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1. 发明申请

US20120270792A1 UROCORTIN-III AND USES THEREOF 有权
标题翻译：胭脂红III及其用途
公开(公告)号：US20120270792A1
公开(公告)日：2012-10-25
申请号：US13328821
申请日：2011-12-16
申请人： Wylie W. Vale, JR. , Kathy A. Lewis , Marilyn H. Perrin , Koichi S. Kunitake , Jean E. Rivier , Jozsef Gulyas
发明人： Wylie W. Vale, JR. , Kathy A. Lewis , Marilyn H. Perrin , Koichi S. Kunitake , Jean E. Rivier , Jozsef Gulyas
IPC分类号： A61K38/02 , A61P9/00
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-R2α or β. 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.
摘要翻译：公众人类基因组数据库的搜索确定了人类EST，GenBank登录号AW293249，其与已知的河豚urocortin序列具有高同源性。从人类基因组DNA扩增全长序列并进行测序。新序列与人尿皮质素I和尿皮质素II的序列同源性比较显示，该序列编码了一种新的人类urocortin，其命名为urocortin III（UcnIII）。虽然urocortin III对CRF-R1或CRF-R2没有高亲和力，但CRF-R2的亲和力大于对CRF-R1的亲和力。 Urocortin III能够刺激表达CRF-R2α或bgr的细胞中的环AMP产生。因此，亲和力足够高，使得尿皮质素III可以作为CRF-R2的天然激动剂。然而，urocortin III也可能是未被鉴定的受体的更强的激动剂。

2. 发明授权

US06495343B1 Cloning and recombinant production of CRF receptor(s) 失效
标题翻译： CRF受体的克隆和重组产生
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。

3. 发明授权

US6023011A Corticotropin-releasing factor overproducing transgenic mice 失效
公开(公告)号：US6023011A
公开(公告)日：2000-02-08
申请号：US68754
申请日：1993-05-28
申请人： Wylie W. Vale, Jr. , Mary P. Stenzel-Poore
发明人： Wylie W. Vale, Jr. , Mary P. Stenzel-Poore
IPC分类号： A01K67/027 , C07K14/47 , C12N15/85 , C12N5/00 , C12N15/00 , C12N15/09 , C12N15/63
CPC分类号： C12N15/8509 , A01K67/0275 , C07K14/47 , A01K2217/05 , A01K2227/105 , A01K2267/03 , A01K2267/0356 , A01K2267/0362
摘要： In accordance with the present invention, there are provided CRF overproducing transgenic mice which exhibit endocrine abnormalities involving the hypothalamic-pituitary-adrenal axis, such as elevated plasma levels of ACTH and glucocorticoids. The transgenic mice of the present invention represent a genetic model of CRF overproduction, providing a valuable tool for investigating the long term effects of CRF excess and dysregulation in the central nervous system.

4. 发明授权

US5844080A CRF binding protein 失效
标题翻译： CRF结合蛋白
公开(公告)号：US5844080A
公开(公告)日：1998-12-01
申请号：US462403
申请日：1995-06-05
申请人： Ellen Potter , Dominic P. Behan , Wolfgang H. Fischer , Elizabeth A. Linton , Philip J. Lowry , Wylie W. Vale, Jr.
发明人： Ellen Potter , Dominic P. Behan , Wolfgang H. Fischer , Elizabeth A. Linton , Philip J. Lowry , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , C07K14/47 , C07K16/18 , C12N15/12 , C12P21/08 , G01N33/566 , G01N33/68 , G01N33/74 , A61K38/17
CPC分类号： G01N33/566 , C07K14/47 , C07K16/18 , G01N33/6872 , G01N33/689 , G01N33/74 , A61K38/00 , G01N2800/368
摘要： A Corticotropin Releasing Factor-binding protein (CRF-BP) is isolated and purified sufficient to provide AA sequence data from which the DNA is obtained, which is then used to produce the protein recombinantly. The CRF-BP is useful for modulating the biological activity of CRF, such as reducing the high ACTH levels in mammals caused by excess CRF. The CRF-BP or fragments thereof and/or antibodies to the proteins may be employed in diagnostic assays to determine the levels of CRF, CRF-BP and the ratio of CRF/CRF-BP in a vascular fluid sample. The DNA or subsequence thereof can be used as probes for genetic material in certain assays. The anti-CRF-BP antibodies are also useful to purify the CRF-BP protein and to modulate the biological effect of CRF-BPs proteins.
摘要翻译：分离和纯化促肾上腺皮质激素释放因子结合蛋白（CRF-BP），以提供获得DNA的AA序列数据，然后将其用于重组产生蛋白质。 CRF-BP可用于调节CRF的生物活性，例如降低由过量CRF引起的哺乳动物中的高ACTH水平。 CRF-BP或其片段和/或抗体可用于诊断测定中以确定血管流体样品中CRF，CRF-BP的水平和CRF / CRF-BP的比例。在某些测定中，DNA或其子序列可用作遗传物质的探针。抗CRF-BP抗体也可用于纯化CRF-BP蛋白并调节CRF-BPs蛋白的生物学作用。

5. 发明授权

US5733790A CRF binding protein antibodies and assays using same 失效
标题翻译： CRF结合蛋白抗体和使用其的测定法
公开(公告)号：US5733790A
公开(公告)日：1998-03-31
申请号：US480756
申请日：1995-06-07
申请人： Ellen Potter , Dominic P. Behan , Elizabeth A. Linton , Philip J. Lowry , Wylie W. Vale, Jr.
发明人： Ellen Potter , Dominic P. Behan , Elizabeth A. Linton , Philip J. Lowry , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , C07K14/47 , C07K16/18 , C12N15/12 , G01N33/566 , G01N33/68 , G01N33/74 , G01N33/543
CPC分类号： C07K14/47 , C07K16/18 , G01N33/566 , G01N33/6872 , G01N33/689 , G01N33/74 , A61K38/00 , G01N2800/368 , Y10S436/811 , Y10S436/817
摘要： Corticotropin Releasing Factor-binding protein (CRF-BP) is produced recombinantly and is useful for modulating the biological activity of CRF. CRF-BP or fragments thereof and/or antibodies to such polypeptides are employed in diagnostic assays to determine the levels of CRF and CRF-BP and the ratio of CRF/CRF-BP in a vascular fluid sample. Following such an assay, pregnancy-related pathological disorders, such as increased risk of premature labor, can be treated, for example, by administering CRF-BP to lower the ratio of CRF/CRF-BP to within a normal range for pregnancy. Anti-CRF-BP antibodies are also useful to purify CRF-BP and to modulate the biological effect of CRF-BPs.
摘要翻译：促肾上腺皮质激素释放因子结合蛋白（CRF-BP）重组产生，可用于调节CRF的生物活性。 CRF-BP或其片段和/或此类多肽的抗体用于诊断测定以确定CRF和CRF-BP的水平以及血管流体样品中CRF / CRF-BP的比例。在这样的测定之后，可以例如通过施用CRF-BP将CRF / CRF-BP的比例降低到怀孕正常范围内来处理怀孕相关的病理学障碍，例如增加的早产风险。抗CRF-BP抗体也可用于纯化CRF-BP并调节CRF-BP的生物学作用。

6. 发明授权

US5049655A Melanin-concentrating hormones 失效
标题翻译：黑色素浓缩激素
公开(公告)号：US5049655A
公开(公告)日：1991-09-17
申请号：US326984
申请日：1989-03-22
申请人： Joan Vaughan , Wolfgang H. Fischer , Jean E. F. Rivier , Jean-Louis M. Nahon , Francoise G. Presse , Wylie W. Vale, Jr.
发明人： Joan Vaughan , Wolfgang H. Fischer , Jean E. F. Rivier , Jean-Louis M. Nahon , Francoise G. Presse , Wylie W. Vale, Jr.
IPC分类号： C12N15/09 , A61K38/00 , A61K38/04 , A61P35/00 , C07K7/06 , C07K7/08 , C07K7/64 , C07K14/00 , C07K14/575 , C12N15/12 , C12N15/16
CPC分类号： C07K7/08 , C07K7/64 , A61K38/00 , Y10S530/827 , Y10S530/854
摘要： Mammalian melanin-concentrating hormone (MCH) is isolated from rat tissue, purified and characterized. These MCH peptides are useful for treating skin disorders, for suppressing the proliferation of skin tumor cells, such as melanomas in mammals, and for modulating the secretion of ACTH. Generally, peptides are provided which have the following formula: ##STR1## or which are naturally occurring homologs of the peptide with said formula. The peptides which are the naturally occurring MCH homologs of mammalian species other than rat can also be obtained using the materials disclosed, as demonstrated specifically with human MCH, which is found to have the same structure as rat MCH. Also disclosed are the amino acid sequences of, and the nucleotide sequences of the cDNAs which encode, the putative precursors of rat MCH and human MCH. These precursors may also include one or more biologically active peptides N-terminally of the mature MCH's. Among these peptides, which are thought to be formed from the MCH precursors, are the peptide with the sequence H-Glu-Ile-Gly-Asp-Glu-Glu-Asn-Ser-Ala-Lys-Phe-Pro-Ile-NH.sub.2, which is cross-reactive with antibodies against alpha-MSH and CRF, and the peptide with the sequence H-Gly-X.sub.NGE -Phe-Pro-Ala-Glu-Asn-Gly-Val-Gln-Asn-Thr-Glu-Ser-Thr-Gln-Glu-OH, wherein X.sub.NGE is Pro-Ala-Val or Ser-Val-Ala, which is cross-reactive with antibodies against GRF.
摘要翻译：从大鼠组织中分离哺乳动物黑色素浓缩激素（MCH），进行纯化和表征。这些MCH肽可用于治疗皮肤病症，抑制皮肤肿瘤细胞增殖，如哺乳动物的黑素瘤，以及调节ACTH的分泌。通常，提供具有下式的肽：＆lt; IMAGE＆gt;或具有所述式的肽的天然存在同系物。作为除大鼠之外的哺乳动物物种的天然存在的MCH同源物的肽也可以使用公开的材料获得，如用人MCH特异性证实的，其被发现具有与大鼠MCH相同的结构。还公开了编码大鼠MCH和人MCH的推定前体的cDNA的氨基酸序列和cDNA的核苷酸序列。这些前体还可以包括成熟MCH的N-末端的一种或多种生物活性肽。在这些被认为由MCH前体形成的肽中，具有序列H-Glu-Ile-Gly-Asp-Glu-Glu-Asn-Ser-Ala-Lys-Phe-Pro-Ile-NH 2的肽，其与抗α-MSH和CRF的抗体具有交叉反应性，并且具有序列H-Gly-XNGE-Phe-Pro-Ala-Glu-Asn-Gly-Val-Gln-Asn-Thr-Glu-Ser -Thr-Gln-Glu -OH，其中XNGE是Pro-Ala-Val或Ser-Val-Ala，其与抗GRF的抗体交叉反应。

7. 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。

8. 发明授权

US4677193A Peptides containing an aliphatic-aromatic ketone side chain 失效
标题翻译：含有脂肪族 - 芳香族酮侧链的肽
公开(公告)号：US4677193A
公开(公告)日：1987-06-30
申请号：US704299
申请日：1985-02-22
申请人： Jean E. F. Rivier , Harry A. Anderson , Wylie W. Vale, Jr.
发明人： Jean E. F. Rivier , Harry A. Anderson , Wylie W. Vale, Jr.
IPC分类号： A61K38/04 , A61K38/00 , A61K38/22 , A61P5/00 , C07K1/113 , C07K7/06 , C07K7/23 , C07K14/00 , C07K14/575 , C07K7/20
CPC分类号： C07K7/23 , A61K38/00 , Y10S930/13
摘要： GnRH peptide analogs which regulate the secretion of gonadotropins by the pituitary gland and either promote or inhibit the release of steroids by the gonads. Administration of an effective amount of a GnRH antagonist prevents ovulation of female mammalian eggs and/or the release of gonadotropins. Administration of GnRH agonists can be used to regulate fertility in male and female mammals.These and other peptide hormones exhibit improved binding efficiency and biological potency as a result having a residue in a critical, generally central location in the chain which residue contains a mixed alkyl ketone side-chain terminating in an aromatic group. Methods for efficiently synthesizing these peptides from readily available compounds are disclosed.
摘要翻译： GnRH肽类似物，其调节垂体分泌促性腺激素并促进或抑制性腺释放类固醇。施用有效量的GnRH拮抗剂可防止雌性哺乳动物卵的排卵和/或释放促性腺激素。 GnRH激动剂的施用可用于调节雄性和雌性哺乳动物的生育力。这些和其它肽激素表现出改善的结合效率和生物效力，因此在链中的关键的，通常中心的位置具有残基，残基含有终止于芳族基团的混合烷基酮侧链。公开了从容易获得的化合物有效地合成这些肽的方法。

9. 发明授权

US4661472A GnRH antagonists IX 失效
标题翻译： GnRH拮抗剂IX
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。

10. 发明授权

US4594329A CRF analogs 失效
标题翻译： CRF类似物
公开(公告)号：US4594329A
公开(公告)日：1986-06-10
申请号：US610110
申请日：1984-05-14
申请人： Wylie W. Vale, Jr. , Jean E. F. Rivier
发明人： Wylie W. Vale, Jr. , Jean E. F. Rivier
IPC分类号： A61K38/00 , C07K14/575 , C07K7/00 , A61K37/02
CPC分类号： C07K14/57509 , A61K38/00 , Y10S436/817
摘要： Analogs of rCRF and oCRF are disclosed that can be administered to achieve a substantial elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels and/or a lowering of blood pressure over an extended period of time. One analog which has been found to be particularly potent is: H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Met-Leu-Glu-Met-Ala-Lys-Ala-Glu-Gln-Glu-Ala-Glu-Gln-Ala-Ala-Leu-Asn-Arg-Leu-Leu-Leu-Glu-Glu-Ala-NH.sub.2. In the analogs, one or more of the first five 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. A number of other substitutions may also be made throughout the chain. These analogs or pharmaceutically or veterinarily acceptable salts thereof, dispersed in a pharmaceutically or veterinarily acceptable liquid or solid carrier, can be administered to mammals, including humans. These analogs may also be used as stimulants to elevate mood and improve memory and learning, as well as diagnostically.
摘要翻译：公开了rCRF和oCRF的类似物，其可被施用以实现ACTH，β-内啡肽，β-促肌动蛋白，前 - 肌动蛋白皮质素基因的其他产物和皮质酮水平的显着升高和/或延长期间的血压降低的时间。已经发现特别有效的一种类似物是：H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu- Leu-Glu-Met-Ala-Lys-Ala-Glu-Gln-Glu-Ala-Glu-Gln-Ala-Ala-Leu-Asn -Arg-Leu-Leu-Leu-Glu-Glu-Ala-NH2。在类似物中，前五个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。还可以在整个链中进行许多其它取代。分散在药学上或兽医学上可接受的液体或固体载体中的这些类似物或其药学或兽医学上可接受的盐可以施用于哺乳动物，包括人。这些类似物也可以用作兴奋剂以提高心情，改善记忆和学习以及诊断。

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