• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Two surprisingly active fragments of human pancreatic GRF have been synthesized, along with an analog which exhibits good biological activity. The synthetic peptides are extremely potent in stimulating the release of pituitary GH in humans and nonhuman animals and have the general formula: 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-lle-Met-Ser-Arg-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-R40-Y wherein R,5 is Gly or D-Ala, R40 is Ala or des-R40, and Y signifies the carboxyl moiety of the amino acid residue at the C-terminal and is the radical -COOR,, -CR1O, -CONHNHR1, -CON(R1)(R2) or -CH2OR1, with R, and R2 being lower alkyl or hydrogen. The two fragments include the 29 or 32 N-terminal residues and are each amidated at the C-terminus. These peptides, as well as nontoxic salts thereof, may be administered therapeutically to animals, including humans.
    公开号:SU1426455A3
    申请号:SU843750475
    申请日:1984-06-01
    公开日:1988-09-23
    发明作者:Эдуард Фредерик Ривье Жан；Шпис Йоахим；Уолкер Вейл Вили
    申请人:Дзе Салк Институт Фор Биолоджикал Стадиз (Фирма)；
    IPC主号:
    专利说明:

    eleven
    The invention relates to a method for producing peptides. -New biologically active compounds that can be used in medicine.
    The purpose of the invention is a method of obtaining new synthetic shortened peptides, low-toxic compounds that have the ability to stimulate the release of growth hormone.
    Example 1. Synthesis of peptide (D-Ala) - human pancreatic hormonal excretory factor (1-39) -NH2, having the formula
    H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-DAla-Gln-Se-Ala-Arg-Lys-Leu-Leu-Leu-Gln- Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-NH
    in a stepwise manner, using a Beckman 990 peptide synthesizer, on a parametyl benzhydrylamine hydrochloride resin, as supplied by Bachem. Inc., having a replacement range of about 0.1-1.5 mlmol / g resin. Binding of tert-butyloxycarbonyl-Gly with 2 g of resin is carried out in a general way, in Schemes A and B, which are used throughout the synthesis, and this gives a substitution of approximately 0.35 ml SL per gram of resin. All solvents used are thoroughly out-cleaned by flushing with an inert gas, such as helium or nitrogen, to ensure the absence of oxygen, which may undesirably oxidize sulfur to Met residue.

    After removal of protection and neutralization, the peptide chain is built step by step on the resin. Deprotection, neutralization and addition of amino acids to the scoop are carried out in accordance with the method of Schemes A and B.
    Unprotect it is preferable to carry out according to scheme A.
    Reagent
    60% trifluoroacetic
    acid / 2% ethanedithiol
    60% trifluoroacetic
    acid / 2% ethanedithiol
    Isopentanol / 1% Etadithiol
    Triethylamine (10%) in
    Meon
    Triethylamine (10%) in
     CHjCl
    MOON (twice)
     (twice)


    The coupling is preferably carried out according to scheme B:
    Reagent
    Mixing time, min
    five
    0 5
    five
    0 5
    0
    five
    N, N -Dicyclohexylcarbodiimide- Tert-butyloxycarbonyl-amino acid 50-90
    Meon (twice) 0.5
     (twice) 0.5 (3 mol / l) in
    CHjCli, 15.0.
    -CHiClj0.5
    MeOH0.5
    (twice) 0.5
    Between one and two millimols of the amino acid protected by tert-butyloxycarbonate in methylene chloride is used per gram of resin in combination with one equivalent of 1.0 molar 30 N, N -dicyclohexylcarbodiimide in methylene chloride for two hours, When tert- Butyloxycarbonyl-Arg (toluenesulfonyl) uses a mixture of 50% dimethylformamide and methylene chloride. Benzyl ether is used as a hydroxyl side chain protecting group for Ser and Thr. Para-nitrophenyl ester is used to activate the carboxyl terminus of Asn or Gin, and, for example, tert-bu, tyloxycarbonyl-Azp (para-nitrophenyl ether) is coupled overnight using one equivalent of butyl alcohol in a 50% dimethylformamide mixture methylene chloride, in which case dicyclohexylcarbonide is added. The amino group of Asn or Glu is protected by xanthyl if dicyclohexylcarbonyl coupling is used instead of the active ester method. Dichlorobenzyloxycarbonyl is used as a protecting group for the side chain of Lys. Toluene sulfonyl is used to protect the guandine group Arg, and the carboxyl group Gly or Asp is protected with benzyl. The phenolic hydroxyl group of Tgr is protected with 2,6-dichlorobenzyl. At the end of the synthesis, a peptide is obtained.
    of the following composition X, -Tug (X2) -Lla- -Asp (X ,,) - Ala-I e-Phe-Thr (X4) -Asp (X) -.-Ser (X4) -Tyr (X7) -Arg (X) -Lys (X) -I-Val-Leu-DAla-Glu (X5) -Leu-Ser (X4) -Ala-Arg (Xj) -Ly5 (X,) - Leu-Leu-Gln ( Xj) - Asp (X) -lle-Met-Ser (XO-Arg (XJ-Gln (Xp-Gln (X5) -Gly-Glu (Xz) -Ser () - -Asn (Xi) -Gln (XJ) -Gly (Xp-Arg (X) - -Gly (Xj),
    where XT is tert-butyloxycarbonyl, 2,6-dichlorobenzyl, Xj is benzyl ether, X 4 is benzyl, Xj is xanethyl, X is toluene sulfonic, X is dichlorobenzylloxycarbonyl, Xj is NH-resin carrier. Xantil can be partially or completely removed by treatment with trifluoroacetic acid used to remove the (/ -amino protecting group.
    ten
    15
    The fractions, independently tested for purity, are carried out with the help of the GHjCN grade in 0.1% trifluoroxoic acid. The central section, lyophilisable, is obtained 107 mlg of the target peptide, the purity of which is about 100%. The magnitude of the optical rotation of the pure peptide rf D -56,3. Example 2. GHHTCS peptide D-Ala J-human pancreatic hormonal excretion factor (1-32) -NH2, having the formula
    H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-D-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu -Leu- -Gln-Asp-Ile-Met-Ser-Arg-Gln-6ly-N
    carried out in a stepwise manner
    After binding to the resin after-20, use the Beckmai 990 peptide synthesizer, on parametbenzhydryls of a new resin in Example 1. 96.5% of the peptide is obtained in 96.5% purity using thin-walled chromate
    of the residue: Tug, t-butyloxycarbonyl is removed with 60% trifluoroacetic acid in -j and 3.4 g of a complete peptide resin are obtained. To pinch off the protective groups from the remaining protected peptide-resin, it is treated with 1.5 ml of anisole, 0.5 ml of methyl ethyl sulfide and 15 ml of hydrogen fluoride per gram of peptide-resin at -20 C for half an hour and for half an hour. After removing the hydrogen fluoride under high vacuum, the residue of the resin-peptide is washed alternately with dry diethyl ether and chloroform, and then the peptide is extracted with a degummed 2N aqueous solution of acetic acid and separated from the resin by filtration.
    The flaked and deprotected peptide is then dissolved in 0.5% acetic acid and purified, which may include fine gel filtration on a Sephadex G-50. Get about 1.62 g of peptide.
    Then the peptide is subjected to further purification using preparative or semi-preparative high-performance liquid chromatography. Cassette installation Water Associates prep. h. G-500 is filled with 17 microns of Gfg silica, supplied by Vudas ZOOA. The CHjGN gradient in TEAR is created using a gradient gradient Eldex low pressure marker. Chromatographic fractions are carefully selected by high performance liquid chromatography and only fractions possessing high purity are collected. Desalted peeled
    The fractions independently tested for purity were performed using a GHJCN gradient in 0.1% trifluoroacetic acid. The central section then lyophilized, gives 107 ml of the target peptide, which is about 100% pure. The optical rotation value of pure rf D peptide is -56.3. Example 2. GHHTCS peptide D-Ala J-human pancreatic hormonal excretion factor (1-32) -NH2, having the formula
    H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-D-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu -Leu- -Gln-Asp-Ile-Met-Ser-Arg-Gln-6ly-NHj,
    carried out in a stepwise manner using the Beckmai 990 peptide synthesizer, on the parameter benzhydryl-amine resin of Example 1. 96.5% of the peptide is obtained at 96.5% purity using thin-walled chromatography and high-performance liquid chromatography. The magnitude of the optical rotation is fo / jD -57.9 °.
    Example 3. Gintez fragment
    human pancreatic hormonal excretory factor, i.e. human pancreas hormonal excretory factor (1- 32) -MN g, 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-Gln-Gln-Gly-NH,
    This is carried out in a stepwise manner using the Beckman 990 peptide synthesizer on the parametyl benzhydrylamino resin of Example 1. This analog is found to be substantially pure using thin layer chromatography and high performance liquid chromatography.
    Example D. Gintez of a fragment of the human pancreatic hormonal excretory factor, i.e. human pancreatic hormonal allocative factor (1–39) -NH j, having the formula
    -Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Glu -Asp-Ile-Met-Ser-Arg-Glu-Glu-Gly-Glu-Ser-Asn-Gln-Gly-Arg-Gly-NH,
    performed in a stepwise manner using the Beckman 990 peptide synthesizer, on the parametyl benzhydrylamine resin of Example 1. The peptide was found to be substantially pure using thin layer chromatography and high performance liquid chromatography.
    Example 5. Synthesis of D-Ala peptide - human pancreatic hormonal excretory factor (1-39) -NH2, having the formula
    H-Tyr-Ala-Asp-Ala-Ale-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-D-Ala-Gln--Leu-Ser-Ala-Arg-Lys-Leu- Leu-Gln-Sep-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Gly-Arg-Gly-NH, is carried out in a stepwise manner using the peptide synthesizer Beman 990 , on the parametyl benzhydrylamine resin of Example 1, the Peptide was found to be substantially pure using thin layer chromatography and high performance liquid chromatography. Biological tests of the compounds obtained were carried out.
    In vitro assays are used to determine the effectiveness of various synthetic peptides in stimulating the release of a hormone, using synthetic human pancreatic hormonal excretory factor as a standard.
    In addition to in vitro growth hormone secretion tests, in vivo experiments were also performed by introducing a synthetic peptide through an implanted catheter into free-running normal male rats, 1 GW pre-treated with FL-63, a dopamine hydroxylase inhibitor that suppresses spontaneous secretion of growth hormone, not influence on the response to exogenous hormonal excretion (hpGRF (1-40) OH, because it is a significant factor. Blood samples are devoid of the equivalent of the native peptide) with parallel comparison with equivalent concentrations natural hpGRF (1-44) Cnt and various other
    40
    synthesized analogs.
    Cultures are used which include rat hypothypis cells removed four or five days before. Cultures that are considered optimal for isolating growth hormone 45 are used for comparative testing. Incubation of the test substance is carried out for 3-4 hours, after which aliquots of the culture medium are taken and processed to measure the content of the immunoreactional growth hormone in them by a well-known method, radioimmunoassay.
    The results of comparative tests in the form of a protocol are given in the table.
    The table shows the level of growth hormone in cell culture samples by radioimmunoassay.
    A root through the same catheter immediately before the injection and 5 and 20 minutes after HeeJ, growth hormone levels in the blood are measured by radioimmunoassay. The results show that the synthetic peptides obtained by the proposed method are powerful stimulators of the secretion of pituitary growth hormone and are comparable in activity to natural hormonal and alkaline factors.
    Thus, the tests showed that the compounds obtained by the proposed method are low-toxic biologically active compounds that promote the secretion of growth hormone, in activity they are close to the human hormonal selective factor (1-44) W5, but it is more accessible, since contain fewer amino acid residues in their chain (32 and 39)
    50
    five
    0
    five
    0
    In tests, cells of the PAP / GRF type were used. Culture medium: 2% FCS + 5 DEX (/ 5-PI) + Incubation medium: 0.1% bis- (tr1-methyl-silyl) -acetamide f ascorbic acid / HDMe; (the term FCS means fetal body DEX - dexamethasone; the term PAP means rat anterior lobe of the pituitary gland and indicates that the primary cultures of rat anterior pituitary cells were used in testing)
    The in vitro tests of these synthetic peptides show that the effective concentration giving a 50% effect (varies from 20 to 100 picomolar, and the lowest effective concentration itself is 3-8 pmol per liter. The maximum effective concentration for human pancreatic hormonal excretory factor was approximately 1 nanomolar.
    In addition to in vitro growth hormone secretion tests, in vivo experiments were also performed by introducing a synthetic peptide through an implanted catheter into free-running normal male rats, 1 GW pre-treated with FL-63, a dopamine hydroxylase inhibitor that suppresses spontaneous secretion of growth hormone, not influence on the response to exogenous hormonal excretion factor. Blood samples to the white factor. Blood samples are taken through the same catheter immediately before the injection and 5 and 20 minutes after HeeJ, growth hormone levels in the blood are measured by radioimmunoassay. The results show that the synthetic peptides obtained by the proposed method are powerful stimulators of the secretion of pituitary growth hormone and are comparable in activity to natural hormonal and alkaline factors.
    Thus, tests have shown that the compounds obtained by the proposed method are low-toxic biologically active compounds that promote the secretion of growth hormone, in activity they are close to the human hormonal secretion factor (1-44) W5, but it is more accessible because they contain there are fewer amino acid residues in their chain (32 and 39)
    and can be obtained synthetically.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of producing peptides of general formula I
    H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-nAla-Gln--Leu-Ser-Ala-Arg-Lys-Leu-Leu- Gln-Asp-Il-Met-Ser-Arg-Gln-Gln-Gly-Q,
    I
    where Q is NH -i or Glu-Ser-Asn-Gln-Glu-Arg-Gly-NHj,
    characterized by the fact that the Tert-Hyloxycarbons I-Gly is reacted with parametbenzhydrylamine hydrochloride resin, the protective group is removed and then the peptide chain is gradually expanded in accordance with the amino acid sequence corresponding to the compound of general formula I and . the obtained peptide resin of General formula II
    X, Tug (Xj) -Ala-Asp (X) -Ala-Ile-Phe- -Thr (X4) -Asn (Xj) -Ser (X) -Tyr (X2) - -Arg (X) -Lys (X7 ) -Val-Leu-DAla-Gln (Xj) - -Leu-Ser (X4) -Ala-Arg (Xt) -Lys (X7) - -Leu-Leu-Gln (Xj) -Asp (X3) -Ile- Met- -Ser (X4) -Airg (X) -Gln (Xj) -Gln (Xp- -Gly-W,
    where W is Xg or -Glu (X3) -Ser (X) - -Asn (Xj) -Gln (Xy) -Glu (X p- -Arg (Xt) -Gly Xj, X, is t-butyloxycarbonyl; Xj- 2,6-dichlorobenzyl; Xj is benzyl ether; benzyl; Xj is xanthyl x-toluenesulfonyl; X cleaving the polymer resin by treating the resulting product with hydrogen fluoride in the presence of anisole.
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    同族专利:
    公开号 | 公开日
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    ES8606399A1|1986-04-16|
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    FI842166A0|1984-05-30|
    KR900006712B1|1990-09-17|
    GR79698B|1984-10-31|
    AU2126983A|1984-04-24|
    FI83660C|1991-08-12|
    HU191263B|1987-01-28|
    NZ205745A|1987-07-31|
    MX7701E|1990-09-20|
    US4563352A|1986-01-07|
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    JPS59501951A|1984-11-22|
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    IL84758A|1987-01-13|1992-03-29|Salk Inst For Biological Studi|Peptides stimulating the release of pituitary growth hormone in fish and amphibians,and pharmaceutical compositions containing them|
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    US5043322A|1988-07-22|1991-08-27|The Salk Institute For Biological Studies|Cyclic GRF analogs|
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    DE69108192T2|1990-12-10|1995-07-20|Hoffmann La Roche|Process for the enzymatic production of GRFNH2.|
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    EP0922446A1|1997-12-03|1999-06-16|Applied Research Systems Ars Holding N.V.|Solution-phase site-specific preparation of GRF-PEG conjugates|
    US7268113B2|2001-02-02|2007-09-11|Conjuchem Biotechnologies Inc.|Long lasting growth hormone releasing factor derivatives|
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    US20090088380A1|2007-07-12|2009-04-02|Pierrette Gaudreau|Ghrh analogs and therapeutic uses thereof|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/432,663|US4563352A|1982-10-04|1982-10-04|Human pancreatic GRF|
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