公开(公告)号：US06399315B1

公开(公告)日：2002-06-04

申请号：US08482746

申请日：1995-06-07

申请人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

发明人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

IPC分类号： G01N3353

CPC分类号： C07K14/723 ,  A61K38/00 ,  C07K14/72

摘要： In accordance with the present invention, there are provided novel G-protein-coupled receptor proteins (CRF-R) characterized by having sufficient binding affinity for corticotropin releasing factor (CRF) such that concentrations of ≦10 nM of CRF occupy ≧50% of the binding sites of said receptor protein. Nucleic acid sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed. Invention CRF-Rs can be employed in a variety of ways, such as, for example, in bioassays, for production of antibodies thereto, in therapeutic compositions containing such proteins and/or antibodies.

摘要翻译： 根据本发明，提供了新颖的G蛋白偶联受体蛋白（CRF-R），其特征在于对促皮质激素释放因子（CRF）具有足够的结合亲和力，使得CRF的<= 10nM的浓度占据≥50 所述受体蛋白的结合位点的百分比。 还公开了编码这种受体的核酸序列，使用其的测定法，以及由其衍生的抗体。 本发明CRF-Rs可以以各种方式使用，例如在生物测定中用于生产抗体，在含有这种蛋白质和/或抗体的治疗组合物中。

公开(公告)号：US06495343B1

公开(公告)日：2002-12-17

申请号：US08374009

申请日：1995-01-17

申请人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

发明人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

IPC分类号： C12P2102

CPC分类号： C07K14/723 ,  A61K38/00 ,  C07K14/72

摘要： In accordance with the present invention, there are provided novel G-protein-coupled receptor proteins (CRF-R) characterized by having sufficient binding affinity for corticotropin releasing factor (CRF) such that concentrations of ≦10 nM of CRF occupy ≧50% of the binding sites of said receptor protein. Nucleic acid sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed. Invention CRF-Rs can be employed in a variety of ways, such as, for example, in bioassays, for production of antibodies thereto, in therapeutic compositions containing such proteins and/or antibodies.

摘要翻译： 根据本发明，提供了新颖的G蛋白偶联受体蛋白（CRF-R），其特征在于对促皮质激素释放因子（CRF）具有足够的结合亲和力，使得CRF的<= 10nM的浓度占据≥50 所述受体蛋白的结合位点的百分比。 还公开了编码这种受体的核酸序列，使用它们的测定法，以及由其衍生的抗体。 本发明CRF-Rs可以以各种方式使用，例如在生物测定中用于生产抗体，在含有这种蛋白质和/或抗体的治疗组合物中。

公开(公告)号：US07358225B2

公开(公告)日：2008-04-15

申请号：US10649193

申请日：2003-08-26

申请人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

发明人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

IPC分类号： C07K14/435 ,  C07K14/72 ,  C07K14/705 ,  A61K38/00 ,  A61K38/17

CPC分类号： C07K14/72 ,  A61K38/00 ,  C07K14/723

摘要： In accordance with the present invention, there are provided novel G-protein-coupled receptor proteins (CRF-R) characterized by having sufficient binding affinity for corticotropin releasing factor (CRF) such that concentrations of £ 10 nM of CRF occupy 350% of the binding sites of said receptor protein. Nucleic acid sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed. Invention CRF-Rs can be employed in a variety of ways, such as, for example, in bioassays, for production of antibodies thereto, in therapeutic compositions containing such proteins and/or antibodies.

摘要翻译： 根据本发明，提供了新颖的G蛋白偶联受体蛋白（CRF-R），其特征在于对促肾上腺皮质激素释放因子（CRF）具有足够的结合亲和力，使得CRF 10nM的浓度占据了3 所述受体蛋白的结合位点的50％。 还公开了编码这种受体的核酸序列，使用其的测定法，以及由其衍生的抗体。 本发明CRF-Rs可以以各种方式使用，例如在生物测定中用于生产抗体，在含有这种蛋白质和/或抗体的治疗组合物中。

公开(公告)号：US06214797B1

公开(公告)日：2001-04-10

申请号：US08981189

申请日：1997-12-10

申请人： Wylie W. Vale, Jr. ,  Joan Vaughan ,  Cynthia J. Donaldson ,  Kathy A. Lewis ,  Paul Sawchenko ,  Jean E. F. Rivier ,  Marilyn H. Perrin

发明人： Wylie W. Vale, Jr. ,  Joan Vaughan ,  Cynthia J. Donaldson ,  Kathy A. Lewis ,  Paul Sawchenko ,  Jean E. F. Rivier ,  Marilyn H. Perrin

IPC分类号： A61K3817

CPC分类号： C07K14/57509 ,  A61K38/00

摘要： Urocortin (Ucn) is a native mammalian peptide generally related to Urotensin I and Corticotropin Releasing Factor (CRF). Human Ucn has the formula: Asp-Asn-Pro-Ser-Leu-Ser-Ile-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Thr-Leu-Leu-Glu-Leu-Ala-Arg-Thr-Gln-Ser-Gln-Arg-Glu-Arg-Ala-Glu-Gln-Asn-Arg-Ile-Ile-Phe-Asp-Ser-Val-NH2 (SEQ ID NO:15). Rat-derived Ucn is identical but for 2 substitutions, Asp2 for Asn2 and Pro4 for Ser4. Ucn or analogs thereof or pharmaceutically acceptable salts can be administered to humans and other mammals to achieve substantial elevation of ACTH, &bgr;-endorphin, &bgr;-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone. They can also be used to lower blood pressure over an extended period of time, as stimulants to elevate mood and to improve memory and learning performance, as well as diagnostically. Shortened fragments may be administered to release endogenous CRF and/or Ucn in the brain and peripherally. Ucn antagonists can be used to block the action of Ucn and/or CRF, as can antibodies to Ucn. Labelled Ucn agonists and antagonists can be used in drug screening assays along with CRF receptors; they may also be used diagnostically along with Ucn antibodies.

摘要翻译： Urocortin（Ucn）是通常与促进素I和促皮质素释放因子（CRF）相关的天然哺乳动物肽。 人Ucn具有下式：Asp-Asn-Pro-Ser-Leu-Ser-Ile-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Thr-Leu-Leu-Glu-Leu-Ala-Arg- Thr-Gln-Ser-Gln-Arg-Glu-Arg-Ala-Glu-Gln-Asn-Arg-Ile-Ile-Phe-Asp-Ser-Val-NH2（SEQ ID NO：15）。 大鼠衍生的Ucn是相同的，但是对于2个取代，As 2的Asp 2和Ser 4的Pro 4。 可以将Ucn或其类似物或药学上可接受的盐施用于人和其它哺乳动物，以实现ACTH，β-内啡肽，β-促脂解素，前 - 肌内注射皮质酮基因和皮质酮的其它产物的显着升高。 它们也可用于在较长时间内降低血压，作为兴奋剂提高心情，提高记忆力和学习表现以及诊断。 可以施用缩短的片段以释放脑中和外周的内源性CRF和/或Ucn。 Ucn拮抗剂可用于阻断Ucn和/或CRF的作用，以及Ucn的抗体。 标记的Uc激动剂和拮抗剂可与CRF受体一起用于药物筛选测定; 它们也可以与Ucn抗体一起在诊断上使用。

公开(公告)号：US06812210B2

公开(公告)日：2004-11-02

申请号：US10099766

申请日：2002-03-15

申请人： Wylie W. Vale, Jr. ,  Jean E. River ,  Koichi S. Kunitake ,  Kathy A. Lewis ,  Marilyn H. Perrin ,  Jozsef Gulyas

发明人： Wylie W. Vale, Jr. ,  Jean E. River ,  Koichi S. Kunitake ,  Kathy A. Lewis ,  Marilyn H. Perrin ,  Jozsef Gulyas

IPC分类号： A61K3800

CPC分类号： A61K38/2228 ,  A61K38/00 ,  C07K14/57509 ,  C07K14/695

摘要： A search of the public human genome database identified a human EST, GenBank accession number AW293249, which has high homology to known pufferfish urocortin sequences. The full length sequence was amplified from human genomic DNA and sequenced. Sequence homology comparisons of the novel sequence with human urocortin I and urocortin II revealed that the sequence encoded a novel human urocortin, which was designated urocortin III (UcnIII). While urocortin III does not have high affinity for either CRF-R1 or CRF-R2, the affinity for CRF-R2 is greater than the affinity for CRF-R1. Urocortin III is capable stimulating cyclic AMP production in cells expressing CRF-R2&agr; or &bgr;. Thus, the affinity is high enough that urocortin III could act as a native agonist of CRF-R2. However, it is also likely that urocortin III is a stronger agonist of a yet to be identified receptor.

公开(公告)号：US4661472A

公开(公告)日：1987-04-28

申请号：US732531

申请日：1985-05-09

申请人： Jean E. F. Rivier ,  Janos I. Varga ,  Arnold T. Hagler ,  R. Scott Struthers ,  Marilyn H. Perrin ,  Catherine L. Rivier ,  Wylie W. Vale, Jr.

发明人： Jean E. F. Rivier ,  Janos I. Varga ,  Arnold T. Hagler ,  R. Scott Struthers ,  Marilyn H. Perrin ,  Catherine L. Rivier ,  Wylie W. Vale, Jr.

IPC分类号： A61K38/04 ,  A61K38/00 ,  A61K38/22 ,  A61K38/27 ,  A61P5/00 ,  C07K7/06 ,  C07K7/23 ,  C07K14/00 ,  C07K14/575 ,  A61K37/43

CPC分类号： C07K7/23 ,  A61K38/00 ,  Y10S930/13

摘要： Peptides which inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount of such GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads. These peptides may be used to treat steroid-dependent tumors, such as prostatic and mammary tumors. The peptides are cyclic analogs of the decapeptide GnRH wherein there is a covalent bond between the residue in the 4-position and the residue in the 10-position. Examples of such bonds include the disulfide linkage between Cys residues, an amide linkage between a side chain amino group and a side chain carboxyl group, a dicarba linkage between side-chain alkyl groups, and a carba linkage between a side-chain alkyl group and a side-chain sulfhydryl group.

摘要翻译： 抑制垂体分泌促性腺激素并抑制性腺释放类固醇的肽。 施用有效量的这种GnRH拮抗剂防止雌性哺乳动物卵的排卵和/或性腺释放类固醇。 这些肽可用于治疗类固醇依赖性肿瘤，例如前列腺和乳腺肿瘤。 肽是十肽GnRH的环状类似物，其中在4-位的残基与10位的残基之间存在共价键。 这些键的实例包括Cys残基之间的二硫键，侧链氨基和侧链羧基之间的酰胺键，侧链烷基之间的二链键和侧链烷基与侧链烷基之间的碳键 侧链巯基。

公开(公告)号：US07851588B2

公开(公告)日：2010-12-14

申请号：US12366816

申请日：2009-02-06

申请人： Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Marilyn H. Perrin ,  Jozsef Gulyas

发明人： Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Marilyn H. Perrin ,  Jozsef Gulyas

IPC分类号： A61K38/12

CPC分类号： C07K14/47 ,  A61K38/00 ,  C07K14/57509

摘要： CRF peptide analogs that bind to CRFR1 with an affinity far greater than they bind to CRFR2. Some of these analogs exhibit CRF agonist activity. One exemplary analog that may be made by solid-phase synthesis is:(cyclo 31-34)[Ac-Pro4,D-Phe12,Nle18,21,Glu31,Lys34]-sucker urotensin(4-41).

摘要翻译： 结合CRFR1的CRF肽类似物的亲和力远远大于它们与CRFR2结合的亲和力。 这些类似物中的一些表现出CRF激动剂活性。 可以通过固相合成制备的一个示例性类似物是：（环31-34）[Ac-Pro4，D-Phe12，Nle18,21，Glu31，Lys34]刺激性尿素转运蛋白（4-41）。

公开(公告)号：US5510458A

公开(公告)日：1996-04-23

申请号：US162178

申请日：1993-12-14

申请人： Wayne D. Kornreich ,  Jean F. Hernandez ,  Jean E. Rivier ,  Catherine L. Rivier ,  Wylie W. Vale, Jr.

发明人： Wayne D. Kornreich ,  Jean F. Hernandez ,  Jean E. Rivier ,  Catherine L. Rivier ,  Wylie W. Vale, Jr.

IPC分类号： A61K38/00 ,  C07K14/575 ,  C07K14/695

CPC分类号： C07K14/57509 ,  A61K38/00 ,  Y10S930/26

摘要： Disclosed are improved CRF peptide antagonists such as those having the formula: Y-D-Phe-Xaa.sub.13 -Leu-Leu-Arg-Xaa.sub.17 -Xaa.sub.18 -Leu-Xaa.sub.20 -Nle-Xaa.sub.22 -Xaa.sub.23 -Xaa.sub.24 -Xaa.sub.25 -Xaa.sub.26 -Leu-Xaa.sub.28 -Xaa.sub.29 -Gln-Xaa.sub.31 -Xaa.sub.32 -Xaa.sub.33 -Xaa.sub.34 -Arg-Xaa.sub.36 -Xaa.sub.37 -Nle-Xaa.sub.39 -Xaa.sub.40 -Xaa.sub.41 -NH.sub.2 wherein Y is Ac or hydrogen; Xaa.sub.13 is His, Tyr or Glu; Xaa.sub.17 is CML, Glu, Asn or Lys; Xaa.sub.18 is Val, Nle or Met; Xaa.sub.20 is Glu, D-Glu, Aib or D-Ala; Xaa.sub.22 is Ala, Aib, Thr, Asp or Glu; Xaa.sub.23 is Arg, Orn, Har or Lys; Xaa.sub.24 is Ala or Aib; Xaa.sub.25 is Asp or Glu; Xaa.sub.26 is Gln, Asn or Lys; Xaa.sub.28 is Ala or Aib; Xaa.sub.29 is Gln, Aib or Glu, Xaa.sub.31 is Ala or Aib; Xaa.sub.32 is His, Aib, Gly, Tyr or Ala; Xaa.sub.33 is Ser, Aib, Asn, Leu, Thr or Ala; Xaa.sub.34 is Asn or Aib; Xaa.sub.36 is Lys, Orn, Arg, Har or Leu; Xaa.sub.37 is Leu or Tyr; Xaa.sub.39 is Glu, Aib or Asp; Xaa.sub.40 is Ile, Aib, Thr, Glu, Ala, Val, Leu, Nle, Phe, Nva, Gly or Gln; and Xaa.sub.41 is Ala, Ile, Gly, Val, Leu, Nle, Phe, Nva or Gln, wherein CML may be substituted for Leu. Specific CRF antagonists disclosed include D-Phe.sup.12, D-Ala.sup.20, Nle.sup.21,38 !-rCRF(12-41), D-Phe.sup.12, Nle.sup.21,38, Aib.sup.34 !-rCRF (12-41) , D-Phe.sup.12, CML.sup.17, Nle.sup.21,38 !-rCRF(12-41) , D-Phe.sup.12, Aib.sup.20, Nle.sup.21,38 !-rCRF(12-41), D-Phe.sup.12, Aib.sup.29, Nle.sup.21,38 !-rCRF(12-41), D-Phe.sup.12, CML.sup.14, Nle.sup.21,38, Aib.sup.24,28,31 !-rCRF(12-41) and D-Phe.sup.12, CML.sup.15, Aib.sup.24,28,31 !-rCRF(12-41).

摘要翻译： PCT No.PCT / US92 / 05101 Sec。 371日期：1993年12月14日 102（e）日期1993年12月14日PCT提交1992年6月12日PCT公布。 出版物WO92 / 22576 日期为1992年12月23日。公开的是改进的CRF肽拮抗剂，例如具有下式的那些：YD-Phe-Xaa13-Leu-Leu-Arg-Xaa17-Xaa18-Leu-Xaa20-Nle-Xaa22-Xaa23-Xaa24-Xaa25- Xaa26-Leu-Xaa28-Xaa29-Gln-Xaa31-Xaa32-Xaa33-Xaa34-Arg-Xaa36-Xaa37-Nle-Xaa39-Xaa40-Xaa41-NH2，其中Y是Ac或氢; Xaa13是His，Tyr或Glu; Xaa17是CML，Glu，Asn或Lys; Xaa18是Val，Nle或Met; Xaa20是Glu，D-Glu，Aib或D-Ala; Xaa22是Ala，Aib，Thr，Asp或Glu; Xaa23是Arg，Orn，Har或Lys; Xaa24是Ala或Aib; Xaa25是Asp或Glu; Xaa26是Gln，Asn或Lys; Xaa28是Ala或Aib; Xaa29是Gln，Aib或Glu，Xaa31是Ala或Aib; Xaa32是His，Aib，Gly，Tyr或Ala; Xaa33是Ser，Aib，Asn，Leu，Thr或Ala; Xaa34是Asn或Aib; Xaa36是Lys，Orn，Arg，Har或Leu; Xaa37是Leu或Tyr; Xaa39是Glu，Aib或Asp; Xaa40是Ile，Aib，Thr，Glu，Ala，Val，Leu，Nle，Phe，Nva，Gly或Gln; Xaa41是Ala，Ile，Gly，Val，Leu，Nle，Phe，Nva或Gln，其中CML可以被Leu取代。 公开的具体CRF拮抗剂包括[D-Phe12，D-Ala20，Nle21,38] -rCRF（12-41），[D-Phe12，Nle21,38，Aib34] -rCRF（12-41），[D-Phe12， C-17，Nle 21,38] -rCRF（12-41），[D-Phe12，Aib20，Nle21,38] -rCRF（12-41），[D-Phe12，Aib29，Nle21,38] -rCRF（12-41 ），[D-Phe12，CML14，Nle21,38，Aib24,28,31] -rCRF（12-41）和[D-Phe12，CML15，Aib24,28,31] -rCRF（12-41）。

公开(公告)号：US06835544B2

公开(公告)日：2004-12-28

申请号：US09742684

申请日：2000-12-19

申请人： Lawrence W. Mathews ,  Wylie W. Vale, Jr. ,  Kunihiro Tsuchida

发明人： Lawrence W. Mathews ,  Wylie W. Vale, Jr. ,  Kunihiro Tsuchida

IPC分类号： G01N3353

CPC分类号： C07K14/71 ,  A61K38/00 ,  C07K2319/00

摘要： In accordance with the present invention, there are provided novel receptor proteins characterized by having the following domains, reading from the N-terminal end of said protein: an extracellular, ligand-binding domain, a hydrophobic, trans-membrane domain, and an intracellular, receptor domain having serine kinase-like activity. The invention receptors optionally further comprise a second hydrophobic domain at the amino terminus thereof. The invention receptor proteins are further characterized by having sufficient binding affinity for at least one member of the activin/TGF-&bgr; superfamily of polypeptide growth factors such that concentrations of ≦10 nM of said polypeptide growth factor occupy ≧50% of the binding sites of said receptor protein. A presently preferred member of the invention superfamily of receptors binds specifically to activins, in preference to inhibins, transforming growth factor-&bgr;, and other non-activin-like proteins. DNA sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed.

摘要翻译： 根据本发明，提供了新的受体蛋白，其特征在于具有以下结构域，从所述蛋白质的N-末端读取：细胞外，配体结合结构域，疏水性，跨膜结构域和细胞内， 受体结构域具有丝氨酸激酶样活性。本发明受体任选地还包含在其氨基末端的第二疏水结构域。 本发明受体蛋白的进一步特征在于对多肽生长因子的激活素/ TGF-β超家族的至少一个成员具有足够的结合亲和力，使得所述多肽生长因子的<= 10nM的浓度占结合物的50％ 所述受体蛋白的位点。 本发明目前优选的受体超家族成员特异性结合激活素，优于抑制素，转化生长因子-β和其他非激活素样蛋白。 还公开了编码这种受体的DNA序列，使用其的测定法，以及由其衍生的抗体。

公开(公告)号：US5493006A

公开(公告)日：1996-02-20

申请号：US078558

申请日：1993-06-16

申请人： Antonio de Miranda ,  Wylie W. Vale, Jr. ,  Jean E. F. Rivier ,  Catherine L. Rivier

发明人： Antonio de Miranda ,  Wylie W. Vale, Jr. ,  Jean E. F. Rivier ,  Catherine L. Rivier

IPC分类号： A61K38/00 ,  C07K14/575 ,  C07K14/695

CPC分类号： C07K14/57509 ,  A61K38/00

摘要： Improved CRF peptide antagonists have the formula: ##STR1## wherein R.sub.20 is Cys or Glu; R.sub.23 is Cys, Lys or Orn; provided that when R.sub.20 is Cys, R.sub.23 is Cys and when R.sub.20 is Glu, R.sub.23 is Lys or Orn; or a nontoxic addition salt thereof. Specific CRF antagonists disclosed include (cyclo 20-23) [D-Phe.sup.12, Lys.sup.23, Nle.sup.21,38, ]rCRF(12-41); (cyclo 20-23) [D-Phe.sup.12, Orn.sup.23, Nle.sup.21,38 ]rCRF(12-41) and (cyclo 20-23) [D-Phe.sup.12, Cys.sup.20, Cys.sup.23, Nle.sup.21,38 ]rCRF(12-41).

摘要翻译： 改进的CRF肽拮抗剂具有下式：其中R 20是Cys或Glu; R23是Cys，Lys或Orn; 条件是当R 20为Cys时，R 23为Cys，当R 20为Glu时，R 23为Lys或Orn; 或其无毒的加成盐。 公开的具体CRF拮抗剂包括（环20-23）[D-Phe12，Lys23，Nle21,38] rCRF（12-41）; （环20-23）[D-Phe12，Orn23，Nle21,38] rCRF（12-41）和（环20-23）[D-Phe12，Cys20，Cys23，Nle21,38] rCRF（12-41）。