Method of obtaining peptides

专利摘要:
PGRF 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-Vai-Leu-Gly-Gln-Leu- Ser-Ala-Ar g-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-R34-Asn-Gln-Glu- R38-Gly-R4 0-R41-R wherein R is OH or NH2, R34 is Ser or Ala, R38 is Arg or Ser, R40 is Ala or Arg and R41 is Arg, Arg-Ala, Arg-Ala-Arg, Arg-Ala-Arg-Leu or des-R41. 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 mammals, including humans, and may be used diagnostically. The peptides are useful in stimulating the release of GH and accelerating growth in warm-blooded non-human animals and in improving agriculture.
公开号:SU1531857A3
申请号:SU833611593
申请日:1983-06-15
公开日:1989-12-23
发明作者:Чай-Кван Линг Николас；Стефен Еск Фредерик；Болен Петер；Эрнест Бразо Поль (Младший)；Чарльз Луис Гвиллемин Роджер
申请人:Дзе Салк Институт Фор Биолоджикал Стадиз (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing peptides of new biologically active compounds which can be Hi, 1 medical use.
The purpose of the invention is to develop a method for producing new peptide derivatives - low-toxic, which have the ability to cause the secretion of natural GH, but more accessible compounds.
Example 1. Synthesis of PGRF (l-44) free acid having the formula

cm
H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Sei-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Seg-Ala-Arg-Lys-Leu-Leu-Gln- . Lsp-lle-Met-Ser-Lrg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-7 eu, is carried out in stages using the Beckman 990 peptide synthesizer based on chloromethylated resin, which is supplied from Lab, Systems Inc., with a content of 0.9 Meq. C1 / g. The GoeflH BOG-Leu resin was prepared according to the procedure described below, and this results in a replacement of approximately 0.22 mmol of Leu by 1 g of resin. All solvents used are thoroughly degassed by passing an inert gas, preferably gels, in order to guarantee the absence of oxygen, which may undesirably oxidize the sulfur of the Met group.
After the protection has been removed and neutralized, the peptide chain is gradually incorporated into the resin. Deprotection, neutralization and the introduction of each amino acid is usually carried out according to the procedure described in Table 2. one.
For the reaction of the compound per g of resin, 1 mmol of a BOG protected amino acid in methylene chloride plus 1 eq. 0.5 M flGGl in methylene chloride or 30% DMR in methylene chloride, the reaction proceeds for 2 hours. When combined with Arg, a mixture of 10% DMH with methylene chloride is used as a protective group with a hydroxyl side chain for Ser and TbGo 2-chlorobenzyloxycarbonyl (2G1-Z) is used as a protecting group for the side chain of Lys. The ToS is used to protect the guanidino group Arg, and the Gin or Asp carboxyl group is protected as Bzl ef1f. The hydroxyl phenolic group Tug is protected as 2,6-dichlorobenzyl. At the end of this synthesis, the following compound is obtained:
X, -Tug (X) -Ala-Asp (Xs) -A1a-11-Ihl-Thr (X) -ABn-Ser (X5) -Tyr (Xj) - Arg (Xg) -Lys (X) -Val- Leu-Gly-Gln-Leu-Ser (Xj) -Ala-Arg (X6) -Lys (X) -
Leu-Leu-Gln-Asp (X,) - Ile-Met-Ser (X5) - Arg (Xg) -Gln-Gln-Gly-Glu (X,) - Ser (X5) - Asn-Gln-Glu (X ,) - Arg (X6) -Gly-Ala-Arg (Xg) -Ala-Arg (Xg) -Leu-X,
where X, is benzyloxycarbonyl;
X is 2,6-dichlorobenzyl;
X, is a benzyl ester;
X is benzyl;
about
five
5 o
0
five
0
five
X - tosil;
Hb - 2C1-Z;
X - X-0-GHi-benzenepolystyrene
resin carrier.
After the last Tug group is bonded to the resin, the BOG is removed with 45% TFA c. In order to remove and remove 3auiji with the remaining peptide-protected resin, it is treated with 1.5 ml of anisole, 0.25 MP of methyl ethyl sulfide (MES) and 10 ml of hydrogen fluoride (HF) per 1 g of peptide-resin at a temperature of - 20 G for 30 minutes and at 0 ° G also for 30 minutes. After removing the HF under high vacuum, the remaining resin — the peptide is washed alternately with dehydrated diethyl ether and chloroform, and the peptide is then extracted with degassed 2N. acetic acid. As a result of the lyophilization of the acetic acid extract, a white, soft substance is obtained. The peptide, which has been separated from the peptide, is then dissolved in 30% acetic acid and subjected to gel filtration on a thin layer.
gel Sephadex G-50, I
This peptide is then further purified by cation exchange chromatography using GM-32 Wliatman carboxymethyl cellulose (18x18 cm, LAYNING), and using a concave slope formed by dropping 1 L of 0.4 M, pH 6.5, into a mixing flask, containing 400 ml of 0.01 M NIIjOAc, pH 4.5. The final purification is carried out by means of distribution chromatography on Phacmain carrier fine powder of Sephadex G-50 using the EtOH: pyridine: 0.2% NHOAc 4: 1: 1: 7o solvent system. The chromatographic fractions are carefully separated by thin layer (TLG) chromatography with using 0.25 mm thickness of pre-coated glass plates, silica gel 60 without a fluorescent indicator, the development is carried out using a solvent system: 1-butanol, pyriline, acetic acid, water 6: 6: 1.2: 4.8. TLG plates are approximately developed by 2 g of ninhydrin in 50 mt of acetic acid and 950 NUI of 1-butanol. R is 0.46A. Only those fractions are collected, KtiTtipbie do not show a significant degree of isotto.
five
The product yield is 80 mg per each 1 g of polystyrene resin.
Amino acid analysis is carried out after hydrolysis in sealed tubes by a method already known in the art using the Liguimat amino acid analyzer to check the correctness of the resulting sequence, and the following results are obtained: Agx (3.62), Thr (0.75), Ser ( 3.5), Glx (6.83), Gly (2.87), Ala (5.10), Val (0.9), Met (1.23), He (1.84), Leu (5.045 ), Tyr (2.09), Phe (0.91), Lys (2.31), Arg (6.61), The analysis confirms the correct sequence,
The rotation of the plane of polarization of light is determined and the following results are obtained: s, -65.6 + 1 (C, 1.30% acetic acid).
Example 2. The synthesis of PGRF (1-40) of the formula H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu is carried out in stages Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-OH,
using the Beckman 990 peptide synthesizer based on chloromethylated resin. The synthesis is carried out as in Example 1. The yield of the product is 37 mg for each 1 g of resin. As a result of processing by thin layer chromatography (TLC) and high performance liquid chromatography (HPLG), the peptide is completely pure. The value of R ,, measured as in Example 1, is 0.414.
Amino acid analysis was performed after hydrolysis in order to verify the correctness of the sequence obtained, and the following results were obtained: Agx (3.89), Thr (0.88), Ser (3.66), Glx (7.04), Gly (3 , 07), Ala (4.02), Val (0.96), Met (1.01), He (1.86), Leu (4.28), Tyr (2.0), Phe (0, 86), Lys (2.24) and Arg (4.15). The analysis confirms the correct sequence. cCj .p -64,0 + 1
Example 3. A synthesis of PGRF (1-34) - free acid having the 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-Glu-Ser-OH using
318576
Bekmlon 990 peptide synthesizer based on chloromethylated resin. Synthesis is carried out as in Example 1. A yield of 121 mg per 1 g of resin. As a result of processing by thin-layer chromatography and high-pressure liquid chromatography, the peptide was shown to be a purely clean product. The value of R is 0.500.
Amino acid analysis is carried out after hydrolysis in order to verify the correctness of the resulting sequence, and the following results are obtained: Agx (2.87), Thr (0.78), Ser (3.78), Glx (5.11), Gly (1.93), Ala (3.03), Val (0.88), Met (0.96), He (1.88), Leu (4.14), Tyr (2.05), Phe .
0 (1.07), Lys (2.29) and Arg (3.22). The analysis confirms the correct sequence. -60,8-t-l.
P p im e p 4a Perform stepwise synthesis of PGRF (1-31) -free acid having the formula
H-Tyr - Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Seg-Ala-Arg-Lys-Leu-Leu-Gin -Asp-11- Met-Ser-Arg-Gln-Gln-OH using the Beckman 990 peptide synthesizer based on chloromethylated resin. The synthesis is carried out analogously to example 1. The yield of the product was 143 mg per each 1 g of resin. As a result of processing by thin-layer chromatography and high-performance liquid chromatography, the peptide, as the analysis showed, is a practically pure product. The value of R / is 0.536,
Amino acid analysis of corestones - south after hydrolysis in order to verify the correctness of the resulting sequence. The analysis shows the following results: Agx (2.73), Thr (0.75), Ser (2.77), Glx (3.95), Gly (0.98), Ala (3.06), Val (0 , 80), Met (0.98), He (1.77), Leu (4.28), Tyr (2.23), Phe (1.14), Lys (2.34)
and Arg (3.22). Analysis confirms 0g 7
the correct sequence. j,
 -65,
P p and M ep 5. Gradually synthesize GRFO-44j-amide, having the following formula: H-Tug-A1-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-ArgLys-Val-Leu-Gly -Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gin-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Cl lias
five
Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NHi using a Beckman 990 peptide synthesizer based on 6 g of MBHA resin, using the same operations (set forth in Table 1) as in Example 1. The gum peptide was treated with 10% anisolo in HF plus MCS, as in Example 1. After the gum was separated and washed, the peptide was extracted with acetic acid and then lyophilized. After purification by gel filtration, ion exchange chromatography and then distribution chromatography, 321.4 mg of peptide is obtained, the yield of which is 54 mg per 1 g of resin. As a result of processing by thin layer chromatography and high performance liquid chromatography, this peptide, as the analysis showed, is a practically pure product. The value of R is.
Amino acid analysis is carried out after hydrolysis in order to check the correctness of the sequence obtained, and the following results are obtained: Agx (3.75), Thr (0.80), Ser (3.60), Glx (6.98), Gly ( 3.16)., Ala (5.04), Val (0.77), Met (1.02), He (1.79), Leu (5.41), Tyr (2.03), Phe ( 0.84), Lys (2.39) and Arg (6.43). The analysis confirms the correct sequence. ut.3-p -63,1 + 1.,
EXAMPLE 6: Poetano synthesis of PGRF (1-40-amide having the 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-Glu-Ser-Asn-Gln-Glu-Arg- Gly-Ala-NH, using the Beckman 990 peptide synthesizer based on MBHA resin The synthesis is carried out as in Example 3. The yield of the product is 60 mg for each 1 g of resin.The analysis showed that the result of processing by thin-layer chromatography and high-performance liquid chromatography is a practically pure product. The Rf value is 0.464.
Amino acid analysis is carried out after hydrolysis in order to verify the correctness of the sequence obtained, the analysis shows the following results: Agx (3.76), Thr (0.8
five
0

5 Q 5
0
five
Ser (3.68), Glx (6.89), Gly (3.12), Ala (4.08), Val (0.88), Met (1.36), He (1.76), Leu (4.24), Tyr (2.00), Phe (0.80), Lys (2.32) and Arg (4.16). The analysis confirms the correct sequence, oi- -62 ,.
Example 7. Step by step synthesis of GRFf1-37) -free acid having the formula H-Tug-A1-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Glu -Leu-Ser-Al a-Arg-Lys-Le u-Leu-G In-Asp-He-He t-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-OH, with using the Beckman 990 peptide synthesizer based on chloromethylated resin. The synthesis is carried out as in Example 1. A yield of 29 mg per each 1 g of resin. As a result of processing by thin-layer chromatography and high-resolution liquid chromatography, the resulting peptide, as the analysis showed, is a practically pure product. R.J is 0.421.
Amino acid analysis was performed after hydrolysis in order to verify the correctness of the desired% sequence, the analysis shows the following results: Agx (3.92), Thr (0.79), Ser (3.62), Glx (7.05), Gly ( 1.97), Ala (3.17), Val (1.03), Met (1.0), He (1.91), Leu (4.37), Tyr (1.86), Phe (0 , 76), Lys (2.15), and Arg (3.40). The analysis confirms the correct sequence. Gos1 -61.7 + 1.
Example 8: Step by step synthesis of a GRF (1-37) -amide having the 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-He-Met-Ser-Arg-Gln-Gln-Glu-Ser-Asn-cUn-G u-Glu- NH, using the Beckman 990 peptide synthesizer based on MBHA resin. The synthesis is carried out analogously to example 1. A yield of 25 mg per each 1 g of resin. According to the analysis by thin layer chromatography and high performance liquid chromatography, the resulting peptide, as the analysis showed, is a practically pure product. The RI value is 0.507.
Amino acid analysis is carried out after hydrolysis in order to verify the correctness of the preparation after the sequence, the analysis shows the following results: Agx (4.02), Thr (0.80), Ser
(3.49), Glx (6.90), Gly (1.92), Ala (3.08), Val (1.05), Met (1.01), He (1.77), Leu ( 4.05), Tyr (2.02), Phe (1.14), Lys (2.50) and Arg (3.27). The analysis confirms the correct sequence, ol- -63,3jf1.
Biological testing of the resulting peptides was performed.
In order to determine the effectiveness of the peptide in accelerating the growth hormone distribution, an in vitro assay was performed using synthetic GRF (1-40) of Example 2 versus equimolar concentrations of extracted and purified natural GRF (1-40) and compared with the control the GRF standard, which has already been known to be effective in accelerating the cleavage of pituitary cells. The control standard is a preparation obtained from a rat hypothalamus, which gives half of the maximum response in relation to the release of GH in the analysis of a multilayer bioprotein of the pituitary cell.
Cultures are used that include rat pituitary gland cells that were previously removed 4–5 days later. Both cultures of a defined standard medium and a culture that are considered optimal for secreting growth hormone are used for comparative testing in a conventional manner. Incubation of the substance to be tested is carried out for 3-4 hours, aliquots of the growth medium are removed and processed to determine their content in the immunoreactive (irGH) well-characterized radioimmunoassay method.
The bioactivity of hpGRF analogs in vitro (the study of rat pituitary cells) the relative efficiencies of hp GRF-44-NH analogues with the excluded end - COOH is given in Table. 2
The results obtained confirm the low toxicity of the peptides synthesized under the conditions of the proposed method and the biological activity expressed in the ability to cause the secretion of natural growth hormone.
.
Yu
15 20 25 30
5 DO DZ
d
five

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing peptides of general formula 1
A-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Ile-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln- Asp-Ile-Met-Rx, where X is OH, R-Ser-Arg-Gln-Gln; Ser-Arg-Gln-Gln-Gly-Glu-Ser; Ser-Asn-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu;
Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala;
Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-piy-Ala-Arg-Ala-Arg-Leu, characterized in that, the-protected amino acid of general formula II
Boc-HN-G (R, Rj) COOH
where R, -H;
R-CHjrCH OH, -GHjGH (CH5) 2, -CH CH GGNHj, .COOH,
MBGA or benzyl polystyrene resin resin is deblocked and the peptide sequence is gradually increased in accordance with the general formula I and the peptidyl polymer of the general formula III (X) -Ala-Asp (X,) - Ala-Ile- Phe-Thr (X) -Asn-Ser (X4) -Tyr (X) -Arg (Xf) - Lys (Xg) -Val-Leu-Gly-Gln-Leu-Ser (X4) - Ala-Arg (Xf) -Lys (Xg) -Leu-Leu-Gln-Asp (Xj) -Ile-Met-RX, where X is 0-GHj- benzylpolystyrene
resin; W - resin CBGD
X (- benzyloxycarbonyl; Xii-2,6 - dichlorobenzl; XJ, - benzyl ester; X - benzyl; Hu - tosyl; X, - 2G1-Z;
R has the indicated meanings
the carrier polymer and protecting groups are cleaved.
Priority signs: 16.06о82 when R - Ser-Arg-Gln-Gln; Ser-Arg-Gln-Gln-Gly-Glu-Ser; Ser-Asn-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu. R--Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala; 09/15/82 when R-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu.
Table 1
Stage
Reagents - and operations
Washing CHjClj (2 times) with 50% trifluoroacetic acid + 5% 1,2-ethanedithiol in 1-fold) 50% trifluoroacetic acid (TFA) + + 5% 1,2-ethanedithiol in (1-fold)
Washing with CH, Cl2 (3 times) Washing (2 times) with 10% triethylamine () in CH, C12, neutralizing (2 times) Washing (2 times) with 10% triethylamine () s, neutralizing (2 times) Washing with CHjOH (2 times ) Wash (2 times) BOC-amino acid (1 mmol / g resin) plus an equivalent amount of dicyclohexylcarbodiimide (DSS) in CHjCl
Washing CHjCl (1-fold) with 50% dimethylformamide in (2-fold washing) Washing with 10% triethnpamine (Et3N) in (1-fold) npoNflbiBKa SI OH (2 times) Washing (2 times) with 25% acetic anhydride (2 ml / resin) Flushing (2 times) Flushing CHjOH (2 times)
For the compound Asn and Gin, a 1.136 M excess of 1-hydroxybenzotriazole (HOBt) is introduced into this step.
table 2
Mixing time, min
0.5 0.5
20.0 0.5 0.5
0.5 0.5
0.5 0.5 0.5
120
0.5 0.5
0.5 0.5 0.5
20.0 0.5 0.5

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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US4518586A|1983-01-13|1985-05-21|The Salk Institute For Biological Studies|GRF Analogs III|

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US4581168A|1983-02-21|1986-04-08|Sanofi|Synthesis of hpGRFin liquid phase and intermediate peptides|

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AU575843B2|1983-08-10|1988-08-11|The Administrators Of The Tulane Eductional Fund|Growth hormone releasing peptides|

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PT79094B|1983-08-29|1986-08-14|Salk Inst For Biological Studi|Grf analogs|

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FR2567524B1|1984-07-10|1987-11-27|Sanofi Sa|PROCESS FOR THE SYNTHESIS OF SOMATOCRININ IN LIQUID PHASE AND INTERMEDIATE PEPTIDES|

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CA1271600A|1985-01-07|1990-07-10|David Howard Coy|Growth hormone-releasing peptides and method oftreating mammals therewith|

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FR2599038B1|1986-05-26|1990-06-29|Sanofi Sa|PROCESS FOR THE PREPARATION OF NONACOSAPEPTIDES AND INTERMEDIATE PEPTIDES|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US8200812|1982-06-16|

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US06/418,248|US4517181A|1982-09-15|1982-09-15|Mammalian PGRF|

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