A means of having immunostimulatory activity

 

(57) Abstract:

The invention relates to medicine, namely to new peptide means having immunostimulatory activity, and aims to expand their Arsenal and increase biological activity. It is proposed to use a new synthetic peptide of structural formula Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu as a means with immunostimulatory activity. Compared with the prototype peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu active 10 times smaller doses. The tool can be used in medicine for the prevention and treatment of a wide range of immunodeficient diseases of different etiology. The technical result - expanding Arsenal of tools to combat HIV. 6 table.

The invention relates to medicine, namely to new peptide means having immunostimulatory activity.

Known substances peptide having immunostimulatory activity. These include drugs, obtained from the thymus of animals, such as thymosin [1] , T-activin [2] , the adjuvant [3] , and isolated from bone marrow and Bursa fabritsiusa: mielopid, burcelin, Gamelin [4] . These drugs consist of complex substances peptide that Enya immune response. Use them as immunostimulatory funds is difficult due to the complexity of the methods of preparation, low output active substances, considerable variability in their physical and chemical properties, as well as due to the presence of unwanted side effects due to the presence of natural preparations of thymus ballast of high molecular weight components. It is preferable to use low molecular weight synthetic peptides. They are effective in very small doses and do not have harmful effects on the body.

Known synthetic peptides having immunostimulatory activity. These include the peptide Glu-Asp-Ser-Ser-Thr-Gly-Trp-Asp-OH (U.S. patent 4478828, 37/00 a 61 K, C 07 C 103/52, 1984); thymopentin Arg-Lys-Asp-Val-Thr (Goldstein G. , Audhya since . Thymopoietin to Thymopentin: Experimental Studies. Survey of immunologic Research. (1985), 4: suppl. 1, pp. 1-10); analogues thymopentin (patent EP 1450798, FROM 07 TO 7/64, 1985; U.S. patent 5013723 And 61 To 37/02, 1991); the peptide of General formula R-NH-CH-(-COOH)-

(CH2-)n-CO-X, where n = 1, 2, R is hydrogen, lower acyl or lower alkyl, X-heteroaromatic amino acid (RF patent 2142958, From 07 To 5/037, a 61 K 38/05, 1999); the peptide of the formula R-Arg-X-Y-Z-R1where R is hydrogen, acetyl, formyl; X is Proline, Y Is L-Ala, L-Asp, L-Val; Z - L-Val, L-Ala; R1IS H, OH, NH2, NH (CH3), N(CH3)21-L-Glx-L-Glx-L-Lys-R2where Glx is Gln or Glu (patent WO 94/09804, 37/00 a 61 K, 73/02, 07 K 5/00, 1994); the peptide Tyr-Gly (U.S. patent 5100663 And 61 To 37/02, 1992); a peptide having the formula L-Thr-L-Ala-L-Glx-L-Glx-L-Lys, where Glx is Gln or Glu (patent WO 95/12810 And 61 To 37/02, 07 K 7/06, 1993); the analogue of the hormone of the thymus, those having the formula: Leu-Glu-Asp-Gly-Pro-Lys-Phe-Leu (patent WO 95/01182 And 61 To 37/00, 37/02, 07 R 5/00, 7/00, 15/00, 17/00, 1995); peptide with immunomodulatory activity of H-Lys-Asn-Pro-Tyr-OH (U.S. patent 5980913, a 61 K 38/04, 1999); the Tripeptide Arg-Lys-Glu possessing immunostimulatory activity and acts primarily on T-cell immunity (U.S. patent 4874844, 07 K 5/08, 1989); the nonapeptide of the formula Glu-Asp-Ser-Ser-Ser-Thr-Gly-Trh-Asn-OH (U.S. patent 4478828, 37/00 a 61 K, 1984); the peptide of the formula a-b-C-And-D, where a is Lys or Arg, Lys or Arg, Asp or Glu, And Val or Tight, Thr, Dr. Thr or Phe (U.S. patent 4650788 And 61 To 37/02, 1987); a peptide consisting of the amino acid sequence of shed-glycol (U.S. patent 4399124, 37/00 a 61 K, 1983); the peptide of the formula A-X-Lys-Y-B, where a Is N, or the Tripeptide Arg-Ala-Arg, or Hexapeptide Glu-Lys-Arg-Arg-Ala-Arg, X and Y - arginine or glutamic acid,-HE, or the Tripeptide Arg-Ala-Arg (U.S. patent 5079231 And 61 To 37/02, 1992); similar serum thymic factor of General formula A-Gly-Gly-Ser-Asn-B-C-NH-R, where a is Glu, Gln, Ala-Lys-Ser or Glu-Ala-L the peptides (WO 98/30581, 07 K 7/06, 1998).

Known immunostimulatory agent timogen [5, 6] , synthesized based on a selection of thymalin by high performance liquid chromatography immunoactive faction, representing the dipeptide Glu-Trp. This substance is the technical essence and the achieved effect is closest to the proposed solution and its prototype. However, this peptide has low biological activity that requires the use of large doses of the drug and cause the appearance of undesirable side effects.

The present invention is directed to expanding Arsenal and increase biological activity means, having an immunostimulating action.

The solution of this problem is achieved by the fact that as a means of having an immunostimulating action, it is proposed to use the new synthetic peptide of structural formula Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu.

The peptide of the formula Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu was detected in the tissue of the Bursa fabritsiusa - the Central organ of the humoral immunity of birds, and later synthesized. The peptide was synthesized by standard methods of solid-phase synthesis by increasing peptide chain with N-to the om in comparison with timagenes, revealed its ability to stimulate the immune system. This is confirmed by the following examples.

1. The influence of the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu on the expression of E-receptors "trypsinisation" thymocytes. With the purpose of obtaining a suspension of lymphoid cells in the thymus of intact Guinea pigs male homogenized in medium 199. Then, the resulting suspension of thymocytes were treated with a proteolytic enzyme trypsin (Sigma), destroying a large part of E-receptors on the surface of cells to rabbit erythrocytes, resulting in a reduced percentage of cells detected in the reaction of rosethorne. In suspensions of intact thymocytes and thymocyte treated with trypsin, and identified the percentage of "active" T-lymphocytes (EA-ROCK) method rosethorne with rabbit erythrocytes [8, 9] .

Found that treatment with trypsin leads to a decrease of more than 2 times the number of thymocytes that have on the surface of E-receptors. The addition of a peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu at a concentration of 0.1-0.001 microg/ml and thymogen in the concentration of 0.1 and 0.01 μg/ml resulted in restoration of the number of E-receptors in lymphoid cells of the thymus (table. 1).

Thus, the minimum concentration at which declare cf is higher immunostimulirutuyu activity of the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu.

2. The influence of the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu on the expression of immunoglobulin receptors In lymphocytes. It is known that IgM is a marker of Mature b cells and is determined at the final stage antigennegative differentiation and proliferation of b-lymphocytes [10] . Lymphocytes were isolated from heparinized (25 U/ml) peripheral blood of patients with burns IIIB-IV degree 15-30% of the body surface, because you know that if you burn the sickness disturbed differentiation of lymphocytes in peripheral blood, there is a large number of immature or "zero" cells [11, 12] . Selected cells were incubated for 2 hours at a temperature of 37oWith full nutrient medium with the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu and timagenes in concentrations from 0.001 to 1 μg/ml, the Level of expression of IgM receptors was assessed by indirect membrane immunofluorescence using monoclonal antibodies CH2 ("Sorbent", Moscow) [13] .

Found that patients with burns of more than 1.5 times the reduced number of lymphocytes bearing surface IgM, which is probably related to a defect in the differentiation of lymphocytes in the bone marrow. The proposed peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu dose-dependently stimulates the expression of immunoglobulin cocktail recipes. what reavley only weak activity at a concentration of 1 µg/ml (table. 2).

Thus, the claimed means of synthetic peptide Thr-The-Ala-Glu-Glu-Arg-Gln-Leu increases the expression of IgM receptors In lymphocytes at doses 10 times smaller than timogen.

3. The influence of the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu expression differencirovannyh antigens of lymphocytes of patients with burns in vitro. To estimate the effects of the proposed drug on lymphocyte subpopulations was performed by indirect membrane immunofluorescence with monoclonal antibodies LT3, LT4, LT8, LT19 and LT21 to differentsirovannym antigens CD3, CD4, CDS, CD19 and CD21, respectively ("Sorbent", Moscow) [13] . Lymphocytes of patients with burns involving secondary immunodeficiency, allocated on the density gradient of ficoll-urografin. The obtained cell suspension was incubated with the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu and timagenes for 60 minutes at 37oWith full nutrient medium RPMI-1640 (Flow) supplemented with 5% fetal calf serum (Flow), 2 mm L-glutamine (Flow), 40 µg/ml gentamicin ("Pharmachem") and 5 mm HEPES-buffer. As control was used saline solution in an appropriate amount.

Found that patients with burns sharply reduced the number of all the studied subpopulations of lymphocytes, excluding CD8+-cells. Tim is the rotary was active at doses from 1.0 to 0.001 µg/ml Both tools are significant changes in the number of CD8+lymphocytes did not cause (PL. 3).

Incubation of lymphocytes burn patients with peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu leads to a significant increase in the number of CD19+and CD21+cells at a concentration of from 0.05 to 1 μg/ml, bringing these figures to normal, and the maximum activity of the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu observed in the concentration of 0.1 μg/ml At the same time known means timogen manifests its activity only at a concentration of 1 µg/ml (table. 4).

Thus, the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu increases the expression differencirovannyh antigens in doses 10 times smaller than timogen, which is a reflection of his high immunostimulatory activity.

4. The influence of the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu immune response in thymectomized rats (table. 5). The biological activity of the proposed drug was studied on the model thymectomized rats [14] . At three months of age produced a surgical removal of the thymus. A control group of rats was subjected to false operation. 2 months after surgery thymectomized animals were injected with the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu and timogen in doses of from 0.001 to 1 μg/kg body weight within Birmingham. Rats were immunized with sheep red blood cells and after 5 days was determined by the immune system.

It was determined that thymectomized rats reduced the titer of hemagglutinin on xenogeneic erythrocytes, reduced the number antitelomerase cells in the spleen and the number of leukocytes in the blood. With the introduction of the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu restored the immune response to thymusdependent antigen that is expressed in the increase of the titer of hemagglutinin and hemolysins, AOK, reduced number of white blood cells and increasing the mass of the spleen. The maximum activity of the proposed drug is manifested in a concentration of 0.1 µg/kg of body weight, while timogen has a similar effect at a concentration of 1 µg/kg body weight.

5. The influence of the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu immune response in bursectomised chickens. The specific biological activity of the inventive tool also studied in experiments in vivo in models of embryonic bursectomy [14] . It is known that the Bursa fabritsiusa the Central organ of the immune system of birds, analogous to that in mammals is missing. Bursa is antigenetically differentiation of b-lymphocytes and its removal is accompanied by disruption of this process. When this occurs vinozito, able to get involved in the immune response. Bursectomised chickens significantly stunted and almost completely killed after 7-8 weeks of life.

The embryonic bursectomy performed surgery on the 19th day of embryonic development, the control group of embryos at the same time subjected to a false operation playback of all stages of surgical intervention except for the removal of Bursa fabritsiusa.

Since months of age during the week bursectomised Chicks intramuscularly received the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu and timogen in doses of from 0.001 to 1 μg/kg body weight 1 time per day during the week. The control were bursectomised chickens that received saline in the same volume. Then birds were immunized with sheep red blood cells and after 5 days was determined by the immune system (table. 6).

It was established that embryonic bursectomised birds reduced immune response to the introduction of xenogeneic erythrocytes, this is reflected in the sharp decrease of the titer of hemagglutinin and hemolysins, antitelomerase of spleen cells. Bursectomised chickens reduced the body weight, spleen, observed radiation. Introduction peptide Trp-Tits, receiving the proposed facility, increased the number of leukocytes, increased body weight and spleen. The maximum activity of the peptide Thr-The-Ala-Glu-Glu-Arg-Gln-Leu registered in a concentration of 0.1 µg/kg body weight. A similar effect was achieved by the introduction of thymogen. The maximum activity of the latter was manifested only at a concentration of 1 µg/kg of body weight.

Thus, the results of experimental study of the proposed drug attest to its high immunostimulatory activity superior to that of known immunostimulant thymogen. Compared with timagenes the claimed peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu capable of stimulate immunity 10 times smaller doses. Reducing the dosage of an immunostimulating agent to achieve the same effect makes it possible to reduce the risk of side effects.

Thus, it was found that the peptide Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu has a pronounced immunostimulating action and may find application in medicine for the prevention and treatment of a wide range of immunodeficient diseases of various etiologies.

SOURCES OF INFORMATION

1. Goldstein, A. L. , on A. , Zatz M. M. et al. Purification and biological activity of thymosin, a hormone of the thymus gland // Proc. Nat. Acad. USA 1972. Vol. 69. N is, 1990. -52 C.

3. Mashkovsky M. D. Medicines. M. : Medicine, 1988, 2, 9 main, 168-175.

4. Kuznik B. I. Stepanov , A. C. , Tsybikov N. N. and other Effects of the polypeptides of the thymus gland, bone marrow and bags fabritsiusa on immunogenesis and hemostasis in neonatal thymectomized and embryonic bursectomised chickens // bul. the experts. biology and medicine. -1987. - 4. - S. 449-451.

5. Yakovlev, M. , Khavinson C. H. , Morozov Century, and other Comparative study of the biological activity of thymalin and synthetic peptide thymus // proc. Dokl. scient. proc. Biochemistry medicine", L. 1988, C. 217 - 218.

6. Khavinson C. H. , Sinkevich N. C. , Gray, S. C. Timogen. -SPb, 1991. -48 C.

7. Steward J. M. , Young, J. D. Solid phase peptide synthesis, San Francisco, 1969.

8. Nekam, K. , Fudenberg N. N. , Strelkanskas A. J. Identification of "activ" T-lymphocytes among effector cells in guinea pigs // Immunopharmacol. -1982-Vol. 5, 1. -P. 85-94.

9. Stadecker, M. J. , Bishop, G. , H. H. Wortis Rosette formation by guinea pig thymocytes and thymus derived lymphocytes with rabbit red blood cells // J. Immunol. -1973. Vol. 111, 6. -P. 1834-1837.

10. Ling, N. R. Immunoglobulin as a differentiation and clonal marker // J. Immunol. Methods. -1983. - Vol. 65. - P. 1-25.

11. P. Kolker, I. I. , S. Vishnevskaya, M. , Panov, Y. M. and other Content of T - and b-lymphocytes In patients with thermal burns // Clinically. medicine. -1985. - 7. -S. 87-93.

12. analogia. -1983. - 6. - S. 51-54.

13. Lymphocytes: Methods. TRANS. from English. Ed. j. Claus. -M. : Mir, 1990, 395 S.

14. Immunological methods / edited, Primes, TRANS. with it. A. P. Tarasova. - M. : Medicine, 1987, 472 S.

The peptide of the formula Trp-Tre-Ala-Glu-Glu-Arg-Gln-Leu with immunostimulatory activity.

 

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