Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Patent
1991-10-17
1993-07-06
Griffin, Ronald W.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
530330, 424 11, 435 23, 435 24, 435975, 436804, C07K 506, C07K 508, C07K 510, C07K 308, C12Q 138, C12Q 156
Patent
active
052255328
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates, by way of novel industrial products, to the bipeptide compounds of formula I below. It further relates to their method of preparation and to their use in the field of the assay of enzymes belonging to the group comprising the proteases and peptidases, in particular as substrates in the field of the quantitative assay of such enzymes, especially the enzymes belonging to the class E.C. 3.4.4 (now the new class "E.C. 3.4.21" as defined in the work "Enzyme Nomenclature", Elsevier Scientific Publishing Company, Amsterdam 1973, pages 238 et seq.).
PRIOR ART
The enzymes belonging to the class referred to above are known to be substances which cleave the amide linkages of the protein or peptide backbone at the carboxyl group of Arg, Lys, Orn and His residues. This cleavage mechanism is well known to those skilled in the art and is amply exemplified in the documents of the prior art cited below.
The currently used substrates for enzymes belonging to said class are essentially tri- or tetrapeptide compounds whose N-terminal end is generally substituted by a blocking group such as benzoyl, benzyloxycarbonyl, t-butoxycarbonyl, t-amyloxycarbonyl, tosyl, acetyl or the like and whose C-terminal end is amidated by an aminated group which can be a radioactive radical or a radical, especially a p-nitroaniline group, capable of imparting coloration or fluorescence before or (preferably) after cleavage. Reference is made in this connection to documents FR-A-2 546 163, FR-A-2 372 798, EP-A-0 004 256, U.S. Pat. No 4,508,644, U.S. Pat. No. 4,448,715, FR-A-2 471 411, FR-A-2 317 280 and FR-A-2 459 226.
It is found that the peptide derivatives known in the prior art have little affinity for water. They have a low solubility or dispersibility in water; consequently, it is sometimes necessary to add an organic solvent to make them usable. The systems comprising mixed solvents are scarcely compatible, in general terms, with biological media: they cause either a decrease in the activity of the substrate or, in certain cases, a deterioration in the enzyme which it is desired to assay. Furthermore, the low affinity of these substrates for water causes a decrease in the sensitivity of the enzyme assay methods.
FR-A-2 546 163 cited above has disclosed a technical solution for improving the solubility of enzyme substrates in water, wherein the peptide contains a polyhydroxycarbonyl group on the N-terminal end.
Also, EP-A-0 025 190 has disclosed a polypeptide compound comprising a polyethylene glycol residue monoetherified by an alkyl group (cf. page 8, lines 6-8), namely the product of the formula glycol residue with a molecular weight of the order of about 600.
Finally, EP-A-0 280 160 has disclosed dipeptide substrates whose N-terminal end contains an alkoxycarbonylalkylenecarbonyl radical such as the methoxymalonyl radical.
SOLUTION ACCORDING TO THE INVENTION
According to the invention, a novel technical solution is recommended which differs from that proposed by FR-A-2 546 163, on the one hand, and that envisaged by EP-A-0 025 190, on the other, in that it uses a compound comprising two monoamino acid or peptide chains which are each bonded by their N-terminal end to a divalent polyalkylene glycol group via a carbonyl bridge, CO.
More precisely, this novel technical solution is based on choosing a polyalkylene glycol group belonging to the group consisting of polyethylene glycols and polypropylene glycols, which is bonded to two monoamino acid chains or two peptide chains, each O-terminal end of the polyalkylene glycol residue being joined via a CO group to the N-terminal end of a monoacid or peptide chain so as to impart the solubility or dispersibility in water which is necessary for the sensitivity of enzyme assays. The fact that the polyalkylene glycol residue is bonded to two chains increases the sensitivity of the assay.
SUBJECT OF THE INVENTION
According to the invention, novel compounds are recommended which belong to the group consisting of amino acids and peptides
REFERENCES:
patent: 4409140 (1983-10-01), Smith et al.
Martinoli Jean-Luc
Quentin Gerard
Griffin Ronald W.
Serbio
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