前苏联专利SU1531858A3 Method of obtaining peptides

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专利摘要:
The invention relates to a process and compounds useful therein for producing a compound having an amino acid sequence defining a biologically active peptide or protein from a compound of the formula in which X is the residue of a naturally occurring amino acid and Peptide is a sequence of amino acids defining a biologically active peptide or protein , which comprises subjecting H-X-Pro-Peptide to conditions under which a diketopiperazine of the H-X-pro- moiety is formed with accompanying cleavage and release of Peptide.
公开号:SU1531858A3
申请号:SU864028458
申请日:1986-10-27
公开日:1989-12-23
发明作者:Деннис ДиМарчи Ричард；Стефен Брук Джеральд
申请人:Эли Лилли Энд Компани (Фирма)；
IPC主号:

专利说明:

The invention relates to an improved method for producing peptides having an amino acid sequence that determines a biologically active peptide or protein that can be used in biochemistry and biotechnology.
The purpose of the invention is to create a universal method for producing peptides.
Treatment of the compound HH-Pro-peptide is carried out in a medium apg) otonic dissolve.h. Examples of aprotic solvents are cjryjKMTb; N-methylpyrrolidone (OTG), N. N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), with MMP being most preferred.
The reaction in an aprotic solvent is carried out in mildly acidic conditions using acetic acid. The process is carried out in a temperature range of 25-50 ° C.
The choice of reaction temperature depends on the stability of the peptide and the nature of the third acid in the H – X – Pro-peptide system. Preferred is the highest temperature possible;
ate
with
00 ate
00

with/
Corresponds to the stability and nature of the third amino acid residue.
The -perio / schl splitting reaction is monitored following the formation of diketopiperazine. If necessary, the reaction is interrupted and the resulting product is separated from the reaction mixture using known methods.
Selected peptides used as models for the proposed method are prepared by solid phase synthesis methods. Their purity is confirmed by high performance liquid chromatography. Prior to cleavage, such peptides are stored as amorphous, lyophilized solids. The number of experimental parameters is changed (their effect on the cleavage reaction is shown).
The following are optimized conditions using organic and aqueous media, respectively, and their use on the Met-Pro-Gly-Gly-HHj peptide, where NH is the presence of the d fragment at the C-terminus of the peptide.
Organic degradation conditions
10 mg Met-Pro-Gly-Gly-NH, 2. Dissolve in 1 ml of HC, which is dehydrated by storing over a 4L molecular sieve for a week. The mixture was kept at 25 ° C with constant stirring and the reaction was initiated by adding 0.33 M glacial acetic acid (HOAc). The course of the cleavage is monitored by the formation of methionine-proline-diketopiperazine and the disappearance of the initial peptide, analyzed by the method of reversal phase chromatography. Chromatographic determination was carried out using a column with a size of 0.46 x 25 cm with a U1trospere in 0.1% trifluoroacetic acid (TFA), using an acetonitrile gradient as eluent. During each analysis, the reaction is stopped by tenfold dilution with a 0.1% solution of TPA. The diketopiperazin peak is collected and its identity is confirmed by a rhinoquy, a light and mass spectral analogue.
In tab. Figure 1 shows the data on the level of formation of diketopiperazine at various concentrations of acid in the cleavage conditions carried out at 25 ° C in the medium. Record a notice (reaction rate and setting
five
0
five
0
five
0
five
0
five
It depends on the concentration of the weak acid. When carrying out a similar treatment in DMSO medium, a decrease in the splitting rate was established.
As shown in the table. 2, an increase in the temperature of the race (heating to 40 ° C in DMSO medium leads to an increase in the reaction rate to values comparable to those achieved in LMF medium at 25 ° C.
From tab. 1, it follows that the optimum acid concentration is in the range of 0.25-0.5 mol.
In tab. Figure 3 shows the results of a study of the effect of temperature on a series of peptides in which only the side chain of the third residue is changed. Severe steric hindrance at this site slows down the reaction rate. However, in all cases a marked splitting is observed. / An important factor is the choice of aprotic solvent. As a solvent, a substance must be selected that promotes, and at least does not inhibit the formation of diketopiperazine, which is accompanied by splitting to form the desired final product, and at the same time has a minimal degrading effect on the peptide product.
In tab. Figure 4 shows the stability of a series of proteins and peptides under conditions of their organic degradation, which is determined by reversible phase high pressure liquid chromatography (HPLC), shows the amount of a specific reaction medium remaining after elevation of the selected protein or peptide for a specified time and relative advantage over DMF.
In tab. 3, similarly table. 4, stability results using methionyl human growth hormone are presented.
In tab. 6 shows the results of a study of the effect of a number of solvents on the splitting of rtet-Pro-Gly-Gly--NH.
As follows from the data presented, preferred solvents are MS, 1 MFA and / C-ICO, which are aprotic organic solvents.
in tab. 7 shows the results of a study of the effect of temperature on a range of peptides using DMF or LMSO as solvent.
From tab. 1-7, it follows that DMF has a greater effect on the formation of diketopiperazine and its cleavage, as compared to D1CO, however, this compound has a stronger degrading effect on the protein or peptide product. To achieve optimal results 18586
desired solvent at least for this application.
Optimum Met-Pro-Gly-Gly -.NH aqueous cleavage is achieved by dissolving 1 mg of peptide in 1M sodium phosphate buffer at pH 8.0. In order to accelerate the splitting 24 hours under 10
The temperature is over (Hold at 55 ° C. The degree of cleavage is determined by the proposed method for organic cleavage.
Water splitting conditions. Opti
A good balance should be established. The maximum aqueous cleavage of Met - Pro Gly - Gly - NHj is achieved by dissolving 1 mg of peptide in 1M sodium phosphate buffer at pH 8.0. In order to accelerate the cleavage
24 hours support the selection of reaction conditions for a particular peptide or protein product.
In tab. Figure 8 shows the data obtained by applying the conditions of organic cleavage on a model peptide that mimics the proposed compound in which the group of peptide is human growth hormone. In the latter, the first two amino acids are Phe-Pro. Thus, it becomes possible to form diketopiperazine from the X-Pro fragment.
20
temperature for
is equal to 55 C. The degree of cleavage is determined by the proposed method for organic cleavage.
In tab. 9 shows the values of the yield of cleavage at pH 7.0 using the peptide Met - Pro - Gly - Gly - NH as the substrate.
The reaction is carried out at three different temperatures using
the proposed compound and the finding .jq of different concentrations of the two buffer
the following form of diketopiperazine from initiating; its fragment Phe - Pro, obtained by the use of human growth hormone.
In tab. 8 shows a comparison of Met - Pro - Phe - Thr - He - NHj with Phe - Pro - Thr - He - NH. The results indicate a slow formation of diketopiperazine from the latter substance.
Thus, the treatment conditions of the proposed Met - Pro compound - human growth hormone can be precisely set in order to maximize the primary formation of diketopiperazine and the accompanying splitting with minimal secondary formation of diketopiperazine. In this regard, MMP is the most desirable solvent, since in its presence the level of formation of diketopiperazine is much higher than in the case of DMSO, and is close to the values achieved in DMF at the later stages of the reaction. Taking into account the increased stability of growth hormone in NMIl in comparison with LMPA (Table 5), it can be concluded that the first of these substances is
35
40
45
50
55
salts. The results show that the phosphate buffer is preferable to the acetate buffer, with the best results provided by a concentration of 1, OM.
In tab. Figure 10 shows the results of a study of the effect of pH on the formation of methionine-proline-diketopiprazine from Met - Pro - Gly - Gly - N11 at 40 ° G in an aqueous buffer medium. Sodium phosphate is used as the buffer salt. The results indicate that alkaline pH is preferred. Since unwanted side reactions such as deamidation and desulfurization are accelerated at elevated pH values, pH 8 is preferred.
In tab. 11 shows the results of studying the effect of various buffer salts on the degree of Met - Gly - Gly - m depression at pH 8.0 and 40 ° C. The preferred buffer is sodium phosphate.
In tab. 12 presents the results of a study of the effect of temperature on the formation of methionine-proline-toketopiperazine from a number of peptides in Kf
24 hours support20
temperature for
is equal to 55 C. The degree of cleavage is determined by the proposed method for organic cleavage.
In tab. 9 shows the yields of the cleavage at pH 7.0 using the peptide Met - Pro - Gly - Gly - NH as substrate.
The reaction is carried out at three different temperatures using
different concentrations of two buffer
salts. The results show that the phosphate buffer is preferable to the acetate buffer, with the best results provided by a concentration of 1, OM.
In tab. Figure 10 shows the results of a study of the effect of pH on the formation of methionine-proline-diketopiprazine from Met - Pro - Gly - Gly - N11 at 40 ° G in an aqueous buffer medium. Sodium phosphate is used as the buffer salt. The results indicate that alkaline pH is preferred. Since unwanted side reactions such as deamidation and desulfurization are accelerated at elevated pH values, pH 8 is preferred.
In tab. 11 shows the results of studying the effect of various buffer salts on the degree of Met - Gly - Gly - m depression at pH 8.0 and 40 ° C. The preferred buffer is sodium phosphate.
In tab. 12 presents the results of a study of the effect of temperature on the formation of methionine-proline-toketopiperazine from a number of peptides in Kf
The latter only change the side chain of the third residue from the N-terminus. As in the case of the study, the results of which are presented in table. 3, it is clear that the enhancement of steric hindrance at the site of the third residue slows down the reaction. However, in all cases, except for two, a noticeable splitting is observed. A temperature increase from 40 to 55 C noticeably increases the speed and degree of splitting of all four tetrapeptides tested.
The analysis of the products obtained as a result of the cleavage of samples of peptides and proteins was carried out by methods of anion-exchange and reversible phase chromatography of high resolution. Anion exchange chromatography was carried out on a Pug Q column with a 0.05 M Tris buffer, pH 8.0, containing 30% acetonitrile. Elution is carried out using a linear gradient of sodium chloride. Reverse phase chromatography was performed on a Zorbax Cg column, 150 L pore size using an acetonitrile gradient in 0.1 M ammonium phosphate at 45 ° C and pH 7.0.
The proposed method allows the cleavage of a protein or peptide having a proline residue, while the presence of methionine and lysine in the peptide chain does not interfere with its implementation.
Methionine-proline-diketopiperazik formation from Met - Pro - Gly - NH, at 25 ° С

权利要求:
Claims (3)
[1]
The claims of the method for producing peptides having an amino acid sequence that determines a biologically active peptide or protein by cleaving natural peptides, characterized in that, in order to create a universal method, a compound of the general formula:
H-Pgo peptide
five
0
five
0
five
where X is Met, Leu, Ser, Asp, Phe, peptide is the amino acid sequence of body pancreatic polypeptide, growth hormone secretion factor, A (SO) 4 -insulin-A-chain sulfonate, B (SO) -insulin-B-chain sulphonate or proinsulin, is subjected to cleavage in mildly acidic conditions at 25–50 s and an acid concentration of 0.25–0.5 mol in an aprotic solvent with the formation and cleavage at the moment of formation of the diketopiperazine derivative with the production of a peptide and diketopiperazine H-X-Rgo - residual.
[2]
2. The method according to claim 1, characterized by the fact that N-methylpyrrolidone, dimethyl sulfoxide, N. N-dimethylformamide is used as an aprotic solvent.
[3]
3. The method according to claim 1, characterized by the fact that 0.33 M acetic acid or acid is used as the acid.
Table 1
Formation of Methionine-Proline-diketopiperazine from Met - Pro - Gly - NH, at 4 ° C
The formation of methionine-proline-diketopiperazine in 1M acetic acid (DOPA)
Peptide
Content of component,%, at temperature, С
100 42 79 100
Table 2
Table 3
Table 4
37 32 O 36
124 52 98 100
117 90 89 100
119 86 86 96
Body pancreatic polypeptide PP (Met - Pro -).
GPF - Growth Hormone Secretion Factor (Met - Pro -).
A (S07) 4 - insulin A-chain 5-sulfonate1
In (80 G) 2 -insulin-In-chain S-sulfonate j
Relative percentage of the balance determined in relation to the untreated external control.
Table 5
Reverse phase HPLC was determined. Determined by anion exchange HPLC.
Met - Pro - Gly - Gly - NH expenditure dependence on Met - Pro - diketopiperazine formation
The amount of the remaining original substance. Determined by DO.C.
Continuation of table 4
Table 6
Ta lb and c and 7
Formation of methionine-proline-diketopiperazine in two selected solvents in the presence of 1M HOAc at 40 ° C.
Table
Effect of various buffer systems and their concentrations on the formation of methionine-proline-diketopiperazine from Met - Pro - Gly - Gly - NH at pH 7.0
The formation of methionine-proline-diketopiperazine at 100 ° C was measured after 2 hours; the formation of this product at 40 and 25 ° C was measured after 72 hours.
-y - t
24
15153185816
Table
The effect of pH on the formation of methionine-proline-diketopiperazine in 1.0 M sodium phosphate at
Table
Effect of different buffer salts on the formation of proline-diketopiperazine
from Met - Pro - Gly - r, ly - NHj pH 8.0 and 40 ° C
35 I
Formation of methionine-proline-diketopiperazine at different temperatures in 1.0 M phosphate buffer at pH 8.0
ten
eleven
at
Table 12

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WO2016049174A1|2014-09-24|2016-03-31|Indiana University Research And Technology Corporation|Lipidated amide-based insulin prodrugs|

US10561806B2|2014-10-02|2020-02-18|Mannkind Corporation|Mouthpiece cover for an inhaler|

CN106855477A|2015-12-09|2017-06-16|中国科学院大连化学物理研究所|Protein C-terminal peptide enrichment method based on Edman degradation|

法律状态:

优先权:

申请号 | 申请日 | 专利标题

US79183785A| true| 1985-10-28|1985-10-28|

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