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1. 发明授权

US5015729A Ovine inhibin 失效
标题翻译：牛抑制素
公开(公告)号：US5015729A
公开(公告)日：1991-05-14
申请号：US210683
申请日：1988-06-23
申请人： Joachim Spiess , Jean E. F. Rivier , C. Wayne Bardin , Wylie W. Vale, Jr.
发明人： Joachim Spiess , Jean E. F. Rivier , C. Wayne Bardin , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , C07K14/575 , C07K16/26
CPC分类号： C07K14/575 , C07K16/26 , A61K38/00
摘要： A dimeric protein with inhibin activity is isolated from ram reta testis fluid using reverse-phase high-performance liquid chromatography and gel filtration. The isolated molecule is composed of two chains having apparent molecular weights of about 18,000 and about 16,500 to 14,500 Daltons, as measured by gel electrophoresis, which are bound together by disulfide bonding and the longer of which is likely glycosylated. Microsequencing revealed the NH.sub.2 -terminal portion of the longer chain to be Ser- Thr-Pro-Pro-Leu-Pro-Trp-Pro-Trp-Ser-Pro-Ala-Ala-Leu-Arg-Leu-Gln-Arg-Pro-Pro- Glu-Glu-Pro-Ala-Ala-His-Ala-Asp-Cys and of the shorther chain to by Gly-Leu-Glu-Cys-Asp-Gly-Lys-Val-Asn-Ile-Cys-Cys-Lys-Lys-Gln-Phe. This dimeric protein specifically inhibits basal secretion of FSH, but not of LH, in a rat anterior pituitary monolayer culture system, exhibiting a half-maximal effective dose of about 0.1 to 0.3 ng/ml. Furthermore, antibodies raised against synthetic replicates of the N-terminal six residues of the longer chain, as well as against the N-terminal 25 residues, are effective to reduce the activity of highly purified intact ovine inhibin and might be used to exert a profertility effect in rams, ewes and other mammals.
摘要翻译：使用反相高效液相色谱和凝胶过滤从ram reta睾丸液中分离具有抑制素活性的二聚体蛋白。分离的分子由具有约18,000和约16,500至14,500道尔顿的两条链组成，通过凝胶电泳测量，其通过二硫键结合在一起，并且其中较长的可能被糖基化。 Microsequencing显示较长链的NH 2末端部分为Ser-Thr-Pro-Pro-Leu-Pro-Trp-Pro-Trp-Ser-Pro-Ala-Ala-Leu-Arg-Leu-Gln-Arg-Pr 通过Gly-Leu-Glu-Cys-Asp-Gly-Lys-Val-Asn-Ile-Cys-Ala-Pro-Glu-Glu-Pro-Ala-Ala-His-Ala-Asp-Cys， Cys-Lys-Lys-Gln-Phe。这种二聚体蛋白特异性抑制大鼠垂体前叶垂体单层培养系统中FSH的基础分泌而不是LH分泌，表现出约0.1至0.3ng / ml的最大有效剂量。此外，针对长链的N末端六个残基以及N末端25个残基的合成重复产生的抗体对于降低高度纯化的完整羊抑制素的活性是有效的，并且可以用于发挥促进作用对公羊，母羊和其他哺乳动物的影响。

2. 发明授权

US4737578A Human inhibin 失效
标题翻译：人抑制素
公开(公告)号：US4737578A
公开(公告)日：1988-04-12
申请号：US848924
申请日：1986-04-07
申请人： Ronald M. Evans , Michael G. Rosenfeld , Gail Cerelli , Kelly E. Mayo , Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
发明人： Ronald M. Evans , Michael G. Rosenfeld , Gail Cerelli , Kelly E. Mayo , Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , C07K14/575 , C07K7/10 , C07K13/00
CPC分类号： C07K14/575 , A61K38/00 , Y10S930/26
摘要： Proteins with inhibin activity having a weight of about 32,000 daltons. The molecule is composed of two chains having molecular weights of about 18,000 and about 14,000 daltons, respectively, which are bound together by disulfide bonding. The 18K chain is obtained from the human inhibin gene and has the formula: H-Ser-Thr-Pro-Leu-Met-Ser-Trp-Pro-Trp-Ser-Pro-Ser-Ala-Leu-Arg-Leu-Leu-Gln-Arg-Pro-Pro-Glu-Glu-Pro-Ala-Ala-His-Ala-Asn-Cys-His-Arg-Val-Ala-Leu-Asn-Ile-Ser-Phe-Gln-Glu-Leu-Gly-Trp-Glu-Arg-Trp-Ile-Val-Tyr-Pro-Pro-Ser-Phe-R.sub.65 -Phe-His-Tyr-Cys-His-Gly-Gly-Cys-Gly-Leu-His-Ile-Pro-Pro-Asn-Leu-Ser-Leu-Pro-Val-Pro-Gly-Ala-Pro-Pro-Thr-Pro-Ala-Gln-Pro-Tyr-Ser-Leu-Leu-Pro-Gly-Ala-Gln-Pro-Cys-Cys-Ala-Ala-Leu-Pro-Gly-Thr-Met-Arg-Pro-Leu-His-Val-Arg-Thr-Thr-Ser-Asp-Gly-Gly-Tyr-Ser-P e-Lys-Tyr-Glu-Thr-Val-Pro-Asn-Leu-Leu-Thr-Gln-His-Cys-Ala-Cys-Ile-OH, wherein R.sub.65 is Ile or Arg. The 18K chain is connected by disulfide bonding to the 14K chain.
摘要翻译：具有约32,000道尔顿重量的具有抑制素活性的蛋白质。该分子由分子量分别为约18,000和约14,000道尔顿的两条链组成，它们通过二硫键结合在一起。 18K链由人抑制素基因得到，具有下式：H-Ser-Thr-Pro-Leu-Met-Ser-Trp-Pro-Trp-Ser-Pro-Ser-Ala-Leu-Arg-Leu-Leu Gln-Arg-Pro-Pro-Glu-Glu-Pro-Ala-Ala-His-Ala-Asn-Cys-His-Arg-Val-Ala-Le-Asn-Ile-Ser-Phe-Gln-Glu- Leu-Gly-Trp-Glu-Arg-Trp-Ile-Val-Tyr-Pro-Pro-Ser-Phe-R65-Phe-His-Tyr-Cys-His-Gly-Gly-Cys-Gly-Leu-His- Ile-Pro-Pro-As n-Leu-Ser-Leu-Pro-Val-Pro-Gly-Ala-Pro-Pro-Thr-Pro-Ala-Gln-Pro-Tyr-Ser-Leu-Leu-Pro-Gly -Ala-Gln-Pro-Cys-Cys-Ala-Ala-Leu-Pro-Gly-Thr-Met-Arg-Pr-Leu-His-Val-Arg-Thr-Thr-Ser-Asp-Gly-Gly- Tyr-Ser-P e-Lys-Tyr-Glu-Thr-Val-Pro-Asn-Leu-Leu-Thr-Gln-His-Cys-Ala-Cys-Ile-OH，其中R65是Ile或Arg。 18K链通过二硫键与14K链连接。

3. 发明授权

US4443368A Peptides affecting gonadal function 失效
标题翻译：影响性腺功能的肽
公开(公告)号：US4443368A
公开(公告)日：1984-04-17
申请号：US437949
申请日：1982-11-01
申请人： Nancy M. Sherwood , Lee E. Eiden , Michael J. Brownstein , Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
发明人： Nancy M. Sherwood , Lee E. Eiden , Michael J. Brownstein , Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , C07K7/23 , C07C103/52
CPC分类号： C07K7/23 , A61K38/00 , Y10S930/13
摘要： The peptide having the following formula has a potent effect on the reproduction processes of fish and is termed Fish GnRH:pGlu-His-Trp-Ser-Tyr-Gly-Trp-Leu-Pro-Gly-NH.sub.2.Spawning of teleostei fish can be promoted by administration of effective amounts of the peptide.
摘要翻译：具有下式的肽对鱼的繁殖过程具有有效的作用，被称为鱼GnRH：pGlu-His-Trp-Ser-Tyr-Gly-Trp-Leu-Pro-Gly-NH2。可以通过施用有效量的肽来促进远端鱼的产生。

4. 发明授权

US4973577A FSH-releasing peptides 失效
标题翻译： FSH释放肽
公开(公告)号：US4973577A
公开(公告)日：1990-11-27
申请号：US091696
申请日：1987-08-31
申请人： Wylie W. Vale, Jr. , Jean E. F. Rivier , Richard A. McClintock , Anne Corrigan , Joan Vaughan , Joachim Spiess , Nicholas C. Ling , Shao-Yao Ying , Frederick S. Esch , Roger C. L. Guillemin
发明人： Wylie W. Vale, Jr. , Jean E. F. Rivier , Richard A. McClintock , Anne Corrigan , Joan Vaughan , Joachim Spiess , Nicholas C. Ling , Shao-Yao Ying , Frederick S. Esch , Roger C. L. Guillemin
IPC分类号： A61K38/00 , C07K14/575
CPC分类号： C07K14/575 , A61K38/00 , Y10S514/80
摘要： A 28,000-dalton protein with FSH-releasing activity is isolated from porcine follicular fluid in a multi-step procedure including gel filtration, ion exchange chromatography and several reverse-phase high-performance liquid chromatography steps. The 28 kD protein promotes secretion of FSH, but not of LH, in a rat anterior pituitary monolayer culture system, exhibiting an EC.sub.50 of 0.5 ng/ml. These peptides are dimers of inhibin .beta.-chains of mammals, and homodimers or heterodimers of the .beta..sub.A and .beta..sub.B chains are biologically active to regulate fertility of various mammalian species, including humans.
摘要翻译：具有FSH释放活性的28,000道尔顿蛋白质以多步法从猪滤泡液中分离，包括凝胶过滤，离子交换层析和几个反相高效液相色谱步骤。在大鼠垂体前叶单层培养系统中，28kD蛋白促进FSH的分泌，但不促进LH的分泌，其表现为0.5ng / ml的EC 50。这些肽是哺乳动物的抑制素β-链的二聚体，βA和βB链的同源二聚体或异源二聚体具有生物学活性，以调节各种哺乳动物物种（包括人类）的生育力。

5. 发明授权

US4843064A GRF analogs V 失效
标题翻译： GRF类似物V
公开(公告)号：US4843064A
公开(公告)日：1989-06-27
申请号：US96513
申请日：1987-09-11
申请人： Joan Vaughan , Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
发明人： Joan Vaughan , Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , C07K14/60
CPC分类号： C07K14/60 , A61K38/00 , Y10S930/12
摘要： The invention provides peptides which are particularly potent in stimulating the release of pituitary GH in fish and amphibians and which have a substantial portion or all of the following sequence: His-Ala-Asp-Gly-R.sub.5 -Phe-Asn-Lys-Ala-Tyr-Arg-Lys-Ala-Leu-Gly-Gln-Leu- Ser-Ala-Arg-Lys-Tyr-Leu-His-Thr-Leu-R.sub.27 -R.sub.28 -R.sub.29 -R.sub.30 -R.sub.31 -Gly-R.sub.33 -R.sub.34 -R.sub.35 -R.sub.36 -R.sub.37 - R.sub.38 -R.sub.39 -R.sub.40 -R.sub.41 -R.sub.42 -R.sub.43 -R.sub.44 -Ser wherein R.sub.5 is Met, Leu, Val, Nva, Gln, Thr, Ile or Nle; R.sub.27 is Met, Leu, Val, Nva, Gln, Thr, Ile or Nle; R.sub.28 is Ala, Ser or Asn; R.sub.29 is Lys or Arg; R.sub.30 is Arg or Gln; R.sub.31 is Val or Gln; R.sub.33 is Gly or Glu; R.sub.34 is Gly, Arg or Ser; R.sub.35 is Ser or Asn; R.sub.36 is Met, Leu, Val, Nva, Gln, Thr, Ile or Nle; R.sub.37 is Ile or Glu; R.sub.38 is Glu, Gln or Arg; R.sub.39 is Asp, Arg or Gly; R.sub.40 is Asp, Ser or Ala; R.sub.41 is Asn, Arg or Lys; R.sub.42 is Glu, Phe, Ala or Val; R.sub.43 is Pro, Asn or Arg; R.sub.44 is Leu or Ala. A sequence beginning at the C-terminus and extending part way or all the way to residue R.sub.27 may be deleted; a 29-residue peptide beginning at the N-terminus may be preferred. These peptides, as well as their nontoxic salts, are considered to be particularly useful in agriculture.
摘要翻译：本发明提供了在刺激鱼类和两栖动物中垂体GH释放特别有效的肽，其具有大部分或全部以下序列：His-Ala-Asp-Gly-R5-Phe-Asn-Lys-Ala- Tyr-Arg-Lys-Ala-Leu-Gly-Gln-Leu- Ser-Ala-Arg-Lys-Tyr-Leu-His-Thr-Leu-R27-R28-R29-R30-R31-Gly-R33-R34- R3为R5，R36-R37-R38-R39-R40-R41-R42-R43-R44-Ser，其中R5为Met，Leu，Val，Nva，Gln，Thr，Ile或Nle; R27是Met，Leu，Val，Nva，Gln，Thr，Ile或Nle; R28是Ala，Ser或Asn; R29为Lys或Arg; R30是Arg或Gln; R31为Val或Gln; R33是Gly或Glu; R34是Gly，Arg或Ser; R35是Ser或Asn; R36是Met，Leu，Val，Nva，Gln，Thr，Ile或Nle; R37是Ile或Glu; R38是Glu，Gln或Arg; R39为Asp，Arg或Gly; R40是Asp，Ser或Ala; R41是Asn，Arg或Lys; R42是Glu，Phe，Ala或Val; R43是Pro，Asn或Arg; R44是Leu或Ala，从C-末端开始并延伸到残基R27的一部分或全部的序列可以被删除; 可以优选从N末端开始的29残基肽。这些肽以及它们的无毒盐被认为在农业中特别有用。

6. 发明授权

US4703035A Human pancreatic GRF amidated fragments 失效
标题翻译：人胰腺GRF酰化片段
公开(公告)号：US4703035A
公开(公告)日：1987-10-27
申请号：US782912
申请日：1985-10-02
申请人： Jean E. F. Rivier , Joachim Spiess , Wylie W. Vale, Jr.
发明人： Jean E. F. Rivier , Joachim Spiess , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , C07K14/60 , A61K37/36 , A61K37/43 , C07K7/10
CPC分类号： C07K14/60 , A61K38/00 , Y10S930/12
摘要： Surprisingly active fragments of human pancreatic GRF have been synthesized which exhibit good biological activity. These synthetic peptides are extremely potent in stimulating the release of pituitary GH in humans and in nonhuman animals and have the general formula: H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Y wherein Y is NH.sub.2, Gln-NH.sub.2, Gln-Gln-NH.sub.2 or Gln-Gln-Gly-NH.sub.2. Two such fragments have been tested, namely the 29 and the 32 N-terminal residue sequences that are amidated at the C-terminus. These peptides, as well as nontoxic salts thereof, may be administered therapeutically to animals, including humans.
摘要翻译：已经合成了人胰腺GRF的惊人活性片段，其表现出良好的生物学活性。这些合成肽在刺激人和非人动物中垂体GH的释放方面非常有效，具有以下通式：H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys -Val-Leu-Gly-Gln-Leu- Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Y，其中Y是NH2，Gln-NH2，Gln-Gln-NH2 或Gln-Gln-Gly-NH 2。已经测试了两个这样的片段，即在C末端酰胺化的29个和32个N-末端残基序列。这些肽以及其无毒盐可以治疗性地给予动物，包括人。

7. 发明授权

US4415558A CRF And analogs 失效
标题翻译： CRF和类比
公开(公告)号：US4415558A
公开(公告)日：1983-11-15
申请号：US378999
申请日：1982-05-17
申请人： Wylie W. Vale, Jr. , Joachim Spiess , Catherine L. Rivier , Jean E. F. Rivier
发明人： Wylie W. Vale, Jr. , Joachim Spiess , Catherine L. Rivier , Jean E. F. Rivier
IPC分类号： A61K38/00 , C07K14/575 , A61K37/00 , C07C103/52
CPC分类号： C07K14/57509 , A61K38/00 , Y10S514/805
摘要： CRF (Corticotropin Releasing Factor) has the formula:H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Leu-Asp-Ile-Ala-NH.sub.2.Analogs have been synthesized that are at least as potent as CRF, and CRF or these analogs or pharmaceutically acceptable salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals to achieve a substantial elevation of ACTH, .beta.-endorphin, .beta.-lipotropin and corticosterone levels and/or a lowering of blood pressure over an extended period of time. In the analogs, one or more of the first three N-terminal residues may be deleted or may be substituted by a peptide up to 10 amino acids long and/or by an acylating agent containing up to 7 carbon atoms. Ala in the 41-position may also be substituted or deleted so long as the remaining C-terminus is amidated. Several other substitutions may also be made throughout the chain.
摘要翻译： CRF（促皮质素释放因子）具有下式：H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu- Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Ar g-Lys-Leu-Leu-Asp-Ile-Ala-NH 2。已经合成至少与CRF一样有效的类似物，并且分散在药学上可接受的液体或固体载体中的CRF或这些类似物或其药学上可接受的盐可以施用于哺乳动物以实现ACTH，β-内啡肽的显着升高，β-促凝血酶和皮质酮水平和/或在长时间内降低血压。在类似物中，前三个N末端残基中的一个或多个可以被缺失或可被长达10个氨基酸的肽和/或被含有至多7个碳原子的酰化剂所取代。 41位的Ala也可以被取代或缺失，只要其余的C末端被酰胺化即可。还可以在整个链中进行几个其它取代。

8. 发明授权

US4628043A Hypothalamic GRF agonists 失效
标题翻译：下丘脑GRF激动剂
公开(公告)号：US4628043A
公开(公告)日：1986-12-09
申请号：US714687
申请日：1985-03-21
申请人： Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
发明人： Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
IPC分类号： A23K1/16 , A61K38/00 , C07K14/60 , A61K37/43 , C07K7/10
CPC分类号： C07K14/60 , A23K20/147 , A61K38/00 , Y10S930/12
摘要： Synthetic peptides are provided which are extremely potent in stimulating the release of pituitary GH in animals and which have the formula: H--R.sub.1 --Ala--Asp--Ala--Ile--Phe--Thr--R.sub.8 --Ser--R.sub.10 --Arg--R.sub.12 --R.sub.13 --Leu--R.sub.15 --Gln--Leu--R.sub.18 --Ala--Arg--Lys--Leu--Leu--R.sub.24 --R.sub.25 --Ile--R.sub.27 --R.sub.28 --Arg--Gln--Gln--Gly--Glu--R.sub.34 --Asn--Gln--Glu--R.sub.38 --R.sub.39 --R.sub.40 --Arg--R.sub.42 --R.sub.43 --Leu--Y wherein R.sub.1 is Tyr, Met, Leu, D--Tyr, D--His or His; R.sub.8 is Ser or Asn; R.sub.10 is Tyr or D--Tyr; R.sub.12 is Arg or Lys; R.sub.13 is Ile or Val; R.sub.15 is Gly or D--Ala; R.sub.18 is Tyr or Ser; R.sub.24 is His or Gln; R.sub.25 is Glu or Asp; R.sub.27 is Met, Ala, Nle, Ile, Leu or Val; R.sub.28 is Asn or Ser; R.sub.34 is Arg or Ser; R.sub.38 is Gln or Arg; R.sub.39 is Arg or Gly; R.sub.40 is Ser or Ala; R.sub.42 is Phe or Ala; R.sub.43 is Asn or Arg; and Y represents the carboxyl moiety of the amino acid residue at the C-terminus and is the radical --COOR,--CRO,--CONHNHR, --CON(R)(R') or --CH.sub.2 OR, with R and R' being lower alkyl, fluoro lower alkyl or hydrogen, or a fragment thereof extending from the N-terminus in a continuous sequence at least to the residue in position 29, which fragment is biologically active to cause the release of GH from the pituitary, or a nontoxic salt of such peptide or peptide fragment. The peptides are analogs of human GRF and contain at least two but less than all of the following residues: R.sub.8 is Asn, R.sub.12 is Lys, R.sub.13 is Val, R.sub.18 is Ser, R.sub.24 is Gln, R.sub.25 is Asp, R.sub.28 is Ser.
摘要翻译：提供了合成肽，其在刺激动物中垂体GH的释放方面非常有效，其具有下式：H-R1-Ala-Asp-Ala-Ile-Phe-Thr-R8-Ser-R10-Arg-R12-R13 -Leu-R15-Gln-Leu-R1 8-Ala-Arg-Lys-Leu-Leu-R24-R25-Ile-R27-R28-Arg-Gln-Gln-Gly-Glu-R34-Asn-Gln-Glu- R38-R39-R40-Arg-R42-R43-Leu-Y，其中R1是Tyr，Met，Leu，D-Tyr，D-His或His; R8是Ser或Asn; R10是Tyr或D-Tyr; R12是Arg或Lys; R13是Ile或Val; R15是Gly或D-Ala; R18是Tyr或Ser; R24是His或Gln; R25是Glu或Asp; R27是Met，Ala，Nle，Ile，Leu或Val; R28为Asn或Ser; R34是Arg或Ser; R38是Gln或Arg; R39是Arg或Gly; R40是Ser或Ala; R42是Phe或Ala; R43是Asn或Arg; 并且Y代表C末端的氨基酸残基的羧基部分，并且是基团-COOR，-CRO，-CONHNHR，-CON（R）（R'）或-CH 2 OR，其中R和R'是低级烷基，氟低级烷基或氢，或其从N末端以连续序列至少延伸至位置29的残基的片段，该片段具有生物学活性以引起GH从垂体中释放，或无毒盐这样的肽或肽片段。肽是人GRF的类似物，并且含有至少两个但少于所有以下残基：R8是Asn，R12是Lys，R13是Val，R18是Ser，R24是Gln，R25是Asp，R28是Ser。

9. 发明授权

US4595676A Rat hypothalamic GRF 失效
标题翻译：大鼠下丘脑GRF
公开(公告)号：US4595676A
公开(公告)日：1986-06-17
申请号：US488748
申请日：1983-04-26
申请人： Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
发明人： Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
IPC分类号： C07K14/61 , A23K1/16 , A61K38/00 , A61K38/25 , C07K14/60 , C07K7/10 , A61K37/43
CPC分类号： C07K14/60 , A23K20/147 , A61K38/00 , Y10S930/12
摘要： Rat hypothalamic GRF has been synthesized and has the formula: H-His-Ala-Asp-Ala-Ile-Phe-Thr-Ser-Ser-Tyr-Arg-Arg-Ile-Leu-Gly-Gln-Leu-Tyr-Ala-Arg-Lys-Leu-Leu-His-Glu-Ile-Met-Asn-Arg-Gln-Gln-Gly-Glu-Arg-Asn-Gln-Glu-Gln-Arg-Ser-Arg-Phe-Asn-OH. The peptide is believed to be and is hereinafter referred to as rhGRF (for rat hypothalamic GH releasing factor). The invention provides synthetic peptides which are extremely potent in stimulating the release of pituitary GH in animals and which have the formula: H-R.sub.1 -Ala-Asp-Ala-Ile-Phe-Thr-R.sub.8 -Ser-R.sub.10 -Arg-R.sub.12 -R.sub.13 -Leu-R.sub.15 -Gln-Leu-R.sub.18 -Ala-Arg-Lys-Leu-Leu-R.sub.24 -R.sub.25 -Ile-R.sub.27 -R.sub.28 -Arg-Gln-Gln-Gly-Glu-R.sub.34 -Asn-Gln-Glu-R.sub.38 -R.sub.39 -R.sub.40 -Arg-R.sub.42 -R.sub.43 -R.sub.44 -Y wherein R.sub.1 is Tyr, Met, D-Tyr, Leu, D-His or His; R.sub.8 is Ser or Asn; R.sub.10 is Tyr or D-Tyr; R.sub.12 is Arg or Lys; R.sub.13 is Ile or Val; R.sub.15 is Gly or D-Ala; R.sub.18 is Tyr or Ser; R.sub.24 is His or Gln; R.sub.25 is Glu or Asp; R.sub.27 is Met, Ala, Nle, Ile, Leu or Val; R.sub.28 is Asn or Ser; R.sub.34 is Arg or Ser; R.sub.38 is Gln or Arg; R.sub.39 is Arg or Gly; R.sub.40 is Ser or Ala; R.sub.42 is Phe or Ala; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid or des-R.sub.44 ; and Y signifies the carboxyl moiety of the amino acid residue at the C-terminus and is the radical --COOR,--CRO,--CONHNHR,--CON(R)(R') or --CH.sub.2 OR, with R and R' being lower alkyl, fluoro lower alkyl or hydrogen.These peptides or biologically active fragments thereof, or analogs thereof having well-known substitutions and/or additions, as well as nontoxic salts of any of the foregoing, may be administered to animals, including humans, to stimulate the release of GH and may be used diagnostically.
摘要翻译：已经合成了大鼠下丘脑GRF，具有下式：H-His-Ala-Asp-Ala-Ile-Phe-Thr-Ser-Ser-Tyr-Arg-Arg-Ile-Leu-Gly-Gln-Leu-Ala -Arg-Lys-Leu-Leu-His-Glu-Ile-Met-Asn-Arg-Gln-Gln-Gly-Glu-Arg-Asn-Gln-Glu-Gln-Arg-Ser-Arg-Phe- 哦。该肽被认为是并且在下文中被称为rhGRF（对于大鼠下丘脑GH释放因子）。本发明提供了在动物中刺激垂体GH的释放非常有效的合成肽，其具有下式：H-R1-Ala-Asp-Ala-Ile-Phe-Thr-R8-Ser-R10-Arg-R12- R13-Leu-R15-Gln-Leu-R1 8-Ala-Arg-Lys-Leu-Leu-R24-R25-Ile-R27-R28-Arg-Gln-Gln-Gly-Glu-R34-Asn-Gln-Glu -R38-R39-R40-Arg-R42-R43-R44-Y，其中R1是Tyr，Met，D-Tyr，Leu，D-His或His; R8是Ser或Asn; R10是Tyr或D-Tyr; R12是Arg或Lys; R13是Ile或Val; R15是Gly或D-Ala; R18是Tyr或Ser; R24是His或Gln; R25是Glu或Asp; R27是Met，Ala，Nle，Ile，Leu或Val; R28为Asn或Ser; R34是Arg或Ser; R38是Gln或Arg; R39是Arg或Gly; R40是Ser或Ala; R42是Phe或Ala; R43是Asn或Arg; R44是天然氨基酸或des-R44; 并且Y表示C末端的氨基酸残基的羧基部分，并且是基团-COOR，-CRO，-CONHNHR，-CON（R）（R'）或-CH 2OR，其中R和R'为低级烷基氟代低级烷基或氢。这些具有众所周知的取代和/或添加的肽或其类似物或其类似物以及前述任何一种的无毒盐可以被给予动物，包括人，以刺激GH的释放，并且可以是用于诊断。

10. 发明授权

US4563352A Human pancreatic GRF 失效
标题翻译：人胰腺GRF
公开(公告)号：US4563352A
公开(公告)日：1986-01-07
申请号：US432663
申请日：1982-10-04
申请人： Jean E. F. Rivier , Joachim Spiess , Wylie W. Vale, Jr.
发明人： Jean E. F. Rivier , Joachim Spiess , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , A23K1/16 , A61K38/04 , A61K38/07 , A61K38/25 , C07C20060101 , C07K1/06 , C07K14/00 , C07K14/575 , C07K14/60 , C07K14/61 , A61K37/02
CPC分类号： C07K14/60 , A61K38/00 , Y10S530/845 , Y10S930/12
摘要： Human pancreatic GRF has been synthesized. The invention provides synthetic peptides which are extremely potent in stimulating the release of pituitary GH in mammals and which have the formula: H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-R.sub.15 -Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-R.sub.40 -R.sub.41 -R.sub.42 -Y wherein R.sub.15 is Gly or D-Ala, R.sub.40 is Ala or des-R.sub.40, R.sub.41 is Phe or des-R.sub.41, R.sub.42 is des-R.sub.42 or 1 to 8 different amino acid residues selected from the group consisting of Gln, Gly, Ile, Leu, Lys, Pro, Thr and Val, and Y signifies the carboxyl moiety of the amino acid residue at the C-terminal and is the radical -COOR.sub.1,-CR.sub.1 O,-CONHNHR.sub.1,-CON(R.sub.1)(R.sub.2) or -CH.sub.2 OR.sub.1, with R.sub.1 and R.sub.2 being lower alkyl or hydrogen. These peptides or biologically active fragments thereof, or analogs thereof having well-known substitutions and/or additions, as well as nontoxic salts of any of the foregoing, may be administered therapeutically to animals, including humans, and may be used diagnostically.
摘要翻译：人胰腺GRF已被合成。本发明提供了非常有效刺激哺乳动物垂体GH释放的合成肽，其具有下式：H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys- Val-Leu-R15-Gln-Leu- Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu -Arg-Gly-R40-R41-R42-Y，其中R15是Gly或D-Ala，R40是Ala或des-R40，R41是Phe或des-R41，R42是des-R42或1到8个不同的氨基酸残基选自Gln，Gly，Ile，Leu，Lys，Pro，Thr和Val组成的组，Y表示C-末端的氨基酸残基的羧基部分，是-COOR1，-CR1O，-CONHNHR1基团，-CON（R 1）（R 2）或-CH 2 OR 1，其中R 1和R 2为低级烷基或氢。具有众所周知的取代和/或添加的这些肽或其类似物或其类似物以及前述任何一种的无毒盐可以治疗性地给予动物，包括人，并且可以在诊断上使用。

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