酸残基,也即,当其在N-末端时为“=N-CH(R)-CO-”、或当其在C-末端时为“-NH-CH(R)-CO-N=”、或当其不在N-或C-末端时为“-NH-CH(R)-CO-”,其中R表示一个氨基酸或其残基的侧链(或识别基团)。例如,Asp的R为-CH2COOH、Gly的R为-H、Ser的R为-CH2OH、Ala的R为-CH3、以及Arg的R为-CH2CH2CH2CH2NH20此外,当氨基酸残基是有光学活性的时,除了特别说明为D-型,则都为L-型构型。
如上所述,以及为了描述本发明的方便,使用了各种氨基酸的常规的及不常规的缩写。这些缩写对本领域的技术人员来说都是熟悉的,但为了清楚起见,列于下面。在此所提及的所有肽序列,都是根据通常的惯例而写,即其N-末端氨基酸在左边、C-末端氨基酸在右边。两个氨基酸残基之间的一条短杠则表示一个肽键。Asp=D=天冬氨酸Ala=A=丙氨酸Arg=R=精氨酸Asn=N=天冬酰胺Cys=C=半胱氨酸Gly=G=甘氨酸Glu=E=谷氨酸Gln=Q=谷氨酰胺His=H=组氨酸Ile=I=异亮氨酸Leu=L=亮氨酸Lys=K=赖氨酸Met=M=甲硫氨酸Phe=F=苯丙氨酸Pro=P=脯氨酸Ser=S=丝氨酸Thr=T=苏氨酸Trp=W=色氨酸Tyr=Y=酪氨酸Val=V=缬氨酸Orn=鸟氨酸Nal=2-萘丙氨酸Thi=2-噻吩丙氨酸Pcp=4-氯苯丙氨酸Bth=3-苯并噻吩丙氨酸Bip=4,4′-联苯丙氨酸Tic=四氢异喹啉-3-羧酸Aib=氨基异丁酸Anb=α-氨基正丁酸Dip=2,2-二苯丙氨酸Thz=4-噻唑丙氨酸
本发明的化合物能以药用可接受的盐的形式提供。优选的盐例子是:那些含有治疗上可接受的有机酸的盐类,如乙酸、乳酸、顺丁烯二酸、柠檬酸、苹果酸、抗坏血酸、琥珀酸、苯甲酸、水杨酸、甲烷磺酸、甲苯磺酸、三氟乙酸、或pamoic acid,以及多聚酸,如鞣酸或羧甲基纤维素;以及含有无机酸的盐类,诸如氢卤酸(如盐酸)、硫酸、或磷酸、等等。
另一方面,本发明描述了存在于治疗用组合物中的上述化合物之一和药用可接受的载体,该组合物可降低过多的肠水及电解质分泌。
在优选的实施方案中,该组合物的形态可以是一种可用于口服的液体、药丸、药片或胶囊;一种可鼻滴或经鼻喷雾给药的液体;或一种可静脉内、皮下、非肠道、腹膜内或直肠给药的液体。此治疗组合物的形态也可以是一种油乳剂或分散体,内含一种亲脂的盐(诸如pamoic acid);或是一种用于皮下或肌肉给药的可生物降解的持久性释放组合物。为了达到最大效力,要求零级释放。
另一方面,本发明描述了一种可降低哺乳动物中过多肠水和电解质分泌的方法,此方法包括,给予该哺乳动物(如,人)治疗有效量的上述化合物。
此外,本发明描述了一种可调节哺乳动物中的细胞繁殖的方法,该方法包括,给予该哺乳动物治疗有效量的含上述化合物的组合物。优选地,该方法调节一种肠细胞的繁殖。
本发明也描述了可在哺乳动物中增加养份运输、调节脂解、及调节血流的方法,这些方法包括,给予该哺乳动物治疗有效量的上述组合物。
本发明的化合物表现出与其抗分泌能力及抗活动性能力有关的广泛的生物学活性。该化合物被认为可通过直接作用于上皮细胞、或者,也有可能是通过抑制可刺激肠分泌的激素或神经递质的分泌,从而抑制胃肠分泌。本发明的化合物也可控制肠血流,进而可调整肠的流体静压力,有利于水的净吸收。
本发明的化合物在对很多胃肠失调的治疗中尤为实用(如见:Harrison′s Principles of Internal Medicine,McGraw-HillInc.,New York,12th Ed.),这类失调不仅与吸收降低有关,也与过多的肠电解质及水分泌有关,如:传染性腹泻(如病毒性的或细菌性的)、炎性腹泻、短暂肠综合征(Short bowel syndrome)、或典型地出现于继手术(如回肠造口术)后的腹泻。传染性腹泻的例子包括(并不局限于):急性病毒性腹泻、急性细菌性腹泻(如沙门氏菌、弯曲杆菌、及梭状芽孢杆菌、或由于原虫感染)、或旅行者腹泻(如诺沃克病毒或轮状病毒)。炎性腹泻的例子包括(并不局限于):吸收不良综合征、热带呕吐(tropical spue)、慢性胰腺炎、节段性回肠炎、腹泻、以及过敏性肠综合征(irritablebowel syndrome)。已发现,本发明的肽能用来治疗涉及胃肠失调的紧急或危及生命的情况,如手术后或由于霍乱。此外,本发明的化合物能用来治疗患获得性免疫缺陷综合症(AIDS)的病人,尤其是在其恶病质期间。
在哺乳动物中,本发明的化合物不仅可增加细胞增生,也有助于抑制小肠液及电解质分泌,增加养分的运输(在胃肠道中)、调节脂解作用(如在脂肪组织中)、以及调节血流。
本发明的化合物有其优点,由于它们是天然PYY肽的截短物,因此,该较短的肽不仅使该化合物的合成和纯化较为容易,而且改善了生产过程,降低了费用。此外,一个较短的PYY化合物还有其优点,因为这类肽将只与PYY受体作用,而不与同源的受体(如NPYY1和Y3)作用,因此,可减小非所愿的兴奋剂或颉抗剂副反应。
关于本发明的其它特点和优点,可从以下对优选实施例的描述中以及从权利要求书中了解到。
附图说明:
图1表示用HF断裂(cleavage)而得的N-α-Ac-[Phe27]PYY(22-36)(SEQ.ID.NO.3)(≈25mg)的半制备性反相层析图。条件:VydacC18半制备性柱(250×10mm,孔径大小300,颗粒大小10微米),流速4.7ml/分钟,收集组分1、2、3、4并用分析层析进行分析。合并同源的组分(1-3),并在一高速真空器(a speed vac.)中干燥。
图2表示随着PYY(SEQ ID.NO.1)、PYY(22-36)(SEQ.ID.NO.10)、[Im-DNP-His26]PYY(SEQ.ID.NO.9)、[Ala32]PYY(22-36)(SEQ.ID.NO.11)、[Ala23,32pyy(22-36)(SEQ.ID.NO.12)、[Glu28]PYY(22-36)(SEQ.ID.NO.13)、N-α-Ac-PYY(22-36)(SEQ.ID.NO.14)、N-α-Ac-[p.Cl-Phe28]PYY(22-36)(SEQ.ID.NO.15)、Nα-Ac-[Glu26]PYY(22-36)(SEQ.ID.NO.16)、N-α-Ac[Phe27]PYY(22-36)(SEQ.ID.NO.3)、N-α-Ac-[N-Me-Tyr26]PYY(22-36)(SEQ.ID.NO.17)、N-α-十四烷酰-PYY(22-36)(SEQ.ID.NO.18)、N-α-萘乙酰-PYY(22-36)(SEQ.ID.NO.19)及PYY(22-26)(SEQ.ID.NO.10)浓度的增加,125I-PYY与鼠空肠膜结合的抑制图。
图3A-3B表示PYY(SEQ.ID.NO.1)、PYY(22-36)(SEQ.ID.NO.10)及其类似物的抗分泌作用,是基于鼠空肠的电压箝制备物中的基底短路电流(baseline short circuit current,SCC)。在SCC中的变化值用μA/0.6cm2表示,均值±SEM来自3-7个不同的空肠制备物。A和B中所示的肽,用与图2中所用的相同符号表示。
图4显示随着PYY、N-α-Ac-PYY(22-36)(SEQ.ID.NO.14)、N-α-Ac-[Tic27]PYY(22-36)(SEQ.ID.NO.25)、N-α-Ac-[Bip27]PYY(22-36)(SEQ.ID.NO.22)、N-α-Ac-[Nal27]PYY(22-36)(SEQ.ID.NO.23)、N-α-Ac-[Bth27]PYY(22-36)(SEQ.ID.NO.21)、N-α-Ac-[Phe27]PYY(22-36)(SEQ.ID.NO.3)、N-α-Ac-[Phe27]PYY(25-36)(SEQ.ID.NO.26)、N-α-Ac-[Trp27]PYY(22-36)(SEQ.ID.NO.5)、及N-α-Ac-[Thi27]PYY(22-36)(SEQ.ID.NO.6)浓度的增加,125I-PYY与鼠空肠膜结合的抑制图。
下面描述本发明的优选实施例的合成、生物学效能及应用。为了确定引发抗分泌作用所必需的结构要求,合成了PYY活性位点PYY(22-36)的几个类似物,并比较了它们在鼠空肠中的结合和抗分泌效力。
现有我们描述本发明优选实施例的结构、合成及应用。结构
本发明的肽具有列举于前面的本发明概述中的通式。它们在第27位均有一个芳香族氨基酸基团,这一点对其抗分泌活性及用作抗腹泻化合物均很重要。合成
本发明的肽可用在肽领域中的技术人员所知的任何技术合成。在“Solid Phase Peptide Synthesis”(第二版)一书(Stewart,J.M.and Young,J.D.Pierce Chemical Company,Rockford,IL,1984)中对多种可行技术作了很好的总结。
列于表1及表2的肽的合成如下:肽的合成是在一个AppliedBiosystem 430A型合成仪上进行的。氨基酸和序列的分析分别用的是Waters Pico-Tag仪和Applied Biosystem 470型仪器。肽的纯化是按照标准规程,用的是配置了481型分光光度计和U6K注射器的Waters600型溶剂分配系统进行的。肽产物是在密执安大学、蛋白化学厂(Ann Arbor,密执安州)按照标准方法测定的。所有Boc-L-氨基酸衍生物、溶剂、化学试剂及树脂都购自市场,使用前未作进一步纯化。
将对-甲基苯羟胺(MBHA)树脂(0.45mmol,-NH2)置于肽合成仪的反应容器内,使用生产厂商所提供的程序并结合双偶联程序(double coupling procedure)(如见:Balasubramaniam et al.,Peptide Research 1:32,1988),将被保护的氨基酸衍生物被顺序地偶联上去。所有氨基酸都是利用2.2当量预先制备的对称酐偶联的。不过,为避免副反应,Arg、Gln和Asn是经预先制成1-羟基苯并三唑(HOBT)酯而偶联的。合成结束时,去除N-α-Boc基团,并且在某些情况下,使自由的α-NH2与乙酐(2当量)和二异丙基乙胺反应使其乙酰化,直至获得阴性的茚三酮试验(Anal.Biochem.34:595,1970)。然后该肽树脂用内含对-甲酚(~0.8g)的HF(10ml)在-2~-4℃下处理1小时。清除HF,将残余物用二乙醚转移到一个多孔滤器漏斗(a fritted filter funnel)中,并用二乙醚反复洗涤,用乙酸(2×15ml)抽提并冻干。如此获得的粗制肽用半制备性RP-HPLC纯化,见图1。
所合成的类似物的例子有:[im-DNP-His26]PYY
YPAKPEAPGEDASPEELSRYYASLR [im-DNP-His26] YLNLVTRQRY-NH2 (SEQ.ID No.9)PYY(22-36)
A S L R H Y L N L V T R Q R Y-NH2 (SEQ.ID No.10)[Ala32]PYY
A S L R H Y L N L V [Ala] R Q R Y-NH2 (SEQ.ID No.11)[Ala23,32]PYY
A [Ala] L R H Y L N L V [Ala] R Q R Y-NH2 (SEQ.ID No.12)[Glu28]PYY(22-36)
A S L R H Y [Glu] N L V T R Q R Y-NH2 (SEQ.ID No.13)N-α-Ac-PYY(22-36)
N-α-Ac-A S L R N Y L N L V T R Q R Y-NH2 (SEQ.ID No.14)N-α-Ac[p.Cl.Phe26]PYY
N-α-Ac-A S L R [p.Cl.Phe26] Y L N L V T R Q R Y-NH2 (SEQ.ID No.15)N-α-Ac[Glu28]PYY
N-α-Ac-A S L R H Y [Glu] N L V T R Q R Y-NH2 (SEQ.ID No.16)N-α-Ac[Phe27]PYY
N-α-Ac-A S L R H [Phe] E N L V T R Q R[N-Me-Tyr]-NH2 (SEQ.ID No.3)N-α-Ac[N-Me-Tyr36]PYY
N-α-Ac-A S L R H Y E N L V T R Q R [N-Me-Tyr] -NH2 (SEQ.ID No.17)N-α-myristoyl-PYY(22-36)
N-α-myristoyl-A S L R H Y L N L V T R Q R Y-NH2 (SEQ.ID No.18)N-α-naphtheleneacetyl-PYY(22-36)
N-α-naphthsleneacetyl-A S L R H Y L N L V T R Q R Y-NH2 (SEQ.ID No.19)N-α-Ac[Phe27]PYY
N-α-Ac-A S L R H [Phe] E N L V T R Q R [N-Me-Tyr]-NH2 (SEQ.ID No.3)N-α-Ac-PYY(22-36)
N-α-Ac-A S L R H Y L N L V T R Q R Y-NH2 (SEQ.ID No.20)N-α-Ac-[Bth27]PYY(22-36)
N-α-Ac-A S L R H [Bth] L N L V T R Q R Y-NH2 (SEQ.ID No.21)N-α-Ac-[Bip27]PYY(22-36)
N-α-Ac-A S L R H [Bip] L N L V T R Q R Y-NH2 (SEQ.ID No.22)N-α-Ac-[Nal27]PYY(22-36)
N-α-Ac-A S L R H [Mal] L N L V T R Q R Y-NH2 (SEQ.ID No.23)N-α-Ac-[Trp27]PYY(22-36)
N-α-Ac-A S L R H [Trp] L N L V T R Q R Y-NH2 (SEQ.ID No.5)N-α-Ac-[Thi27]PYY(22-36)
N-α-Ac-A S L R H [Thi] L N L V T R Q R Y-NH2 (SEQ.ID No.6)N-α-Ac-[Tic27]PYY(22-36)
N-α-Ac-A S L R H [Tic] L N L V T R Q R Y-NH2 (SEQ.ID No.25)N-α-Ac-[Phe27]PYY(25-36)
N-α-Ac-H [Phe] L H L V T R Q R Y-NH2 (SEQ.ID No.26)N-α-Ac-[Phe27,Thi36]PYY(22-36)
N-α-Ac-A S L R H [Phe] L N L V T R Q R [Thi]-NH2 (SEQ.ID No.27)N-α-Ac-[Thz26,Phe27]PYY(22-36)
N-α-Ac-A S L R [Thz] [Phe] L N L V T R Q R Y-NH2 (SEQ.ID No.28)N-α-Ac-[Pcp27]PYY(22-36)
N-α-Ac-A S L R H [Pcp] L N L V T R Q R Y-NH2 (SEQ.ID No.29)N-α-Ac-[Phe22,27]PYY(22-36)
N-α-Ac- [Phe] S L R H [Phe] L N L V T R Q R Y-NH2 (SEQ.ID No.30)N-α-Ac-[Tyr22,Phe27]PYY(22-36)
N-α-Ac- [Tyr] S L R H [Phe] L N L V T R Q R Y-NH2 (SEQ.ID No.7)N-α-Ac-[Trp28]PYY(22-36)
N-α-Ac-A S L R H Y [Trp] N L V T R Q R Y-NH2 (SEQ.ID No.31)N-α-Ac-[Trp30]PYY(22-36)
N-α-Ac-A S L R H Y L N [Trp] V T R Q R Y-NH2 (SEQ.ID No.32)N-α-Ac-[Ala26,Phe27]PYY(22-36)
N-α-Ac-A S L R [Ala] [Phe] L N L V T R Q R Y-NH2 (SEQ.ID No.33)N-α-Ac-[Bth27]PYY(22-36)
N-α-Ac-A S L R H [Bth] L N L V T R Q R Y-NH2 (SEQ.ID No.34)N-α-Ac-(Phe27]PYY(22-36)
N-α-Ac- A S L R H [Phe] L N L V T R Q R Y-NH2 (SEQ.ID No.35)N-α-Ac-[Phe27,36]PYY(22-36)
N-α-Ac- A S L R H [Phe] L N L V T R Q R[Phe]-NH2 (SEQ.ID No.36)N-α-Ac-[Phe27,D-Trp32]PYY(22-36)
N-α-Ac- A S L R H [Phe] L N L V [D-Trp] R Q R Y-NH2 (SEQ.ID No.37)(上表中,myristoyl-为十四烷酰基,naphthaleneacetyl-为萘乙酰基)
分析
结合研究
制备仅在Thr36处作标记的125I-PYY和鼠空肠上皮质膜的方法按照标准的方法进行(如见:Laburthe et al.Endocrinology,文献同上;Servin et al.文献同上;Voisin et al.Ann.N.Y.Acad.Sci.611:343,1990)。结合试验是在总体积为0.25ml的60mM HEPES缓冲液(pH7)中进行的,内含2%BSA(牛血清白蛋白)、0.1%杆菌肽、5mM MgCl2、和0.05nM125I-PYY(含或不含竞争性肽)。20,000×g离心10分钟以分开结合肽和游离肽。在含1μM不标记的PYY(代表10%的总结合量)时测定非特异性125I-PYY结合。
短路电流的测定
肽的抗分泌作用是通过测定被架置在Ussing箱中并被自动地加上电压的鼠空肠粘膜中的短路电流(SSC)来进行研究的,如Cox etal.所描述的(J.Physiol.文献同上)。简单地说,把粘膜条放置在有机玻璃Ussing箱的两个半部之间(窗口大小为0.6cm2),Ussing箱内含充氧(95%O2/5%CO2)的Krebs-Henseleit溶液(117mMNaCl、4.7mM KCl、2.5mM CaCl2;1.2mM MgSO4、24.8mM NaHCO3及11.1 mM葡萄糖),pH7.4,37℃。常规作法是从每一只动物中获得4个空肠制备物,这些制备物表现出类似的电位差和SCC,但没将其配对。用一个W-P二极电压夹给制备物自动加电压,SCC即在笔式记录仪上连续显示出来。一旦达到一稳定的基底SCC,只把肽加到嗜碱侧储存器(the basolateral reservoir)中,从而构建出渐增的浓度-反应曲线图。
数据分析
在结合试验中,所有点都是取至少三次试验的平均值、每次试验重复两次。为清楚起见,结合试验中的SEMs(平均标准误)未在图2中表示出来,但均小于10%。SCC中的变化值表示为均值±1SEMμA/0.6cm2,来自3-7个不同的制备物。EC50值是从合并的“渐增浓度-反应”曲线中采用一迭代曲线选配程序(an iterativecurve fitting program)计算而得。数据组(SCC记录)的比较采用不成对的Student′s的t-检验,当p值<0.5时,认为有统计学差异。
下面是关于本发明的化合物的生物学活性的结果(见表1和表2)。如下所述,对所检测的化合物分析了纯度及它们在鼠空肠中的结合效力和抗分泌效力。
反相分析层析表明,纯化的肽中,有>96%是同源的,此外,具有预期的氨基酸组成和含量。例如,图1显示了N-α-Ac-[Phe27]PYY(22-36)(SEQ.ID.NO.3)的RT-HPLC层析图。通过序列分析进一步鉴定了该游离肽(见表1和表2)。肽的总产率在10%-30%范围内。
PYY、[im-DNP-His26]PYY(SEQ.ID.NO.9)、及PYY(22-36)(SEQ.ID.NO.10)的类似物取代125I-PYY结合到鼠空肠上皮质膜,是以一种浓度依赖的方式。尽管根据IC50值,[im-DNP-His26]PYY(SEQ.ID.NO.9)及PYY(22-36)(SEQ.ID.NO.10)的效力比PYY低20倍,但它们显示出与完整的激素相同的最大反应(图2、表1)。用Ala替代Thr32(正如在[Ala32]PYY(22-36)(SEQ.ID.NO.11)中的结果是降低了结合效力,当用Ala替代Ser23和Thr32时,则进一步降低受体亲和力。此外,在第28位引进一个负电荷但不改变螺旋结构(正如在[Glu28]PYY(22-36)(SEQ.ID.NO.13)中)时,降低了结合,原因可能是由于破坏了离子间的相互作用。由于已知疏水基可增加与受体的相互作用(Bala-subramaniam et al.Biochem.Biophys.Res.Comm.137:1041,1986),也测定了PYY(22-36)的N-α-十四烷酰-及N-α-萘乙酰-衍生物的结合。这两种类似物均表现出比PYY(22-36)(SEQ.ID.NO.10)稍低的结合亲和力,可能是由于增加了位阻。而另一方面,PYY(22-36)(SEQ.ID.NO.14)的N-α-乙酰化反应使受体亲和力增加了4倍。用N-α-Ac-PYY(22-36)(SEQ.ID.NO.20)对结构-活性的进一步研究表明,用N-Me-Tyr替代Tyr36或用p.Cl-Phe替代His26,降低了结合效力。然而,用Phe替代Tyr27,却使受体的亲和力增加了28%。作为对照,对PYY(22-36)(SEQ.ID.NO.10)及其几个类似物的结合效力也作了检测,然而,所有这些类似物都不抑制125I-PYY的结合,甚至在浓度达10μM时。
在鼠空肠的粘膜制备物中,PYY(22-36)(SEQ.ID.NO.10)类似物以一种浓度依赖的方式降低基底SCC(图3A及B),计算所得的EC50值列于表1。PYY(22-36)(SEQ.ID.NO.10)类似物作为抗分泌剂的效力普遍低于作为结合抑制剂的效力。类似物的抗分泌效力顺序与结合研究中的相似,但有两个明显的例外,即N-α-十四烷酰-PYY(22-36)(SEQ.ID.NO.18)和N-α-萘乙酰-PYY(22-36)(SEQ.ID.NO.19)。N-α-乙酰化反应以及用Phe替代Tyr27,增加了PYY(22-36)的抗分泌效力,这种类似物(N-α-Ac-[Phe27]PPY(22-36)(SEQ.ID.NO.3))的效力比完整的激素仅小9倍。此外,在最大抑制反应中没有显著性差异:对PYY(440nm,n=6)(SEQ.ID.NO.1)及N-α-Ac-[Phe27]PYY(22-36)(1.4μM,n=7)(SEQ.ID.NO.3)分别为-12.6±2.4及-12.0±1.3μA/0.6cm2。表1:PYY、PYY片断及其类似物的结合效力及抗分泌效力的比较肽 RTa MH+(Calc.) 结合b SCCb
(分) IC50(nM) EC50(nM)
PYY(SEQ.ID.NO.1) | 4.8 | 4240.2(4241.7) | 0.2 | 1.7 |
NPY(SEQ.ID.NO.24) | 34.0c | 4253.8(4254.7) | 2.0 | 9d |
[im-DNP-His26]PYY(SEQ.ID.NO.9) | 8.7c | 4406.9(4407.8) | 4.0 | 72 |
PYY(22-36)(SEQ.ID.NO.10) | 4.4 | 1888.8(1890.2) | 4.0 | 77 |
[Ala32]PYY(22-36)(SEQ.ID.NO.11) | 4.7 | 1858.8(1860.2) | 71 | n.d. |
[Ala23,32]PYY(22-36)(SEQ.ID.NO.12) | 4.3 | 1842.8(1844.2) | >10,000 | n.d. |
[Glu28]PYY(22-36)(SEQ.ID.NO.13) | 3.8 | 1905.1(1906.2) | 199 | n.d. |
N-α-Ac-PYY(22-36)(SEQ.ID.NO.14) | 10.0 | 1930.9(1932.2) | 1.12 | 40 |
N-α-Ac-[p.ClPhe26]PYY(22-36)(SEQ.ID.NO.15) | 14.9c | 1975.4(1976.7) | 50 | 124 |
N-α-Ac-[Glu28]PYY(22-36)(SEQ.ID.NO.16) | 3.9 | 1947.0(1948.2) | 44.7 | 3,000 |
N-α-Ac-[N-Me-Tyr36]PYY(22-36)(SEQ.ID.NO.17) | 13.5 | 1945.3(1946.3) | 354 | 792 |
N-α-Ac-[Phe27]PYY(22-35)(SEQ.ID.NO.3) | 8.3 | 1915.3(1916.2) | 0.80 | 15.1 |
N-α-Nyristoyl-PYY(22-36)(SEQ.ID.NO.18) | 4.8 | 2099.0(2100.6) | 17.8 | 3,300 |
N-α-Naphthaleneacetyl-PYY(22-36)(SEQ.ID.NO.19) | 17.0 | 2056.9(2058.4) | 8.9 | 19,500 |
a:恒溶剂成份的(isocratic),27%CH3CN,内含0.1%TFA;b:三次独立试验的平均值;c:恒溶剂成份的,32%CH3CN,内含0.1%TFA;d:摘自文献10;n.d.:未测定
与其中等程度的结合效力相反,N-α-十四烷酰-PYY(22-36)(SEQ.ID.NO.18)及N-α-萘乙酰-PYY(22-36)(SEQ.ID.NO.19)类似物表现出很弱的抗分泌反应,临界浓度为约20nM,EC50分别大于2μM和30μM。当浓度渐增至7.4μM后,N-α-十四烷酰-PYY(22-3 6)(SEQ.ID.NO.18)使基础的SCC降低了-5.2±0.6μA/0.6cm2(n=7)。随后加入PYY(100nM)进一步使SCC降低了-10.2±0.7μA/0.6 cm2(n=7),这与对PYY(22-36)(SEQ.ID.NO.10)的对照反应没有显著性差异。能中和PYY反应,用类似物(1μM)处理3种组织,构建出“PYY浓度-反应”曲线,并与对照进行比较。该片段使基础电流减少了-0.4±0.3μA/0.6 cm2,但所得的PYY EC50值(4.4±1.2nM,n=3)并不显著不同于未经处理的对照(2.6±1.1nM,n=3)。
这些结果表明,对PYY(SEQ.ID.NO.1)的活性位点:PYY(22-36)(SEQ.ID.NO.10),进行修饰,能导致这些片段的结合效力和抗分泌效力的很大增加。在这一系列中,其主要类似物的效力顺序如下:PYY(SEQ.ID.NO.1)>N-α-Ac-[Phe27]PYY(22-36)(SEQ.ID.NO.3)>N-α-Ac-PYY(22-36)(SEQ.ID.NO.14)>PYY(22-36)(SEQ.ID.NO.10)。此外,我们的研究显示Ser23和Thr32的羟基、以及His26的咪唑基对于与肠PYY-优选受体的相互作用来说很重要。尽管一般来说,类似物的结合效力与抗分泌效力之间有很好的相关性,但也有明显的例外。N-α-十四烷酰-PYY(22-36)(SEQ.ID.NO.18)和N-α-萘乙酰-PYY(22-36)(SEQ.ID.NO.19)类似物抑制125I-PYY结合的效力属中等,但却表现出很弱的抗分泌反应。这一观察结果提示,这些类似物可能是颉抗物。然而,用这些类似物预先处理空肠膜却没能显著改变对PYY的抗分泌反应。此差异的原因目前尚不清楚。
表2和图4给出了其它的PYY(22-36)(SEQ.ID.NO.10)及PYY(25-36)类似物的IC50值。根据表2所示结果,在这一系列中,类似物表现出如下的效力顺序:N-α-Ac-[Tic27]PYY(22-36)(SEQ.ID.NO.25)<N-α-Ac-[Bip27]PYY(22-36)(SEQ.ID.NO.22)<N-α-Ac-[Nal27]PYY(22-36)(SEQ.ID.NO.23)<N-α-Ac-[Bth27]PYY(22-36)(SEQ.ID.NO.21)<N-α-Ac-[Phe27]PYY(22-36)(SEQ.ID.NO.3)<N-α-Ac-[Phe27]PYY(25-36)(SEQ.ID.NO.26)<N-α-Ac-[Trp27]PYY(22-36)(SEQ.ID.NO.5)<N-α-Ac-[Thi27]PYY(22-36)(SEQ.ID.NO.6)<N-α-Ac-PYY(22-36)(SEQ.ID.NO.14)<PYY(SEQ.ID.NO.1)。
表2:PYY和PYY类似物的受体结合数据的比较
肽编号 | 肽结构 | IC50(nM) |
PYY(SEQ.ID.NO.1) | 0.04 | |
N-α-Ac-PYY(22-36)(SEQ.ID.NO.14) | O.08 | |
905 | N-α-Ac-[Bth27]PYY(22-36)(SEQ.ID.NO.21) | 0.22 |
906 | N-α-Ac-[Bip27]PYY(22-36)(SEQ.ID.NO.22) | 4.46 |
911 | N-α-Ac-[Nal27]PYY(22-36)(SEQ.ID.NO.23) | 0.39 |
915 | N-α-Ac-[Trp27]PYY(22-36)(SEQ.ID.NO.5) | 0.10 |
916 | N-α-Ac-[Thi27]PYY(22-36)(SEQ.ID.NO.6) | 0.095 |
914 | N-α-Ac-[Phe27]PYY(25-36)(SEQ.ID.NO.26) | 0.15 |
913 | N-α-Ac-[Tic27]PYY(22-36)(SEQ.ID.NO.25) | 4.50 |
到目前为止被鉴定的NPY/PYY受体主要被归入Y-1、Y-2、和Y-3亚型(Balsubramaniam et al.J.Biol.Chem.265:14724,1990;Mi-chel,Trends Pharmacol.Sci.12:389,1991)。Y-1和Y-2受体均表现出对PYY的亲和力大于对NPY,而且更有意义的是,NPY和PYY的C-末端片段仅在Y-2亚型中是有效的。而另一方面,Y-3受体对NPY表现出比对PYY更大的亲和力。由于鼠空肠粘膜抗分泌反应显示出一种兴奋剂效力顺序:PYY(SEQ.ID.NO.1)>NPY(SEQ.ID.NO.24)>PYY(13-36)(SEQ.ID.NO.32)>NPY(13-36)(SEQ.ID.NO.33),所以这些上皮受体象是属于Y-2类,而且对Y-1选择性兴奋剂[Pro34]NPY完全不敏感(Cox et al.Peptides,文献同上)。他们的结果进一步描述了N-α-Ac-PYY(22-36)(SEQ.ID.NO.14)及N-α-Ac-[Phe27]PYY(22-36)(SEQ.ID.NO.3)比PYY(22-36)(SEQ.ID.NO.10)及不同长度NPY的相应C-末端片段更有效(Cox et al.Br.J.Pharmacol.文献同上)。与对NPY(SEQ.ID.NO.24)及其各个片段相比,这些受体对PYY(SEQ.ID.NO.1)及其C-末端片段具有更高的亲和力,该结果与用鼠肠上皮膜进行受体结合研究所获得的效力顺序是一致的(Laburthe et al.文献同上;Laburthe,文献同上;Voisin et al.Ann.N.Y.Acad.Sci.文献同上);Voision et al.Am.J.Physiol.)。
此外,如上所述,合成了表3中所列的类似物并检测了结合活性。表3中所示结果表明,N-α-Ac-[Tyr22,Phe27]PYY(22-36)(SEQ.ID.NO.7)在其竞争性结合中,与PYY(SEQ.ID.NO.1)相似,表明在第22位引进一个芳香族氨基酸(如Tyr),是一种有效的PYY类似物。
表3
肽编号 | 肽结构 | IC50(nM) |
PYY(SEQ.ID.NO.1) | 0.10 | |
917 | N-α-Ac-[Phe27,Thi36]PYY(22-26)(SEQ.ID.NO.27) | 4.46 |
918 | N-α-Ac-[Thz26,Phe27]PYY(22-36)(SEQ.ID.No.28) | 4.50 |
904 | N-α-Ac-[Pcp27]PYY(22-36)(SEQ.ID.NO.29) | 1.58 |
908 | N-α-Ac-[Phe22,27]PYY(22-36)(SEQ.ID.NO.30) | 11.22 |
910 | N-α-Ac-[Tyr22,Phe27]PYY(22-36)(SEQ.ID.NO.7) | 0.10 |
应用
在本发明的方法的实施中,将有效量的本发明的类似物(如:N-α-Ac-[Phe27]PYY(22-36)(SEQ.ID.NO.3)、N-α-Ac-[Trp27]PYY(22-36)(SEQ.ID.NO.24)、N-α-Ac-[Phe27]PYY(25-36)(SEQ.ID.NO.3)、N-α-Ac-[Thi27]PYY(22-36)(SEQ.ID.NO.6)或其衍生物)的任一种或其组合,通过为本领域所知的任何一种一般的和可接受的方法,施用单独的或以与其它化合物或本发明的化合物的组合物。因此,这些化合物或组合物可经口(如经口腔)、舌下、肠胃外(如经肌肉、静脉、或皮下)、直肠(如经栓剂或洗涤)、皮肤(如皮肤电穿孔)、或经吸入(如经气溶胶),以固体、液体或气体剂型给药,包括片剂和悬液。给药方式可任意地采用单个单位剂量的形式进行连续治疗,或一次剂量治疗。
因此,本发明的方法可用于非常有必要解除症状时或危急时。此外,本发明的方法也可有效地用作连续治疗或预防性治疗。
在制备本发明中的组合物时,可利用的制药载体可以是固体、液体或气体。因此,该组合物的形态可以是药片、药丸、胶囊、栓剂、粉末、肠包被的或其它的被保护的制剂(如结合到离子交换树脂上或包埋在脂蛋白的小泡中)、持续释放性制剂、溶液、悬液、酏剂、气溶胶、等等。载体可选自不同的油,包括源自石油、动物、植物、或合成的油,如花生油、大豆油、矿物油、芝麻油、等等。水、盐水、含水的右旋糖、以及乙二醇则是优选的液体载体,尤其(当与血液等渗时)可用于注射的溶液。例如,用于静脉内注射的制剂包括活性成分的无菌水溶液,即把固体的活性成分溶于水中制成水溶液,然后对此溶液作无菌处理。合适的制药赋形剂包括:淀粉、纤维素、滑石、葡萄糖、乳糖、明胶、麦芽、米、面粉、白垩、二氧化硅、硬脂酸镁、硬脂酸钠、单硬脂酸甘油(glycerol mono-stearate)、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇、等等。该组合物中可加入常规的制药添加剂,如防腐剂、稳定剂、润湿剂或乳化剂、调节渗透压的盐、缓冲液、等等。关于合适的制药载体以及它们配制方法的描述见E.W.Martin的Remington′s Pharmaceuti-cal Sciences。总之,此组合物中须包含:有效量的活性化合物以及一合适的载体,以便制备出可用适当的给药方式给予接受者的、适当的剂型。
为治疗前面所提及的疾病所需的本发明的化合物的剂量大小取决于给药的方式、施药对象的年龄和体重、以及施药对象有待治疗的状况,并最终将由参诊的医师或兽医决定。由参诊的医师或兽医所确定的该活性化合物的这种剂量,在此被称作“治疗有效量”。因此,典型的给药方式是口服给药或非肠胃给药。口服给药每天的剂量一般在0.1-100mg/kg体重的范围;非肠胃给药,每天的剂量一般在0.001-50mg/kg体重的范围。
重要的是,对于有效地预防或治疗胃肠病,尤其是传染性腹泻(如病毒性的或细菌性的)、炎性腹泻、或手术所致的腹泻,该治疗剂在其实际应用中的含量水平,是相对无毒、无抗原性、及无刺激性的。
在此所描述的例子及实施例应理解为,仅仅是为了说明的目的,本领域的技术人员将能由此而作各种不同的修改和改变,这些修改或改变都包括在此申请的精神和范围之内以及所附录的权利要求范围之内。
Claims (20)
其中:
X为一条含有0-5个氨基酸的链,包括,其N-末端氨基酸与R1和R2相连;
Y为一条含有0-4个氨基酸的链,包括,其C-末端氨基酸与R3和R4相连;
R1为H、C1-C12烷基、C6-C18芳基、C1-C12酰基、C7-C18芳烷基、或C7-C18烷芳基;
R2为H、C1-C12烷基、C6-C18芳基、C1-C12酰基、C7-C18芳烷基、或C7-C18烷芳基;
A22为一个芳香族氨基酸、Ala、Aib、Anb、N-Me-Ala、或被删去;
A23为Ser、Thr、Ala、Aib、N-Me-Ser、N-Me-Thr、N-Me-Ala、D-Trp、或被删去;
A24为Leu、Gly、Ile、Val、Trp、Aib、Anb、N-Me-Leu、或被删去;
A25为Arg、Lys、homo-Arg、二乙基homo-Arg、Lys-ε-NH-R
(其中R为H、一个分支或直链的C1-C10烷基、或一个芳基)、Orn、或被删去;
A26为Ala、His、Thr、3-Me-His、1-Me-His、β-吡唑基丙氨酸
(pyrozolylalanine)、N-Me-His、Arg、Lys、homo-Arg、二
乙基-homo-Arg、Lys-ε-NH-R(其中R为H、一个分支或直
链的C1-C10烷基、或一个芳基)、Orn、或被删去;
A27为一个除Tyr外的芳香族氨基酸;
A28为Leu、Ile、Val、Trp、Aib、Anb、或N-Me-Leu;
A29为Asn、Ala、Gln、Gly、Trp、或N-Me-Asn;
A30为Leu、Ile、Val、Trp、Aib、Anb、或N-Me-Leu;
A31为Val、Ile、Trp、Aib、Anb、或N-Me-Val;
A32为Thr、Ser、N-Me-Ser、N-Me-Thr、或D-Trp;
R3为H、C1-C12烷基、C6-C18芳基、C1-C12酰基、C7-
C18芳烷基、或C7-C18烷芳基;以及
R4为H、C1-C12烷基、C6-C18芳基、C1-C12酰基、C7-
C18芳烷基、C7-C18烷芳基。
2、权利要求1的化合物或其药用可接受的盐,其中的A27为Phe、Nal、Bip、Pcp、Tic、Trp、Bth、Thi、或Dip。
3、权利要求1的化合物,其中的X为A17-A18-A19-A20-A21,其中:
A17为Cys、Leu、Ile、Val、Aib、Anb或N-Me-Leu;
A18为Cys、Ser、Thr、N-Me-Ser、或N-Me-Thr;
A19为Cys、Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-ε-
NH-R(其中R为H、一个分支或直链的C1-C10烷基、或C6-C18芳
基)、或Orn;
A20为一个芳香族氨基酸或Cys;以及
A21为一个芳香族氨基酸、Cys。
4、权利要求1的化合物或其药用可接受的盐,其中Y为A33-A34-A35-A36,其中:
A33为Cys、Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-ε-
NH-R(其中R为H、一个分支或直链的C1-C10烷基、或C6-C18芳
基)、或Orn;
A34为Cys、Gln、Asn、Ala、Gly、N-Me-Gln、Aib、或Anb;
A35为Cys、Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-ε-
NH-R(其中R为H、一个分支或直链的C1-C10烷基、或C6-C18芳
基)、或Orn;以及
A36为一个芳香族氨基酸、Cys。
5、权利要求4的化合物或其药用可接受的盐,其中该化合物有公式:N-α-Ac-Ala-Ser-Leu-Arg-His-Phe-Leu-Ash-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ.ID.NO.3)。
6、权利要求4的化合物或其药用可接受的盐,其中该化合物有公式:H-Ala-Ser-Leu-Arg-His-Phe-Leu-Ash-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ.ID.NO.4)。
7、权利要求4的化合物或其药用可接受的盐,其中该化合物有公式:N-α-Ac-Ala-Ser-Leu-Arg-His-Trp-Leu-Ash-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ.ID.NO.5)。
8、权利要求4的化合物或其药用可接受的盐,其中该化合物有公式:N-α-Ac-Ala-Ser-Leu-Arg-His-Thi-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ.ID.NO.6)。
9、权利要求4的化合物或其药用可接受的盐,其中该化合物有公式:N-α-Ac-Tyr-Ser-Leu-Arg-His-Phe-Leu-Ash-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ.ID.NO.7)。
N-末端氨基酸与R1和R2相连;
Y为一条含有0-4个氨基酸的链,包括,其C-末端氨基酸与R3和R4相连;
R1为H、C1-C12烷基、C6-C18芳基、C1-C12酰基、C7-
C18芳烷基、或C7-C18烷芳基;
R2为H、C1-C12烷基、C6-C18芳基、C1-C12酰基、C7-
C18芳烷基、或C7-C18烷芳基;
A25为Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-ε-NH-R
(其中R为H、一个分支或直链的C1-C10烷基、或一个芳基)、
Orn、或被删去;
A26为Ala、His、Thr、3-Me-His、1-Me-His、β-吡唑基丙氨酸、
N-Me-His、Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-
ε-NH-R(其中R为H、一个分支或直链的C1-C10烷基、或一个
芳基)、Orn、或被删去;
A27为一个芳香族氨基酸;
A28为Leu、Ile、Val、Trp、Aib、Anb、或N-Me-Leu;
A29为Asn、Ala、Gln、Gly、Trp、或N-Me-Asn;
A30为Leu、Ile、Val、Trp、Aib、Anb、或N-Me-Leu;
A31为Val、Ile、Trp、Aib、Anb、或N-Me-Val;
A32为Thr、Ser、N-Me-Ser、N-Me-Thr、或D-Trp;
R3为H、C1-C12烷基、C5-C18芳基、C1-C12酰基、C7-C18芳烷基、或C7-C18烷芳基;以及
R4为H、C1-C12烷基、C6-C18芳基、C1-C12酰基、C7-
C18芳烷基或C7-C18烷芳基。
11、权利要求10的化合物,其中的A27为Phe、Nal、Bip、Pcp、Tic、Trp、Bth、Thi、或Dip。
12、权利要求10的化合物或其药用可接受的盐,其中的Y为A33-A34-A35-A36,其中:
A33为Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-ε-NH-R
(其中R为H、一个分支或直链的C1-C10烷基、或C6-C18芳
基)、Cys、或Orn;
A34为Cys、Gln、Asn、Ala、Gly、N-Me-Gln、Aib、或Anb;
A35为Arg、Lys、homo-Arg、二乙基-homo-Arg、Lys-ε-NH-R
(其中R为H、一个分支或直链的C1-C10烷基、或C6-C18芳
基)、Cys、或Orn;以及
A36为一个芳香族氨基酸、Cys。
13、权利要求12的化合物或其药用可接受的盐,其中该化合物是有公式:N-α-Ac-Arg-His-Phe Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2(SEQ.ID.NO.26)。
14、一种能降低过多的肠水及电解质分泌的治疗用组合物,所说组合物含有治疗有效量的权利要求1和权利要求10的化合物、以及一种药用可接受的载体物质。
15、一种可降低哺乳动物中过多的肠水和电解质分泌的方法,所说方法包括,给所说哺乳动物施用治疗有效量的权利要求14的组合物。
16、一种可调节哺乳动物中的细胞增生的方法,所说方法包括,给所说哺乳动物施用治疗有效量的权利要求14的组合物。
17、一种可增强哺乳动物中的养分运输的方法,所说方法包括,给所说哺乳动物施用治疗有效量的权利要求14的组合物。
18、一种可调节哺乳动物中的脂解作用的方法,所说方法包括,给所说哺乳动物施用治疗有效量的权利要求14的组合物。
19、一种可调节哺乳动物中的血流的方法,所说方法包括,给所说哺乳动物施用治疗有效量的权利要求14的组合物。
20、一种含有权利要求10的两条肽、或权利要求1的1条肽或权利要求10的1条肽的二聚化合物,其中,所说二聚体是通过一个酰胺键、或所说两条肽间的一个二硫键形成的。
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EP (1) | EP0692971A4 (zh) |
JP (1) | JPH08510205A (zh) |
KR (1) | KR960701653A (zh) |
CN (1) | CN1124927A (zh) |
AU (1) | AU685803B2 (zh) |
CA (1) | CA2157766A1 (zh) |
FI (1) | FI954559A0 (zh) |
HU (1) | HUT73494A (zh) |
NZ (1) | NZ265452A (zh) |
PL (1) | PL310897A1 (zh) |
SG (1) | SG52542A1 (zh) |
SK (1) | SK121895A3 (zh) |
WO (1) | WO1994022467A1 (zh) |
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FR2735983B1 (fr) * | 1995-06-29 | 1997-12-05 | Centre Nat Rech Scient | Peptide permettant de modifier l'activite du systeme immunitaire humain ou animal |
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EP2277527A3 (en) | 2003-01-17 | 2011-08-31 | Ipsen Pharma | Peptide YY analogs |
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EP2335716A3 (en) * | 2004-02-11 | 2011-10-19 | Amylin Pharmaceuticals Inc. | Pancreatic polypeptide family motifs and polypeptides comprising the same |
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CA2560166A1 (en) * | 2004-03-17 | 2005-09-29 | 7Tm Pharma A/S | Y2/y4 selective receptor agonists for therapeutic interventions |
CN1933848A (zh) * | 2004-03-17 | 2007-03-21 | 7Tm制药联合股份有限公司 | 用于治疗性干预的y2选择性受体激动剂 |
JP5743371B2 (ja) | 2004-12-13 | 2015-07-01 | アミリン・ファーマシューティカルズ, リミテッド・ライアビリティ・カンパニーAmylin Pharmaceuticals, Llc | 膵臓ポリペプチドファミリーモチーフ、ポリペプチドおよびこれらを含む方法 |
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US8283312B2 (en) * | 2005-02-04 | 2012-10-09 | The Research Foundation Of State University Of New York | Compositions and methods for modulating body weight and treating obesity-related disorders |
GB0504857D0 (en) * | 2005-03-09 | 2005-04-13 | Imp College Innovations Ltd | Novel compounds and their effects on feeding behaviour |
GB0511986D0 (en) * | 2005-06-13 | 2005-07-20 | Imp College Innovations Ltd | Novel compounds and their effects on feeding behaviour |
BRPI0614649A2 (pt) * | 2005-08-11 | 2011-04-12 | Amylin Pharmaceuticals Inc | polipeptìdeos hìbridos com propriedades selecionáveis |
EP1922336B1 (en) * | 2005-08-11 | 2012-11-21 | Amylin Pharmaceuticals, LLC | Hybrid polypeptides with selectable properties |
BRPI0520563A2 (pt) * | 2005-09-21 | 2009-05-19 | 7Tm Pharma As | agonistas de receptores y4 seletivos para intervenções terapêuticas |
JP2009508886A (ja) * | 2005-09-21 | 2009-03-05 | 7ティーエム ファーマ エイ/エス | 治療的介入のためのy2選択性レセプターアゴニスト |
AU2006297443B2 (en) | 2005-09-29 | 2010-08-12 | Merck Sharp & Dohme Corp. | Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators |
US20070232537A1 (en) * | 2005-12-19 | 2007-10-04 | Nastech Pharmaceutical Company Inc. | Intranasal pyy formulations with improved transmucosal pharmacokinetics |
US20070197445A1 (en) * | 2006-01-18 | 2007-08-23 | University Of Cincinnati | Compounds for control of appetite |
US8173629B2 (en) | 2006-09-22 | 2012-05-08 | Merck Sharp & Dohme Corp. | Method of treatment using fatty acid synthesis inhibitors |
TWI428346B (zh) | 2006-12-13 | 2014-03-01 | Imp Innovations Ltd | 新穎化合物及其等對進食行為影響 |
US20090099074A1 (en) * | 2007-01-10 | 2009-04-16 | Conjuchem Biotechnologies Inc. | Modulating food intake |
EP2145884B1 (en) | 2007-04-02 | 2014-08-06 | Msd K.K. | Indoledione derivative |
GB0708226D0 (en) * | 2007-04-27 | 2007-06-06 | 7Tm Pharma As | Y-receptor agonists |
JP5497006B2 (ja) | 2008-04-14 | 2014-05-21 | ザ ジェネラル ホスピタル コーポレイション | 膵管腺癌の検出および治療のためのプレクチン−1標的化剤 |
US8299023B2 (en) | 2008-09-17 | 2012-10-30 | Hoffmann-La Roche Inc. | Neuropeptide-2 receptor (Y-2R) agonists |
NZ628987A (en) | 2009-02-03 | 2015-11-27 | Amunix Operating Inc | Extended recombinant polypeptides and compositions comprising same |
US9260500B2 (en) | 2009-07-02 | 2016-02-16 | Takeda Pharmaceutical Company Limited | Peptide and use thereof |
TW201138808A (en) | 2010-05-03 | 2011-11-16 | Bristol Myers Squibb Co | Serum albumin binding molecules |
US9278123B2 (en) | 2010-12-16 | 2016-03-08 | Novo Nordisk A/S | Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid |
SG10201700340WA (en) | 2012-02-27 | 2017-03-30 | Amunix Operating Inc | Xten conjugate compositions and methods of making same |
RS64460B1 (sr) | 2012-03-22 | 2023-09-29 | Novo Nordisk As | Kompozicije glp-1 peptida i njihova priprema |
RS59026B1 (sr) | 2013-11-15 | 2019-08-30 | Novo Nordisk As | Selektivna pyy jedinjenja i njihova upotreba |
JP6629198B2 (ja) | 2013-11-15 | 2020-01-15 | ノヴォ ノルディスク アー/エス | 35位にβ−ホモアルギニン置換を有するHPYY(1−36) |
CA2988500A1 (en) * | 2015-06-12 | 2016-12-15 | Novo Nordisk A/S | Selective pyy compounds and uses thereof |
US11812746B2 (en) | 2016-08-28 | 2023-11-14 | The State Of Israel, Ministry Of Agriculture & Rural Development, Agricultural Research Organization (Aro) (Volcani Center) | Method of controlling fungal infections in plants |
PL3746111T3 (pl) | 2018-02-02 | 2024-01-15 | Novo Nordisk A/S | Stałe kompozycje zawierające agonistę glp-1 i sól kwasu n-(8-(2- hydroksybenzoilo)amino kaprylowego i substancję poślizgową |
MX2022005676A (es) | 2019-11-13 | 2022-10-27 | Amunix Pharmaceuticals Inc | Polipéptidos xten con código de barras y composiciones de estos, y métodos para preparar y usar los mismos. |
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JPS646294A (en) * | 1987-02-09 | 1989-01-10 | Ajinomoto Kk | Novel peptide derivative |
US5026685A (en) * | 1988-07-15 | 1991-06-25 | The Salk Institute For Biological Studies | NPY peptide analogs |
-
1994
- 1994-03-29 JP JP6522278A patent/JPH08510205A/ja active Pending
- 1994-03-29 PL PL94310897A patent/PL310897A1/xx unknown
- 1994-03-29 SK SK1218-95A patent/SK121895A3/sk unknown
- 1994-03-29 AU AU66214/94A patent/AU685803B2/en not_active Ceased
- 1994-03-29 NZ NZ265452A patent/NZ265452A/en unknown
- 1994-03-29 KR KR1019950704035A patent/KR960701653A/ko not_active Application Discontinuation
- 1994-03-29 CN CN94192277A patent/CN1124927A/zh active Pending
- 1994-03-29 SG SG1996005776A patent/SG52542A1/en unknown
- 1994-03-29 CA CA002157766A patent/CA2157766A1/en not_active Abandoned
- 1994-03-29 WO PCT/US1994/003380 patent/WO1994022467A1/en not_active Application Discontinuation
- 1994-03-29 HU HU9502833A patent/HUT73494A/hu unknown
- 1994-03-29 EP EP94913965A patent/EP0692971A4/en not_active Withdrawn
- 1994-10-24 US US08/329,151 patent/US5604203A/en not_active Expired - Lifetime
-
1995
- 1995-09-26 FI FI954559A patent/FI954559A0/fi unknown
Also Published As
Publication number | Publication date |
---|---|
AU685803B2 (en) | 1998-01-29 |
FI954559A (fi) | 1995-09-26 |
JPH08510205A (ja) | 1996-10-29 |
EP0692971A1 (en) | 1996-01-24 |
WO1994022467A1 (en) | 1994-10-13 |
PL310897A1 (en) | 1996-01-08 |
EP0692971A4 (en) | 1997-11-12 |
FI954559A0 (fi) | 1995-09-26 |
SG52542A1 (en) | 1998-09-28 |
SK121895A3 (en) | 1996-10-02 |
NZ265452A (en) | 1997-09-22 |
KR960701653A (ko) | 1996-03-28 |
HUT73494A (en) | 1996-08-28 |
US5604203A (en) | 1997-02-18 |
CA2157766A1 (en) | 1994-10-13 |
AU6621494A (en) | 1994-10-24 |
HU9502833D0 (en) | 1995-11-28 |
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