The peptide having the influence on regeneration of the hematopoietic and immune systems, and pharmaceutical composition based on it

 

(57) Abstract:

The claimed peptide of formula H-Ile-Glu-Trp-OH, have influence in the regeneration of the hematopoietic and immune systems. The pharmaceutical composition contains an effective amount of the peptide. The composition may be in any form suitable for oral, nasal, topical application and injection. Preferably it contains 0.001 to 0.01 wt.% the peptide. The invention extends the range of drugs specified action with high activity, low toxicity in the absence of side effects. 2 S. and 3 C.p. f-crystals, 2 ill.,12 table.

The invention relates to medicine, namely to methods of producing biologically active substances that have immunoregulatory properties, and may find application in medicine, veterinary medicine, as well as in experimental biochemistry.

In practical medicine widely known as regulators of the immune processes timoshii extracts, in particular thymosin fraction 5 (Goldstein A. L., Guna, A., Latz, M. M., Hardy H. A., White A.), thymalin and its solutions (M. D. Mashkovsky "Drugs" M Medicine, H. 2, S. 171, 1986; CH, N 659586). These extracts are composed of complex substances polypeptide of nature and getting them from natural sources is iziko-chemical characteristics and biological properties. In addition, due to the presence in the natural preparations of thymus ballast components when used in patients sometimes experience side effects. The latter fact was the impetus for the creation of synthetic peptides. Currently, the synthesis of several peptides, which have immunoregulatory properties: SU N 1582393, EP N 230052, US N 5008246, US N 5013723. Each of the obtained synthetic peptides with a limited set of relevant properties has a high activity, low toxicity, no side effects, which determine their possible application in medicine.

In the present invention is proposed for use in experimental and therapeutic purposes, a new peptide of the formula

H - Ile - Glu - Trp - OH

Peptide and composition based on it can be used as a tool with the ability to influence the regeneration of the hematopoietic and immune systems.

According to the invention the inventive peptide is used as a dietary component for the preparation of pharmaceutical compositions. The pharmaceutical composition includes an effective amount of a peptide and a carrier suitable for use in combination with this billinge and outdoor applications, and also in the form of injections.

Typically, the composition contains from 0.001 to 0.1 wt.% (preferably from 0.01 to 0.05 wt.%) the peptide. This number also depends on the method of introduction of the composition into the body. The pharmaceutical composition prepared by mixing the carrier and the peptide at a temperature of 40 - 70oC, the composition is stable in solution for 24 hours (3 years) at a temperature of 70oC (20oC), respectively.

In the composition for injection as solvent can be used in any pharmaceutically acceptable solvent, including distilled water, physiological saline, buffer solutions. The content of the peptide may be from 0.001 to 0.1 wt.%.

Preparation of solution for injection carried out traditionally, the volume-weighted method. While to a certain weight amount of powder peptide add solvent to obtain the desired volume of solution. Then, the solution is filtered through sterilizing filters, bottled in vials or ampoules. The resulting solution is a colorless transparent liquid, does not contain chemicals or other impurities, stable.

Solid form for oral administration can be Cai, including colors, flavors, etc. the content of the peptide may be from 0.01 to 1 wt.% and is usually selected depending on the type of composition for oral administration.

The method is illustrated by the following example.

Example 1. H-Ile-Glu-Trp-OH.

1. Obtain Boc-LEU-OPFP.

The mixture 46,0 g (0.2 mol) of Boc-Ile-OH and 40.5 g (0.22 mol) of pentafluorophenol in 100 ml of ethyl acetate, cooled to -5oC and add 45,3 g (0.22 mol) of N, N-dicyclohexylcarbodiimide. The reaction mixture is stirred 3 h at room temperature, dicyclohexylamine filtered off, the solvent evaporated in vacuum, the residue is crystallized in a mixture of ethyl acetate-hexane. The precipitation is filtered off. The output from 71.3 g (90%).

2. Obtain Boc-Ile-Glu-Trp-OH.

19,8 g (0.05 mol) of Boc-Ile-OFP dissolved in 100 ml of dimethylformamide and added with stirring a solution of 20 g (0.06 mol) Glu-Trp and 5.0 g (0.06 mol) of NaHCO in the water. The solution is stirred for 20 h at room temperature, then evaporated the solvent under vacuum. To the residue is added 200 ml of ethyl acetate and 200 ml of 2% aqueous solution of sulfuric acid, and mix. The organic layer is washed with a solution of sulfuric acid (2100 ml), saturated NaCl solution to pH 7, dried over anhydrous sodium sulfate, races who shat in a vacuum. The output of 20.5 g (75%),

3. Obtaining H-Ile-Glu-Trp-OH.

20.5 g of BOC-H-Ile-Glu-Trp-OH was dissolved in 150 ml of formic acid, stirred 3.5 h at 45oC and the solvent evaporated in vacuum. To the residue is added 200 ml of water and evaporated in vacuo again. The residue is poured a mixture of 300 ml of isopropanol and 200 ml of ether and incubated for 10 hours. The precipitate is filtered and dried in vacuum. The output of 15.3 g (75%).

Purification of the peptide is carried out using reversed-phase chromatography in the system acetonitrile-0.1% solution triperoxonane acid. Yield 13 g (85%).

A study of the physico-chemical properties of the peptide were obtained following its characteristics.

The primary structure is H-Ile-Glu-Trp-OH.

Brutto-formula - C24H30N4O4.

Molecular weight - 446,5 Da.

The exterior is white with a yellowish tint or gray powder.

The solvent is easily soluble in water, sparingly in alcohol, practically insoluble in chloroform.

U. F. - spectrum in the region of 250-300 mm has a maximum (2802) mm, shoulder (2872) mm

The biological activity of a new peptide H-Ile-Glu-Trp-OH

a) the Study of radiotherapy properties of the peptide and the impact on the population of hematopoietic cells, p is the current peptide in the regulation of haematopoiesis.

In the experiments used 2500 mice (CBAC57BL)F1 females at the age of 2 months and weighing about 20 g

Known close relationship of T-cells with hematopoietic predecessors (Poverenny A. , Semina o., Semenets T. et al. Exp. Hematal, 1980, 8. 1221; F. Monette, Wassa W. Exp. Hematel. 1981, 9, 1011). It was shown that the formation of colonies in the spleens of irradiated mice along with colony-forming unit spleen (CFU-C) participate and thymocytes exercising control of proliferation of hematopoietic precursor cells. It is installed in the test system, the essence of which consists in the selective removal of accessory T-cells from the bone marrow using a rabbit serum against brain of mice (SPGM) and replace them with other factors. A suspension of bone marrow incubated with SPGM in the following proportions: 0.1 ml of cells (2107) 0.1 ml serum, 0.1 ml of saline. After incubation for 1 h at 37oC, washing by centrifugation and resuspendable bone marrow cells injected lethally irradiated mice. When the colonies on the spleen registered a significant decrease in their number compared with control. Recovery of colony-is achieved by the introduction of additional mice thymocytes along with clicks the LASS="ptx2">

Instead of thymocytes in the above scheme, the mice receive an injection of 10 μg/kg of peptide for 30 min prior to the introduction of processed SPGM bone marrow suspension. For injection use saline solution containing about 0.001 wt.% the peptide. In table. 1 presents the results.

It is shown that the peptide contributes significantly to the increase in the yield of colonies and almost acts at the level of T-cells

Example 3.

This example describes the ability of the peptide to remove cytotoxic effect of irradiation (4 Gy) of stem and Mature cells of the hematopoietic system test recovery number of kariolou and size of the population of CFU-C bone marrow of the femur and blood leukocytes (1 mm3).

Apply 2 regimens mice irradiated with dose of 4 Gy, peptide, administered at a dose of 10 mg/kg intramuscularly. For injection use saline solution containing 0.005 wt.% the peptide.

a) the first treatment of mice peptide start typing immediately after exposure daily. There were groups of mice: control and irradiated at doses of 4 Gy, and experienced - irradiated at doses of 4 Gy and treated with peptide 1, 2, 3 and 4 times daily. After 4 h after the last injection of the peptide, the percentage of lymphocytes among them and the number of cells and the size of the population of CFU-C in the bone marrow of the femur (4,8 and 14 days). The results are presented in table. 2 and 3, Fig. 1.

As can be seen from the table. 2 up to 16 days after exposure to any one group experienced mice the number of leukocytes in the blood does not exceed the reference level. On the 16th day their number in all groups of treated mice was significantly higher than in control.

From table. 3 shows that the percentage of lymphocytes during the whole observation period treated mice more than in the control, and the increase in their absolute number occurs more rapidly. In mice that received the peptide more than 1 time, the number of lymphocytes in the blood during the period of greatest devastation pool of Mature cells (4 days after exposure) significantly exceeds their content in the control.

Example 4.

This example describes the possibility of stimulation of regeneration of populations of CFU-C bone marrow of mice subjected to irradiation with a dose of 4 G by intramuscular injection of the peptide.

For injection use saline solution containing about 0.001 wt.% the peptide.

With this purpose are selected from each group of at least 5 mice, hammer, bone marrow, preparing a suspension of cells and injected her lethally irradiated mice. After 9 days the number LASS="ptx2">

The results are presented in Fig. 1. It is noted that when injecting a peptide, the number of CFU-C in the bone marrow of irradiated mice, since 4 days, steadily growing much faster than the rate of the control mice. Especially effective peptide entered twice.

This navel, going all the way to division and maturation from stem cell to Mature functioning, lasting about 8 days, leaves of Mature cells in the blood that is marked as the increase in the number of cells on the 16th day. Therefore, treatment of irradiated mice peptide, started immediately after exposure to radiation, that is, before the devastation of the bone marrow, increases survival surviving hematopoietic precursor cells or their rate of proliferation.

b) a second treatment regimen peptide enter on the 3rd day after exposure to ionizing radiation, in the moment of maximum devastation pool of Mature leukocytes and bone marrow. Mice groups formed in the same manner as in the first treatment regimen. Selection of the blood passes through 4 h after the last injection, i.e., on the 6th day, and at 11, 14, 18, 21 days.

In table. 4 and 5 shows the data you provide is about the number of leukocytes during all periods of observation of the same order in the experimental and control groups, with the exception of mice that received the peptide 4 times: at 6 and 11 days (phase abortive rising, the number of cells is higher than in the control mice. Draws attention to the fact significant reduction in the level of these cells at 14 days and especially in the group that received 4 injections of the peptide. Apparently, this is due to the fact that under the influence of peptide surviving after irradiation CFU-C are faster path maturing to functioning cells quickly exhausted their pool and 14 days of receipt in the Mature blood cells from this pool is terminated, whereas the control mice still observed abortive rise in the number of cells. During the whole observation period, the proportion of lymphocytes among blood leukocytes significantly higher in mice treated with peptide than in the control. The absolute number of lymphocytes in the blood of the mice of the experimental groups is higher than in the control during the abortive rise (6-11 days after exposure) and 21 day recovery period, at the time of the second Decimator (14-18 days) number of lymphocytes in the experimental and control groups are equal.

The results presented in table. 6, reflect the process of regeneration of bone marrow from control and treated by the peptide according to the second scheme irradiated registriruetsya a significant increase in the number of leukocytes in the bone marrow experienced mice.

The influence of the peptide on the size of the population of CFU-C bone marrow has a positive effect on the 11th day in groups of mice treated with the peptide for 3 and 4 days, and 14 days in all groups the number of CFU-C more than in the control. The results are shown in Fig. 2.

Studied was the influence of the peptide on erythropoiesis. The number of erythrocytes in experimental and control groups do not differ, the level of hemoglobin in the treated mice recovered more intensively and to 11 days he reaches the norm, whereas in controls to 14 days.

In table. 7 presents the results.

Particularly effective in this case is four course of treatment.

Thus, the experimental results allow to conclude that the most effective treatment of irradiated mice by peptide was started on day 3 after exposure to ionizing radiation, that is, at the moment of maximum devastation bone marrow pool and Mature blood cells, is a four-day course of treatment.

Example 5.

This example describes the immunostimulatory properties of the peptide.

In this series of experiments was determined immunostimulirutuyu activity of the peptide with secondary immunodeficiency,the F1 males and females at the age of about 2.5 months and weighing about 20 g Irradiation is carried out on the apparatus "Beam-1 gamma-rays. Immunological activity determined by the method of Jerne (number of antibody productive cell - AOK). The number of T-cells in the spleen were determined by the method of spontaneous rosethorne with sheep erythrocytes (E-POK). The peptide is administered intramuscularly.

Mice were irradiated with dose of 2 Gy, the peptide is administered in an amount of 10 mg/kg according to the scheme (to determine the number of T-cells by the method of spontaneous rosethorne) : 1 times within 1 h after irradiation, 2 - fold after 1 h and 1 day after exposure, 3 times in 1 hour, 1 day and 2 days after exposure, 4 times in 1 hour, 1, 2, 3 days after irradiation (to determine the number of T-cells by the method of spontaneous rosethorne). For injection use saline solution containing of 0.003 wt,% of the peptide. Intact mice receiving peptide 3 and 4 times. The control group (irradiation of 2 Gy) at the same time receive injections of saline. After treatment with peptide 10 mice from each group are subjected to immunization with sheep red blood cells (EB) and 4-5 days after that, they determine the number of AFC in the spleen. The rest of the mice to determine the number of T-cells by the method of spontaneous rosethorne, the number of cells in timechange irradiated mice peptide (one and four injections) leads to a significant increase in the number of kariolou in the spleens per mg body mass, a slight rise in the number of kariolou in the thymus (3 and 4 incli) increase the number of antibody productive cells almost in 2 times, the peptide-treated irradiated mice in all groups registered an increase in the number of T-cells in the spleens, it significantly in the groups that received three or four injections

Immunostimulirutuyu activity of the peptide is observed in the treatment not only of irradiated mice, but also in the induction of humoral immune response in intact mice to EB (number of KLA increases 5-fold), although the number of T-cells does not change. Therefore, the peptide has a pronounced immunomodulatory activity that is observed with the introduction of its both irradiated and normal mice.

Example 6.

This example describes the determination of the toxicity of the peptide.

To determine toxicity to mice-males injected peptide, dissolved in saline solution, in the amount of 0.15 g/kg of body weight once, which is more than therapeutic dose, has a positive effect in post-radiation recovery of hematopoietic precursor cells in 15 thousand times. The second group of mice injected with the peptide at 10 µg/kg (therapeutic dose) daily for 5 days. C is the Rowan. At 14 days after injection of the peptide in 10 mice from each group put to death for the analysis of cellular systems. Determine the number of nucleated cells in the spleen and thymus (mg body mass), bone marrow, blood (in ml), number of erythrocytes and hemoglobin levels. In table. 10 and 11 shows the results.

As can be seen from the data presented in tables 14 days after administration of a single high dose of peptide there is an increasing number of kariolou in the spleen and thymus, after the introduction of the five-fold therapeutic dose is only significant elevation of nucleated cells in the thymus in mg of body weight. The values of the other identified parameters in both experimental groups did not differ from control. Thus, even superior therapeutic 15 thousand dose of the peptide does not cause the death of the mice, no toxic effects on the blood cells, spleen, thymus, bone marrow. The same applies to long-term (within 5 days) the application of the peptide. It should be noted that during the entire experience was not observed weight loss of mice, moreover it increased towards the end of the experience, on average, 2 g, as well as in the control group.

Thus, LD50peptide discover what was, does not cause the peptide and side effects.

Example 7.

This example describes the ability of the peptide to stimulate hematopoietic progenitor cells (splenic eksikalori) after exposure to ionizing radiation dose of 1 Gy. Analyzed the correlation between the number of peptide and the output of the colonies formed by the irradiation of the bone marrow. A suspension of bone marrow from healthy donors irradiated in vitro a dose of 1 Gy. and immediately impose lethally irradiated recipients, after 30 minutes, these mice also receive an injection of intravenous peptide at various concentrations (physiological solution). On the 9th day the animals kill and count the number of colonies on the spleen. The results of the experiments are given in table. 12.

Analysis of the dependences allows to conclude the following: the peptide at 10 µg/kg increases the output of the colonies of irradiated bone marrow almost to the level of the intact control, and in the amount of from 25 to 100 µg/kg in 2 times in comparison with the number of colonies of only irradiated bone marrow. Therefore, the peptide injected after injection of irradiated CFU-C, has the ability to reduce the damaging effects of irradiation dose the mules

H-Ile-Glu-Trp-OH

and pharmaceutical composition thereof having biological activity, can find application in medicine.

1. The peptide of formula H-Ile-GIu-Trp-OH, have influence in the regeneration of the hematopoietic and immune systems.

2. Pharmaceutical composition having impact on the regeneration of the hematopoietic and immune systems, including the active ingredient and pharmaceutically acceptable carrier, characterized in that the active ingredient it contains an effective amount of the peptide under item 1.

3. The composition according to p. 2, characterized in that it is made in the form of a solution.

4. The composition according to p. 3, characterized in that it is an injectable solution.

5. The composition according to p. 3, characterized in that it contains 0.001 to 0.01 wt.% the peptide.

 

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