Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-05-02
1999-11-30
Saunders, David
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530324, 530325, 530326, 530327, 530328, 530329, 530330, 530331, 530350, 530356, 530363, 530385, 530403, 514 12, 514 13, 514 14, 514 15, 514 16, 514 17, 435 721, 435371, 435372, A61K 3806, A61K 3808, A61K 3816, A61K 3839
Patent
active
059943114
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to adhesion peptides for modifying the adhesion capacity of eukaryotic cells between each other and their use to promote or inhibit the cell/cell adhesion of eukaryotic cells. The invention relates in particular to the use of the cell adhesion polypeptides in the manufacture of pharmaceuticals to influence the cell/cell interactions of eukaryotic cells.
The term "(cell) adhesion"/"cell adhesiveness" is used in the narrower sense to describe the way in which cells adhere to another, e.g. as a result of the binding of complementary membrane surface molecules. The term "adherence" is commonly used in the art of cell culturing for cells which bind in vitro to solid surfaces. The terms "(cell) adhesion" and "adherence" are often used synonymously.
The cells of the various tissues or organs of a multi-celled organism possess a specific function in a defined environment. Apart from a small number of exceptions, such as the cells circulating in the vascular system for example, eukaryotic cells are as a rule fixed firmly in place. This immobilisation is mediated by two kinds of adhesion, namely cell/cell interactions on the one hand, and cell/matrix interactions on the other. The intercellular contacts, i.e. cell/cell interactions (FIG. 1B) are supported in particular at the cellular basal membrane by a heterogeneous network of fibres, rather like scaffolding, which is referred to as the extracellular matrix (ECM), consisting of proteins, glycoproteins (for example: fibronectins, the collagens, laminin, thrombospondin and vitronectin) and other macromolecules associated with the basal membrane (for example: proteoglycanes and glucosaminoglucanes), i.e. by forming cell/matrix interactions (FIG. 1A). A reorganisation of these adhesion structures occurs for example in the course of repair processes, such as the healing of wounds, or in the formation and growth of tumours.
The two kinds of adhesion, i.e. the cell/cell and the cell/matrix interactions, are shown schematically in FIGS. 1A and 1B. From that illustration, it can be seen that the interaction between cells and the extra-cellular matrix is promoted by different types of structures, similar to the "lock and key principle". Cell/cell adhesion, on the other hand, mainly takes place through interaction between similar types of cell surface structures, i.e. by similar molecules with a receptor character.
Among the ECM factors which promote cell/matrix adhesion on the parts of the basal membrane, a particular role is played by fibronectins. In its native form, the fibronectin molecule is a dimer composed of identical sub-units with a relative molecular mass M.sub.r of 220 KD in each case, which are linked together via disulphide bridges. One feature that is particularly pronounced in fibronectin, as also on other proteinogenic ECM components, is its composition of short repeating amino acid sequence units. Several of these sequences, which are homologous--though not identical--to one another, for their part form clearly delimited domains in the individual fibronectin chains, and these domains facilitate binding to fibrin, collagen or heparin. Only one of these domains possesses the ability to bind to cells. The section of the sequence responsible for the ability of this fibronectin domain to adhere to cells was identified and sequenced by Pierschbacher et al. (Proc. Natl. Acad. Sci. USA 80 (1983) 1224-1227). This section contains the tetrapeptide "RGDS" (Arg-Gly-Asp-Ser). This recognition sequence was characterised by Pierschbacher and Ruoslahti (Nature 309 (1984) 30-33), by testing smaller and smaller synthetic peptides of the cell recognition domains with regard to their ability to promote cells' adhesion capacity. The RGD sequence (Arg-Gly-Asp) is essential in promoting the binding activity, whereas the amino acid serine in position 4 can also be replaced by other amino acids (Pierschbacher and Ruoslahti, loc. cit.).
The RGDX sequence has been found not only in the fibronectin molecule, but also in numerous other matrix proteins, th
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Doerschner Albrecht
Eichner Wolfram
Kock Katharina
Mielke Heiko
Beiersdorf AG
Saunders David
Tung Mary Beth
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