Serum glycoprotein that has biological activity in midget doses

 

(57) Abstract:

The invention relates to preparative and process biochemistry for the production of biologically active chemical compounds, protein product used in cell biology and in medicine and veterinary medicine. The subject of invention is a glycoprotein isolated from the serum of animals and humans, characterized by the following formula N-terminal fragment: R-Asn-Thr-Pro-Lys-Leu-Gly-Ile-Ala-Ala-Ala-Phe-Lys, where R is the residue of the oligosaccharide, the General formula (Man)3-5- (GlcNAc)2, Man - mannose residue, Glc NAc - N-acetylglucosamine. Serum glycoprotein of this structure has biological activity in midget doses at concentrations of 10-14-10-19M is the Molecular mass of 12.5 kDa. 6 table.

The invention relates to biologically active compounds and can be used in cell biology, clinical medicine and veterinary medicine.

Glycoproteins are conjugated to proteins or protein containing in addition to the protein part of nonprotein organic or inorganic component may be associated with polypeptides chain covalently, heteropolar or koorde be submitted neutral sugars (galactose, mannose, fucose), amino sugars ( N-acetylglucosamine, N-atsetilgalaktozamin or acid derivatives of monosaccharides.) (H.-D. Jakubke, X. Escaut "Amino acids, peptides, proteins M., the World. 1985, S. 345).

Glycoproteins are common in nature: these are the most important components of blood serum (immunoglobulins, transferin and others), the group of substances of blood antigens many viruses (influenza, measles, and others), some hormones, lectins, enzymes.

A large group of glycoproteins are lectins, protein part of the molecule which is characterized by the absence of sulfur-containing amino acids and a high content of residues serine and threonine, through which the binding of the carbohydrate component of the lectin molecules with the polypeptide chain. The average carbohydrate content of lectins is about 5%, their composition is mainly limited to residues of galactose, mannose, fucose, N-acetylglucosamine (see ibid. X.-D. Jakubke, X. Escaut "Amino acids, peptides, proteins M., the World. 1985, S. 428 - 429).

From the FVO and Ceneva P. falciparum isolated and studied homogeneous glycoprotein with a molecular mass of 56 kDa, the value of the isoelectric point of which is in the field of pH 5.5 containing carbohydrate portion of N-acetylglucosamine with a molecular mass of 5 are 300 kDa, the value of the isoelectric points in the pH of 2.5 to 5.0, the ratio of protein and carbohydrate parts (by weight) of 50:50 to 80:20, containing the carbohydrate portion of the remains of fucose, ribose, arabinose, xylose, mannose, galactose, glucose and glucosamine, and in the protein part of the remains of aspartic and glutamic acid, threonine, serine, Proline, glycine, alanine, cysteine, valine, methionine, cystathionine, isoleucine, leucine, tyrosine, phenylalanine, tryptophan, ornithine, lysine, histidine, arginine (US, 4663438, class. C 07 K 15/14, 1987).

An object of the invention is to obtain a peptide having biological activity in ultra-low doses (at concentrations of 10-14- 10-19M).

This technical result is achieved by the new structure of glycoprotein isolated from the serum of animals and humans, namely the structure of N-terminal fragments:

R-Asn-Thr-Pro-Lys-Leu-Gly-Ile-Ala-Ala-Ala-Phe-Lys,

where R is the residue of the oligosaccharide General formula

(Man)3-5- (GlcNAc)2-

Map - mannose residue,

GlcNAc - residue N-acetylglucosamine.

Serum glycoprotein (SGP) the above formula has a molecular mass (MM) of 12.5 kDa and contains about 50 wt.% residues of carbohydrates. C is here after boiling for 30 minutes, after exposure to 6 M urea solution, a saturated solution of ammonium sulfate. EGR is not subject to the action of proteolytic enzymes (trypsin, chymotrypsin, pepsin, pronase).

Study the primary structure of the SGP has caused certain difficulties in connection with the fact that the N-terminal amino acid of its polypeptide chain was closed (SGP does not react with tonsilloliths); EGR is not affected by the action of glycopeptides and endoglycosidase. Therefore, for analysis of the primary structure of the SSA method has been selected deglycosylation using triftoratsetata. This method allows to hydrolyze peripheral remnants of carbohydrates without affecting intactness peptide part of the molecule.

The study found no products of hydrolysis of the protein part of the EGR with a simultaneous reduction of the MM by an amount corresponding MM carbohydrate components of the EGR. After hydrolysis EGR is reduced to 5-7 MM kDa.

Determination of N-terminal amino acid sequence was carried out by an automatic method of Edman after applying the homogeneous peptide on the membrane "Immobilon".

The sequence of amino acids found the following:

R-Asn-Thr-Pro-Lys-Leu-Gly Detected oligosaccharide General formula:

(Man)3-5- (GlcNAc)2-

Comparison of N-terminal amino acid sequence of EGR with the existing structures in the data Bank on the structure of proteins and peptides (Suissproe) showed no homology with known proteins.

The invention is illustrated in 9 examples, and 6 tables.

Example 1. The selection of the glycoprotein from bovine serum.

To 5 l of blood serum was added under stirring 3550 g of dry ammonium sulfate at pH 8.0. After keeping the mixture for 4 hours was centrifuged at 10000 g for 15 min, the precipitated protein was removed, the supernatant was collected and were dialyzed against distilled water until complete removal of ammonium ions, and then freeze-dried and pererestorani in distilled water to a volume of 0.5 liter To the resulting solution was added with stirring 355 g of dry ammonium sulfate at pH 8.0, withstood the mixture for 4 hours at 4oC, then centrifuged at 10,000 g for 15 minutes. Supernatant were dialyzed against distilled water until complete removal of ammonium ions, and then freeze-dried.

Liofilizovannye the supernatant fraction was dissolved in 20 ml of a solution containing 10-3M calcium chloride and 10-3M calcium chloride and 10-5M manganese chloride. The elution of glycopeptide spent a 0.1 M solution of alpha-Metalmania containing 10-3M calcium chloride and 10-5M manganese chloride, within 24 hours. The eluate was collected, were dialyzed against distilled water and freeze-dried. Got 0,55 mg

The resulting preparation in the study represented a homogeneous glycoprotein - poorly painted in cream color, fine powder, had an isoelectric point in the pH regions 4,6-4,7, factor mobility in a 7.5% wage polyacrylamide gel (PAG) - 0,01 - 0,02, showed biological activity at concentrations of 10-14- 10-19M, MM and 12.5 kDa.

Example 2. Receiving glycoproteins from serum of Wistar rats.

To 0.2 l of serum was added under stirring 142 g of dry ammonium sulfate at pH 8.0. After keeping the mixture for 4 hours was centrifuged at 10000 g for 15 min, the precipitated protein was removed, the supernatant was collected and were dialyzed against distilled water until complete removal of ammonium ions, and then freeze-dried and pererestorani in distilled water to a volume of 0.05 l To the resulting solution were added when premedieval at 10,000 g for 15 minutes. Supernatant were dialyzed against distilled water until complete removal of ammonium ions, and then freeze-dried.

Liofilizovannye the supernatant fraction was dissolved in 20 ml of a solution containing 10-3M calcium chloride and 10-5M manganese chloride, was applied for 24 hours on a column (100 x 10 mm) with sorbent 4B SEF - Con A. the Column was washed for 4 hours with a solution containing 10-3M calcium chloride and 10-5M manganese chloride. The glycoprotein elution was performed with 0.1 M solution of alpha-Metalmania containing 10-3M calcium chloride and 10-5M manganese chloride, within 24 hours. The eluate was collected, were dialyzed against distilled water and freeze-dried. The resulting preparation in the study represented a homogeneous glycoprotein - poorly painted in cream color, fine powder, had an isoelectric point in the pH regions 4,6-4,7, factor mobility in a 7.5% wage polyacrylamide gel (PAG) - 0,01 - 0,02, showed biological activity at concentrations of 10-14- 10-19M MM to 12.5 kDa.

Example 3. Receiving glycoprotein from the blood serum of dogs.

To 0.2 l of serum was added under stirring 142 g dry what, the precipitated protein was removed, the supernatant was collected and were dialyzed against distilled water until complete removal of ammonium ions, and then freeze-dried and pererestorani in distilled water to a volume of 0.05 l To the resulting solution was added with stirring 35.5 g of dry ammonium sulfate at pH 8.0, withstood the mixture for 4 hours at 4oC, then centrifuged at 10,000 g for 15 minutes. Supernatant were dialyzed against distilled water until complete removal of ammonium ions, and then freeze-dried.

Liofilizovannye the supernatant fraction was dissolved in 20 ml of a solution containing 10-3calcium chloride and 10-5M manganese chloride, was applied for 24 hours on a column (100 x 10 mm) with sorbent 4B SEF - Con A. the Column was washed for 4 hours with a solution containing 10-3M calcium chloride and 10-5M manganese chloride. The glycoprotein elution was performed with 0.1 M solution of alpha-Metalmania containing 10-3calcium chloride and 10-5M manganese chloride, within 24 hours. The eluate was collected, were dialyzed against distilled water and freeze-dried. The resulting preparation in the study represented a homogeneous glycoprotein - poorly obrashaitesy 7.5% wage polyacrylamide gel (SDS page) - 0,01 - 0,02, showed biological activity at concentrations of 10-14- 10-19M, MM and 12.5 kDa.

Example 4. Receiving glycoproteins from serum of a horse.

To 2 l of blood serum was added under stirring 1420 g of dry ammonium sulfate at pH 8.0. After keeping the mixture for 4 hours was centrifuged at 10000 g for 15 min, the precipitated protein was removed, the supernatant was collected and were dialyzed against distilled water until complete removal of ammonium ions, and then freeze-dried and pererestorani in distilled water to a volume of 0.5 liter To the resulting solution was added with stirring 355 g of dry ammonium sulfate at pH 8.0, withstood the mixture for 4 hours at 4oC, then centrifuged at 10,000 g for 15 minutes. Supernatant were dialyzed against distilled water until complete removal of ammonium ions, and then freeze-dried.

Liofilizovannye the supernatant fraction was dissolved in 20 ml of a solution containing 10-3M calcium chloride and 10-5M manganese chloride, was applied for 24 hours on a column (100 x 10 mm) with sorbent 4B SEF - Con A. the Column was washed for 4 hours with a solution containing 10-3M calcium chloride and 10-5M chlorite is aristovo calcium and 10-5M manganese chloride, within 24 hours. The eluate was collected, were dialyzed against distilled water and freeze dried.

The resulting preparation in the study represented a homogeneous glycoprotein - poorly painted in cream color, fine powder, had an isoelectric point in the pH regions 4,6-4,7, factor mobility in a 7.5% wage polyacrylamide gel (PAG) - 0,01 - 0,02, showed biological activity at concentrations of 10-14- 10-19M MM to 12.5 kDa.

Example 5. Receiving glycoprotein from human serum.

To 2 l of blood serum was added under stirring 1420 g of dry ammonium sulfate at pH 8.0. After keeping the mixture for 4 hours was centrifuged at 10000 g for 15 min, the precipitated protein was removed, the supernatant was collected and were dialyzed against distilled water until complete removal of ammonium ions, and then freeze-dried and pererestorani in distilled water to a volume of 0.5 liter To the resulting solution was added with stirring 355 g of dry ammonium sulfate at pH 8.0, withstood the mixture for 4 hours at 4oC, then centrifuged at 10,000 g for 15 minutes. Supernatant were dialyzed against distilled water to complete the Yali in 20 ml of solution, contains 10-3M calcium chloride and 10-5M manganese chloride, was applied for 24 hours on a column (100 x 10 mm) with sorbent 4B SEF - Con A. the Column was washed for 4 hours with a solution containing 10-3M calcium chloride and 10-5M manganese chloride. The glycoprotein elution was performed with 0.1 M solution of alpha-Metalmania containing 10-3M calcium chloride and 10-5chloride of manganese, within 24 hours. The eluate was collected, were dialyzed against distilled water and freeze dried.

The resulting preparation in the study represented a homogeneous glycoprotein - poorly painted in cream color, fine powder, had an isoelectric point in the pH regions 4,6-4,7, factor mobility in a 7.5% wage polyacrylamide gel (PAG) - 0,01 - 0,02, showed biological activity at concentrations of 10-14- 10-15M, MM and 12.5 kDa.

Example 6. The action of the glycoprotein from the blood serum of rats on the proliferation of peripheral blood lymphocytes of human culture.

Lymphocytes in human peripheral blood were cultured according to the method of His (Moorchead et al. 1960). 1 ml of whole or pooled blood incubated with 4 ml of medium 199 and 1 ml serum large regininha. Glycoprotein was added in Wednesday, 48 hours after the start of culturing cells in the control vials was added an appropriate volume of saline. The cells were fixed 72 hours after the start of cultivation. For 2.5-3 hours before fixation in the vials was added colchicine to a final concentration of 0.1 mg/ml Before fixing the cells were besieged by centrifugation and incubated in hypotonic solution at 37oC for 20 min and fixed with a mixture of methanol and acetic acid (3 : 1). From the obtained cell suspension was prepared smears and stained them with dye from the Institute. Effect of glycoprotein on the proliferative activity of lymphocytes was assessed by the change in the number of metaphases in the cells compared with the control. In each experimental and control variant was calculated not less than 10,000 cells. The experiment was repeated three times.

Data are combined in the table. 1.

Conclusion: in the presence of serum glycoprotein at a concentration of 10-14- 10-19M number of metaphases in the cells in the culture of lymphocytes was increased in 2.5 - 6.5 times compared with the control. Therefore, the effects of the glycoprotein dramatically increases the proliferative activity of cells.

Example 7. Action Gligor CLASS="ptx2">

The study was performed on male hybrid mice CBA x C57BI weighing 20 to 22 g In each version of the experiment and in the control was taken 3 animals. Glycoprotein at concentrations of 10-12and 10-16M was administered to the animals intraperitoneally in a volume of 0.5 ml for 1 animal. Control animals were injected with 0.5 ml of medium 199. 3 hours prior to slaughter all animals were injected intraperitoneally with 0.2 ml of 0.04% aqueous solution of colchicine. Mice were scored after 4, 6, 12, 24 and 32 hours after administration of the drug. Bone marrow was extracted from both femurs and incubated in 0.5% th KCl solution for 7 min at 37oC. Sedimentation centrifugation, the cells were fixed with a mixture of methanol and glacial acetic acid (3:1). From the obtained cell suspension of bone marrow smears were prepared and stained with the dye from the Institute. The drugs were calculated the number of metaphases in 10,000 cells. The number of experiments - 3. The results are shown in table 2.

Conclusions: starting from 4 and up to 32 hours after administration of glycoprotein has established a significant increase in the number of metaphases in bone marrow cells. The magnitude of the biological effect varied from 30 to 90% and was maximal at 18 - 24 hours of exposure.

Table 2 shows the effects of the glycoprotein of the glycoprotein on the growth of fibroblast culture.

Experiments were performed on transplantable lines of fibroblasts Chinese hamster, strain 11 dii FAF-28, clone 431. Monoclonal culture was grown at 37oC in medium 199, mixed (1:1) with medium Needle with the addition of 20% inactivated bovine serum and antibiotics in the atmosphere (6% CO2in the air). Analyzed the influence of the peptide on growth of the fibroblasts and the efficiency of cloning.

When analyzing the dynamics of growth of culture cells were planted in a growth medium (1.2 x 106cells/ml) and after 1-2 days on a logarithmic growth phase produced a change of environment and added glycoprotein. Then the cells were removed with trypsin every 24 hours for 3-5 days and counted the number of viable. Served as control culture, inkubirovanie in the growth medium without glycoprotein. To determine the viability of the cells were stained with 1% solution Trypanosoma blue.

Effect of glycoprotein on the effectiveness of clone fibroblasts was assessed by the number of colonies grown in the cups KARELA on day 7 after seeding (400 cells per Cup).

Glycoprotein was added to the culture in log phase growth for 24 hours prior to the cloning of cells. The effectiveness of seeding in control (growth medium without gigliati study of the effect of the glycoprotein from the blood serum of cattle on the dynamics of the number of fibroblasts Chinese hamster in the culture and performance of their cloning in vitro.

Example 9. Effect of glycoprotein from the blood serum of cattle on the healing of wounds.

The analysis was carried out on male rats weighing 180-250 g

Animals under anesthesia produced linear cut the entire thickness of the skin on the back. An incision of approximately 5 cm Wound was sealed surgical 3-4 brackets. Treatment was started immediately after the operation applique drugs to the wound 2 times a day. The treatment duration is 2 days. Animals were monitored for 5 days. On the 6th day anesthetized animals cut out areas of skin with scar tissue the size of 1 x 1 cm and produced their tensiometry. therapeutic effect of the drugs was judged by weight of the cargo in the tensiometer at the moment of rupture of the scar tissue. The results are presented in table 5.

In tables 5 and 6 show the results of the study wound healing actions of glycoproteins from serum, conducted on experimental animals

The results of biomedical tests conducted in MNTK "eye microsurgery"; research Institute of eye diseases. Helmholtz; Institute of pharmacology RAMS, showed complete security of serum glycoprotein - absence of acute and chronic toxicity.

Jle-Ala-Ala-Ala-Phe-Lys,

where R is the residue of the oligosaccharide General formula (Man)3-5(GlcNAc)2-Man - mannose residue, GlcNAc - residue N-acetylglucosamine possessing biological activity at extremely low doses.

 

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