Oligopeptide having transformation growth factor (tgf-β) and oncostatin m (osm) towards fibroblast proliferation

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to bioengineering and specifically to obtaining biologically active substances of peptide nature, which have growth factor activity towards fibroblast proliferation and can be used in medicine. An oligopeptide of formula A-X1-X2-X3-X4-X5-B is obtained through in silico construction, where A is F; X1 is E, or Q, or S; X2 is N, or Q, or A, or G; X3 is K, or R, or T; X4 is K, or E, or is absent, X5 is K, or L, or is absent and B is OMe - methyl.

EFFECT: invention enables obtaining an oligopeptide with transformation growth factor (TGF-β) and oncostatin M (OSM) towards fibroblast proliferation, and expansion of the range of effective therapeutic agents with wound-healing effect, which take part in closing wounds during inflammation and cicatrisation.

4 dwg, 2 ex

 

The present invention relates to the field of Bioorganic chemistry, biochemistry and medicine, namely to biologically active substances peptide having the activity of growth factors to the proliferation of fibroblasts, and may find application in medicine, veterinary medicine, as well as in experimental biochemistry.

The fibroblast is the main specialized, widespread in the connective tissue cell that synthesizes and secretes the main components of the intercellular substance is a polysaccharide precursors of collagen, which are formed of collagen, elastic and reticular fibers. As the main cellular form of connective tissue in animals and human fibroblasts form of fibers and ground substance of this tissue, involved in the closure of wounds in inflammation and the development of scars.

The main growth factors involved in proliferation of fibroblasts and induce the synthesis of extracellular matrix proteins, are transforming growth factor TGF-β and oncostatin M (OSM).

TGF-β is a protein from the family of transforming growth factors that stimulate proliferation of fibroblasts, inducing the development of the epithelium and promotes angiogenesis. In studies [1] have shown that even short-term (30 min) the presence of TGF-β in culture cells induces long-term stimulation about what operacii cells in the direction of fibroblasts. This suggests that TGF-β is one of the main growth factors, which triggers a cascade reaction, leading to proliferation of fibroblasts and further to the synthesis of extracellular matrix proteins.

Oncostatin M - a cytokine that stimulates the growth of normal fibroblasts and is involved in the regeneration of wounds, limiting tissue defeat regulate the expression of acute phase proteins and protease inhibitors [2].

The present invention is to expand the Arsenal of effective therapeutic agents with wound healing properties involved in the closure of wounds in inflammation and the development of scars.

The main technical result that can be obtained by carrying out the present invention is the implementation of this assignment: the creation of oligopeptides having the activity of growth factors to the proliferation of fibroblasts.

In contrast to the production of pure protein (growth factor TGF-β and oncostatin M) synthesis of the claimed peptides is carried out on a simplified and inexpensive technology that reduces the cost of the drug affects its availability and, therefore, expands the possibilities of its application.

The main technical result is achieved through the creation of oligopeptides (number of peptides with similar kind of activity, distinguished only by the value of active is ti) General formula:

A-X1-x2-X3-X4-X5 -,

where

And represents Phe;

X1 represents Glu, Gln or Ser;

X2 represents Asn, Gln, Ala or Gly;

X3 represents Lys, Arg or Thr;

X4 represents Lys, Glu or is absent

X5 represents Lys, Leu or absent, and

In represents OMe,

with the activity of growth factors to the proliferation of fibroblasts.

In the formula Phe - phenylalanine, Glu is glutamic acid, Ser is serine, Asn - aspargine, Gln is glutamine, Gly is glycine, Lys is lysine, Arg is arginine, Thr is threonine, Leu is leucine, OMe - methyl. The dimensions of the oligopeptides, exhibiting this activity, ranging from three - to pentapeptides that explains the optimal size (compliance site of the receptor) and the preservation of conformational match the active center.

The formula proposed oligopeptides was revealed by the results of computer design binding sites of the transforming growth factor TGF-β and oncostatin M with receptors on the surface of stem cells. Computer design of binding sites of TGF-β and OSM with their receptors was performed using software system [3], performing computer modeling of the spatial structure of protein molecules and the design of low molecular weight compounds responsible for the biological function of a protein.

Nizes ewusie drawings constitute part of the description of the present invention and are included to further demonstrate certain aspects of the present invention. The present invention can be better understood by reference to one or more of these drawings in combination with the detailed description presented here are specific embodiments of the present invention.

The drawings show:

figure 1 - spatial structure of the protein TGF-β [4];

figure 2 - spatial structure of the protein TGF-β with identified functional site functional site dedicated);

3 - dimensional structure of the protein OSM [5];

figure 4 - spatial structure of the protein OSM identified with functional site functional site is highlighted).

Example 1

In silico design of functional site of TGF-β on the basis of the spatial structure of the protein TGF-β

To implement design and functional site of TGF-β was used a computer program.

The source data for the work was the primary and the spatial structure of proteins imported from the database Protein Data Bank [6]. In the database of the Bank conducted a search of the spatial structure of TGF-β. Result for computer design of selected spatial structure of TGF-β [4] (figure 1).

Next conducted a computer simulation, which allowed us to identify spatially contiguous amino acid residues located on the surface of the globule protein TGF-β and PR is taking part in the interaction of TGF-β to its receptor (figure 2). Based on these results, predicted the formula proposed oligopeptides.

Example 2

in silico design of functional site OSM based on the spatial structure of the protein OSM

To implement design and functional website OSM was used a computer program.

The source data for the work was the primary and the spatial structure of proteins imported from the database Protein Data Bank [6]. In the database of the Bank conducted a search of the spatial structure of OSM. Result for computer design of selected spatial structure of OSM [5] (figure 3).

Next conducted a computer simulation, which allowed us to identify spatially contiguous amino acid residues located on the surface of the protein globule OSM and participating in the interaction OSM with its receptor (figure 4). Based on these results, predicted the formula proposed oligopeptides.

The identified binding sites are structural analogues of epitopes specific for TGF-β (see example 1), which confirms the activity of the in silico predicted compounds in relation to proliferation of fibroblasts.

Presented in figure 2 and figure 4 data on computer simulation results, we can conclude that the claimed oligopeptides predstavljaetsja functional website TGF-β and OSM, involved in the binding with receptors on the surface of stem cells and stimulating the proliferation of fibroblasts. This connection can be used in medicine and veterinary medicine as a means to healing actions involved in the closure of wounds in inflammation and the development of scars.

Sources of information

1. Grotendorst, G.R. Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation / G.R.Grotendorst, H.Rahmanie, M.R.Duncan // The FASEB Journal. - 2004. - Vol.18. - P.469-479.

2. Wahl, A.F. Oncostatin M in the anti-inflammatory response / A.F.Wahl, P.M.Wallace // Ann. Rheum. Dis. - 2001. - Vol.60, No. .3. - P.75-80.

3. Shutov, I. Computer simulation of the spatial structure of protein molecules / Iveta, Limonnikova, Vpopovic // Chemistry, structure and function of biomolecules: abstracts of the reports. - Minsk : 2006. - .PR-162.

4. http://www.rcsb.org/pdb/explore.do?structureld=1KLA

5. http://www.rcsb.org/pdb/explore/explore.do?structureld=1EVS

6. http://www.rcsb.org/pdb/home/home.do

Oligopeptide having the activity of transforming growth factor (TGF-β) and oncostatin M (OSM) in relation to the proliferation of fibroblasts, the General formula
A-X1-x2-X3-X4-X5-In,
where a represents F;
X1 is E or Q, or S;
X2 represents N, or Q, or A, or G;
X3 represents K or R, or T;
X4 is a, or E, or is absent
X5 represents a K, or L, or is absent
In represents OMe,
where F is phenylalanine, E - glutam the new acid, S - series, N - asparagine, Q - glutamine, G is glycine, lysine, R is arginine, T - threonine, And alanine, L - leucine, OMe - methyl, the size of oligopeptides ranging from three to Pentapeptide.



 

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