WO1998055136A1 - Fsh-releasing peptides - Google Patents

Fsh-releasing peptides Download PDF

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Publication number
WO1998055136A1
WO1998055136A1 PCT/US1998/011512 US9811512W WO9855136A1 WO 1998055136 A1 WO1998055136 A1 WO 1998055136A1 US 9811512 W US9811512 W US 9811512W WO 9855136 A1 WO9855136 A1 WO 9855136A1
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Prior art keywords
peptide
seq
recited
xaa
animal
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PCT/US1998/011512
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English (en)
French (fr)
Inventor
Samuel M. Mccann
Wen H. Yu
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Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College
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Application filed by Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College filed Critical Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College
Priority to EP98926280A priority Critical patent/EP0996457A4/de
Priority to CA002293664A priority patent/CA2293664A1/en
Priority to US09/297,989 priority patent/US6407205B1/en
Priority to JP11502855A priority patent/JP2000513749A/ja
Publication of WO1998055136A1 publication Critical patent/WO1998055136A1/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/82—Vectors or expression systems specially adapted for eukaryotic hosts for plant cells, e.g. plant artificial chromosomes (PACs)
    • C12N15/8241—Phenotypically and genetically modified plants via recombinant DNA technology
    • C12N15/8242—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits
    • C12N15/8257—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits for the production of primary gene products, e.g. pharmaceutical products, interferon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A61P5/08—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
    • 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
    • C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • C07K14/43563—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from insects
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/82—Vectors or expression systems specially adapted for eukaryotic hosts for plant cells, e.g. plant artificial chromosomes (PACs)
    • C12N15/8241—Phenotypically and genetically modified plants via recombinant DNA technology
    • C12N15/8242—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • This invention pertains to compositions and methods for selectively stimulating or inhibiting the release of follicle-stimulating hormone from the anterior lobe of the pituitary gland.
  • FSH follicle-stimulating hormone
  • LH luteinizing hormone
  • FSH is critical for spermatogenesis and for ovarian follicle development
  • LH is critical to androgen secretion in males, and estrogen secretion, ovulation, and formation of the corpus luteum in females.
  • a hormone with specific activity for releasing FSH but not LH could be used to increase fertility in humans or other animals, or to correct fertility problems caused by defective hypothalamic control of FSH secretion.
  • an FSH-specific releasing factor will inhibit FSH secretion, thereby inhibiting spermatogenesis in males, or inhibiting development of follicles and ovarian development in females, providing a new antifertility drug. It is also possible that very high doses of an FSH-specific releasing factor will inhibit FSH secretion, rather than stimulate it. Prior indirect evidence has suggested that separate factors could be responsible for triggering the release of FSH and for triggering the release of LH in mammals. However, this hypothesis could not previously be confirmed, because no previous work successfully isolated a potent factor that selectively induces the release of FSH, but not LH. See McCann, S.
  • Luteinizing hormone releasing hormone (LHRH, also known as gonadotropin-releasing hormone, or GnRH) has both LH-releasing activity and FSH-releasing activity. See Schally,
  • Gonadotropin-releasing hormone one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones, Science, 173:1036-1038, 1971; and D. Lincoln, Gonadotropin-releasing hormone (GnRH): basic physiology, pp. 218-229 in L. DeGroot et al., Endocrinology, 1995. The latter states at page 218: "There is no convincing evidence for the existence of a separate and specific FSH-releasing hormone, although some components of the GnRH precursor and some GnRH analogues appear to differ in the degree to which they stimulate the secretion of the two gonadotropins.”
  • Lamprey 1-LHRH-I has been reported to have relatively low activity in releasing either FSH or LH in rats. Yu, W. et ⁇ l., Selective FSH-releasing activity of comparison with gonadotropin-releasing abilities of analogs of GAP and natural LHRHs, Brain Res. Bull., 25:867-873, 1990.
  • Neurons that are immunopositive for 1-LHRH-I have been identified in human hypothalami. projecting from the arcuate region to the median eminence. Stopa, E. et al, Polygenic expression of gonadotropin-releasing hormone (GnRH) in human?, Peptides, 9:419- 423, 1988.
  • GnRH gonadotropin-releasing hormone
  • United States patent 4,973,577 discloses a 28,000 dalton protein isolated from porcine follicular fluid that stimulates the release of FSH, but not of LH. This protein has a relatively slow onset of action, and is relatively difficult to synthesize. The protein was said to be a homodimer of two chains of 116 amino acid residues each, or 232 residues total.
  • United States patent 3,888,836 discloses a method for synthesizing mammalian
  • LHRH Mammalian LHRH causes increased serum levels of both LH and FSH.
  • United States patent 4,721,775 discloses certain peptides that non-selectively induce the secretion of both LH and FSH.
  • FSH-RF FSH-releasing factor
  • LHRH's from various species are disclosed in Lumpkin et al., 1987.
  • One analog was found to have only FSH-releasing activity, but its potency was very low, and the slope of its dose- response curve was flat.
  • LHRH-II had slightly preferential FSH-releasing activity in vivo (unpublished data).
  • 1-LHRH-III is the long-sought FSH-releasing factor. This activity has been confirmed in vitro by incubation with hemi-anterior pituitaries of adult male rats. Following intravenous injection at the lowest dose tested to date (10 picomoles), this peptide produced an increase in FSH in vivo (P ⁇ 0.01) within ten minutes, but no significant increase in LH. Such a selective effect has not previously been reported for any analog of mammalian LHRH.
  • Lamprey III pGlu-His-Trp-Ser-His-Asp-Trp-Lvs- Pro-Gly-NH 2 (SEQ. ID NO. 1)
  • Rats Male and female Sprague-Dawley rats (Holtzmann, Madison, WI; 200-250 g) were housed two per cage under controlled conditions of temperature (23-25°C) and lighting (on from 0500 to 1700 hr). The animals had free access to a pellet diet and to tap water.
  • the 1-LHRH-III used in the experiments reported here was synthesized by standard solid-state peptide synthesis methods, and was purified to greater than 97% purity by preparative reverse-phase high performance liquid chromatography. All other peptides used were purchased from Peninsula Laboratories (Belmont, CA), except as otherwise noted.
  • AP anterior pituitary
  • the APs were incubated for 3 hr in fresh KRB buffer alone (control), or in KRB containing one of various concentrations of synthetic mammalian (m)-LHRH, 1-LHRHr III, 1-LHRH-I, chicken (c)-LHRH-II, or salmon (s)-LHRH.
  • the medium was then aspirated, and was stored frozen at -20°C until radio-immunoassays (RIA) for FSH and LH were conducted.
  • FSH and LH were measured using kits supplied by the National Institute of Arthritis Digestive Diabetes and Kidney Disease; hormone values were expressed in terms of
  • estradiol benzoate Sigma Chemical Co., St. Louis, MO
  • progesterone Eli Lilly, Indianapolis, IN
  • PE-50 polyethylene tubing
  • Lamprey l-LHRH-III caused FSH release in a dose-related fashion, with a minimal effective concentration (MEC) of 10 "9 M (the lowest concentration tested) or lower, and a maximal effect at about 10 "6 M. Thereafter, release of FSH levelled off through the highest concentration tested (10" M).
  • MEC minimal effective concentration
  • Lamprey l-LHRH-I caused a small but statistically significant release of FSH at a concentration of 10 s M; the amount of FSH released was significantly less than that caused by l-LHRH-III at the two concentrations tested (10 ⁇ 6 and 10 "5 M).
  • m-LHRH produced equivalent levels of FSH release at the two concentrations tested (4 x 10 "9 and 2 x 10 "8 M) as compared to the levels induced by l-LHRH-III. See Table 2.
  • Table 2 Table 2
  • n 6 in each case; * signifies p ⁇ 0.05; ** signifies p ⁇ 0.01; *** signifies p ⁇ 0.001; and **** signifies p ⁇ 0.0001 versus KRB control
  • l-LHRH-III had a much weaker effect on LH release. In fact, l-LHRH-III only caused the release of significant and comparable concentrations of LH at the three highest concentrations tested (10 6 - 10 "4 M). We found that l-LHRH-I was inactive at the two concentrations tested (10 ⁇ 6 and 10 '5 M). Mammalian LHRH gave a dose-related stimulatory effect on LH release, and was active at the lowest concentration tested (4 x 10 "9 M). See Table 3.
  • n 6 in each case; * signifies p ⁇ 0.05; ** signifies p ⁇ 0.01; versus KRB control
  • Salmon (s)-LHRH stimulated the release of both FSH and LH at the two concentrations tested (10 " ⁇ and 10"" M). See Tables 4 and 5.
  • Chicken (c) LHRH-II stimulated LH release at doses from 10' 8 to 10" M, but the dose effect was not statistically significant.
  • the c-LHRH-II had equivalent LH-releasing activity to that of m-LHRH, but l-LHRH-III showed no LH-releasing activity in this experiment.
  • the c-LHRH-II only significantly increased FSH release at the highest concentration tested (10 "6 M).
  • the MEC for l-LHRH-III for a statistically significant release of FSH was two orders of magnitude lower than that for c-LHRH-II.
  • n 6 in each case; * signifies p ⁇ 0.05; ** signifies p ⁇ 0.01; and *** signifies p ⁇ 0.001 versus KRB control
  • n 6 in each case; * signifies p ⁇ 0.05 versus KRB control
  • l-LHRH-III is the first highly specific and potent FSH-releasing peptide discovered.
  • the l-LHRH-III behaves completely differently from the other polypeptides tested.
  • Salmon LHRH and chicken LHRH-II had low potency, and lacked specificity for FSH release.
  • the in vivo assays using the other known vertebrate LHRH's showed that only one of them, c-LHRH-II, possessed even slight selectivity for FSH release.
  • l-LHRH-III is a highly conserved peptide in vertebrates, and in particular that it or a closely related peptide is the mammalian peptide hormone responsible for the potent and specific release of FSH. If l-LHRH-III is not identical to the mammalian FSH-RF, the degree of homology between the two is quite high.
  • Mammalian m-LHRH and l-LHRH-III were approximately equipotent toward releasing FSH.
  • the decreased potency of l-LHRH-III toward releasing LH is probably accounted for by the fact that l-LHRH-III only has 60% homology with m-LHRH (see Table 1).
  • the differences in sequences are accounted for by the differing amino acids in positions 5-8, which presumably cause a drastic decrease in LH-releasing activity and an increase in FSH-releasing capabilities. It is probable that the tetrapeptide l-LHRH-III 5-8 binds to the active site of a putative specific FSH-RF receptor.
  • FSH-RF receptor confers this specificity for FSH release, whereas the LHRH receptors stimulate the release of both hormones, albeit with a greater sensitivity for LH than FSH release.
  • FSH-RF receptors may reside on gonadotropes that contain only FSH.
  • LHRH receptors may cause release of both hormones from gonadotropes that contain both FSH and LH.
  • LHRH receptors may also be located on gonadotropes that only contain LH.
  • Pulsatile gonadotropin release in the rat is characterized by simultaneous pulses of FSH and LH, by pulses of LH alone, and by pulses of FSH alone. We hypothesize that the first two types of pulses may be accounted for by LHRH, and the third by FSH-RF.
  • FSH-RF farnesoid follicles and subsequent ovulations
  • FSH-RF may be used as a drug to increase fertility in humans.
  • peptides are expected to be agonists or "superagonists" of l-LHRH-III. These agonists will be prepared and tested in similar assays. Particular examples include peptides in which (a) the Asp 6 amino acid residue has been replaced with another amino acid residue (naturally occurring or xenobiotic); or (b) in which the Pro 9 residue has been replaced with ProNHEt (prolyl ethyl amide) and the Gly 10 -NH 2 has been deleted; or (c) both. Examples of such agonists include the following: pGlu-His-T ⁇ -Ser-His-Asp-T ⁇ -Lys-(ProNHEt) (SEQ. ID NO. 6)
  • inhibitory analogs of the peptide, or antibodies against the peptide may be used as potent antifertility drugs.
  • Monoclonal or polyclonal antibodies against the peptide may be raised using standard techniques, initially conjugating the peptide to a carrier such as bovine serum albumin or keyhole limpet hemocyanin.
  • a carrier such as bovine serum albumin or keyhole limpet hemocyanin.
  • antagonists include peptides in which one or more of residues 1, 2, 3, 6, and 10 have been replaced with another amino acid residue (naturally occurring or xenobiotic). Examples of such antagonists include the following:
  • the effect of the peptide, its agonists, and its antagonists will be characterized in rats, and then in large mammals, such as sheep and pigs. After successful testing in large mammals, in vivo tests in primates will be conducted, in monkeys and in humans, in accordance with applicable laws and regulations.
  • the peptide, an agonist, or an antagonist, combined with a pharmaceutically acceptable carrier may be administered to mammals, including humans, intravenously, subcutaneously, percutaneously, intramuscularly, or intranasally to increase fertility. It may also be administered to other vertebrates to increase fertility, for example sheep, cattle, pigs, chickens, turkeys, channel catfish, tilapia, and koi.
  • the active compound may be administered as a pharmaceutically acceptable salt, such as an acid addition salt; metal complex, e.g. with zinc, iron; or the like (which are considered salts for pu ⁇ oses herein).
  • a pharmaceutically acceptable salt such as an acid addition salt; metal complex, e.g. with zinc, iron; or the like (which are considered salts for pu ⁇ oses herein).
  • acid addition salts are hydrochloride, hydrobromide, sulfate, phosphate, maleate, acetate, citrate, benzoate, succinate, malate, ascorbate, tartrate, and the like.
  • Intravenous or other injections may be administered in isotonic saline, phosphate buffers, and the like. The dosage will vary depending on the specific pu ⁇ ose for which the peptide is administered; appropriate dosages may readily be determined by those of skill in the art, an
  • a patient experiencing infertility of unknown cause may be tested for 1- LHRH-III or FSH deficit through means otherwise known in the art, such as radio immunoassay.
  • Abnormally low FSH levels may indicate a deficiency in l-LHRH-III.
  • Such patients may be tested for a positive response to exogenous l-LHRH-III. If administration of exogenous l-LHRH-III produces an increase in FSH, that finding indicates that administration of exogenous l-LHRH-III is a potential treatment for infertility.
  • the l-LHRH-III may be synthesized through any of various means known in the art, for example, synthesis on a solid-state peptide synthesizer, or expression of a cloned gene in E. coli.
  • Xaa at 2 is (D-p-Cl-Phe)
  • Xaa at 3 is (D-Trp)
  • Xaa at 6 is (D-L-Arg-Et2)
  • Xaa at 10 is (D-Ala-NH2)

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PCT/US1998/011512 1997-06-04 1998-06-03 Fsh-releasing peptides WO1998055136A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP98926280A EP0996457A4 (de) 1997-06-04 1998-06-03 Fsh freisetzende peptide
CA002293664A CA2293664A1 (en) 1997-06-04 1998-06-03 Fsh-releasing peptides
US09/297,989 US6407205B1 (en) 1997-06-04 1998-06-03 FSH-releasing peptides
JP11502855A JP2000513749A (ja) 1997-06-04 1998-06-03 Ｆｓｈ放出ホルモン

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US86915397A 1997-06-04 1997-06-04
US08/869,153 1997-06-04

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09/297,989 A-371-Of-International US6407205B1 (en) 1997-06-04 1998-06-03 FSH-releasing peptides
US10/109,331 Continuation US20020165159A1 (en) 1997-06-04 2002-03-28 FSH-releasing peptides

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WO1998055136A1 true WO1998055136A1 (en) 1998-12-10

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6372263B1 (en) 1997-03-28 2002-04-16 Gyula Magvasi Active substance and composition inhibiting tumorous proliferation in ectoderm derived tissues
US6635740B1 (en) 1997-03-27 2003-10-21 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Ligand/lytic peptide compositions and methods of use
US7105487B2 (en) * 2000-10-05 2006-09-12 Veyx-Pharma Gmbh Method for inducing onset of the reproductive cycle of female breeding animals

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101264096B (zh) * 2007-03-12 2011-11-09 中国医学科学院药物研究所 人参皂苷Rg1在制备生精产品中的应用
JP5764854B2 (ja) * 2009-11-05 2015-08-19 株式会社サウスプロダクト ポリクローナル抗体およびその利用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4721775A (en) * 1985-08-26 1988-01-26 Board Of Regents, The University Of Texas System Effective peptides related to the luteinizing hormone releasing hormone from L-amino acids
US4973577A (en) * 1986-04-04 1990-11-27 The Salk Institute For Biological Studies FSH-releasing peptides

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69532578T2 (de) * 1994-08-10 2004-12-23 Lovas, Sandor, Omaha NEUARTIGE GnRH - ANALOGE MIT ANTITUMORALEN EFFEKTEN UND SIE ENTHALTENDE PHARMAZEUTISCHE ZUBEREITUNGEN

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4721775A (en) * 1985-08-26 1988-01-26 Board Of Regents, The University Of Texas System Effective peptides related to the luteinizing hormone releasing hormone from L-amino acids
US4973577A (en) * 1986-04-04 1990-11-27 The Salk Institute For Biological Studies FSH-releasing peptides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0996457A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6635740B1 (en) 1997-03-27 2003-10-21 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Ligand/lytic peptide compositions and methods of use
US7566777B2 (en) 1997-03-27 2009-07-28 Board Of Supervisors Of Louisana State University And Agricultural And Mechanical College Genes encoding hormone and lytic peptides
US6372263B1 (en) 1997-03-28 2002-04-16 Gyula Magvasi Active substance and composition inhibiting tumorous proliferation in ectoderm derived tissues
US7105487B2 (en) * 2000-10-05 2006-09-12 Veyx-Pharma Gmbh Method for inducing onset of the reproductive cycle of female breeding animals

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EP0996457A4 (de) 2001-09-19
CA2293664A1 (en) 1998-12-10
EP0996457A1 (de) 2000-05-03

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