Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Reduced antigenicity – reduced ability to bind complement – or...
Patent
1981-12-26
1984-10-02
Phillips, Delbert R.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Reduced antigenicity, reduced ability to bind complement, or...
2601125R, A61K 3700, C07C10352
Patent
active
044747616
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new peptides having biological properties, particularly a capacity of interacting with blood platelets and an ability to inhibit the aggregation of platelets induced by collagen or collagen containing substances.
It also relates to processes for preparing said peptides and lastly to pharmaceutical compositions containing them.
It is known that the vessel wall plays an important role in the maintenance of balance between haemmorrhage and thrombosis. The endothelial lining is thrombo-resistant, while the subendothelium is thrombogenic.
If the endothelium is pathologically or experimentally damaged, adhesion of the blood platelets to the subendothelial surfaces becomes possible.
The subendothelium comprises different constituents among which can be cited collagen, microfibrils, elastin, etc.
Studies have shown that notably subendothelial collagens and microfibrils are potent inducers of platelet adhesion, which adhesion is responsible for cellular activation with the release of numerous intraplatelet constituents, such as serotonin, and the involvement of many complex biochemical phenomena, which ultimately lead to the aggregation of the platelets.
All these mechanisms are so far but little known.
It is not known in particular which portion of subendothelial collagen, preferably of type III collagen is responsible for platelet adhesion and for the resulting subsequent platelet aggregation.
Recent studies have shown that a 149 aminoacid peptide (hereafter called .alpha..sub.1 (III)CB4) obtained by enzymatic cleavage of type III collagen, seems responsible for platelet adhesion, whereas the other derived peptidic fragments, resulting from the same enzymatic cleavage, are inactive as regards platelet adhesion (FAUVEL et al. Thrombosis Research, vol. 12, no. 5, p. 841-850).
Further studies and experiments on .alpha..sub.1 (III)CB4 peptide have been carried out .alpha..sub.1 (III)CB4 peptide was cleaved by chymotrypsin, hydroxylamin and trypsin to give three fragments, respectively designated as C2 (located between the 63rd and 149th aminoacyl residue of .alpha..sub.1 (III)CB4), and HA4 (located between the 76th and 149th aminoacyl residue of .alpha..sub.1 (III)CB.sub.4), and T6 (located between the 52nd and 84th aminoacyl residue of .alpha..sub.1 (III)CB.sub.4) (FAUVEL et al., Thrombosis Research, 16, p. 269-273).
The three peptidic fragments have been found to be active as regards platelet adhesion, and the attendant intracellular modification of the metabolism as well as release of intraplatelet constituents, particularly serotonin. A non isolated sequence: possibly representing the "adhesive site" of collagen towards platelets.
It was however found subsequently that the above adhesion active fragments inhibit the aggregation of platelets induced by the type III collagen molecule (FAUVEL et al. Thrombosis Research, 17, p. 285-287) thereby making any prevision on any possible relationship between adhesion and aggregation virtually impossible.
Applicants have now synthesized much smaller peptides, including a nonapeptide including the nine aminoacyl residues defined hereabove in the same order, which have unexpectedly been found to selectively inhibit the aggregation of platelets induced by collagen, yet while being free of the major phenomena that are consequent to adhesion, that is cellular activation and the attendant liberation of platelet constituents.
These small peptides are the first compounds that have been found to inhibit the aggregation of blood platelets as induced by collagen, yet without modifying the natural intracellular metabolism of the platelets, without causing cellular activation and liberation of intraplatelet constituents.
In addition, these peptides specifically inhibiting the interaction between platelet and collagen, are specific inhibitors of platelet aggregation induced by collagen with, suprisingly, no activity against the aggregation induced by other platelet aggregation inducers.
An object of the invention is to provide peptides enabling the minimum sequenc
REFERENCES:
J. M. Seyer, et al., Biochemistry 16, No. 6, (1977), 1158-1164.
Chem. Abstr. vol. 92, 1980, 55858r.
Chem. Abstr. vol. 92, 1980, 144153z.
The Journal of Biological Chemistry 250, No. 13, 5076-5081, 1975.
Biochemistry 1981, 20, 2621-2627.
Biochem. & Biophys. Research Commun., 1579-1585, 96, (1980).
The Journal of Biological Chem. 250, 1975, 7428-7434.
Biochemistry 10, (1971), 2076-2081.
C. R. Acad. Sc. Paris 4290, (Apr. 28, 1980), Serie D, 1115-1118.
Caen Jacques
Lefrancier Pierre
Legrand Yves
Choay S.A.
Phillips Delbert R.
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