Lat peptides and their use in assays for identifying immunosuppressants
OwnerFrancois Cardinauxinventor
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Abstract
The invention relates to novel peptides and their use in assays for identifying novel immunosuppressants. More particularly the present invention provides methods and compositions for identifying compounds that will modulate the interaction of protein tyrosine kinase substrates with their intracellular ligands, as well as between their intracellular ligands and other members of the signaling pathway.
Claims11
A compound of formula I
- R1-Tyr-R2 (I)
- wherein
- R1 is HOOC(CH2)2CO— or R3-Asp- wherein R3 is hydrogen, an amino acyl residue or an oligopeptidyl residue;
- and
- R2 is an amino acid or an oligopeptide;
- with the proviso that compounds represented by SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4 are excluded.
A compound of formula IIa or IIb
- R4—Y1—(X6)a(X5)b(X4)c(X3)d(X2)eAspTyrX1′(X2′)r(X3′)q(X4′)p(X5′)o(X6′)n—NHCH(R6C(O)—R5 (IIa)
- HOOC(CH2)2CO-Tyr-X1′—(X2′)r—(X3′)q—(X4)p—(X5′)o—(X6′)n—NHCH(R6)C(O)—R5 (IIb)
- wherein
- each of X6, X5, X4, X3, X2, X1′, X2′, X3′, X4′, X5′and X6′ is an amino acid;
- Y1 is a linking group or single bond;
- R4 is hydrogen, a labelling group, C1-C8alkoxycarbonyl, Ra—C(O)—, Ra—OC(O)— or Ra—NHC(O)— wherein Ra is linear or branched C1-C8alkyl, carboxy-C1-C8alkyl, aryl or aralkyl wherein the aryl group is unsubstituted or substituted by halogen, C1-C4alkyl or C1-C8alkoxy;
- R5 is NR7R8 or OR9 wherein R7 and R8 independently are hydrogen, C1-C8alkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic residue, and R9 is hydrogen or C1-C8alkyl;
- R6 is an amino acid side chain;
- and
- (a) a, b, c, d and e are 1;
- (b) a is 0 and b, c, d and e are 1;
- (c) a and b are 0 and c, d and e are 1;
- (d) a, b and c are 0 and d and e are 1;
- (e) a, b, c and d are 0 and e is 1;
- or
- (f) a, b, c, d and e are 0;
- and
- (a′) n, o, p, q and r are 1;
- (b′) n is 0 and o, p, q and r are 1;
- (c′) n and o are 0 and p, q and r are 1;
- (d′) n, o and p are 0 and q and r are 1;
- (e′) n, o, p and q are 0 and r is 1;
- or
- (f′) n, o, p, q and r are 0.
A compound represented by SEQ ID NO:21, wherein Xaa is H3CC(O)—, and SEQ ID NO:12, wherein Xaa is L(+)-biotinyl-aminohexanoyl and SEQ ID NO:
- 25 wherein Xaa is L(+)-biotinyl-aminohexanoyl.
A method of screening for an inhibitor of ZAP-70 or Syk comprising
- (a) incubating the ZAP-70 protein and/or the Syk protein with a compound of formula I, adenosine 5′-triphosphate (ATP), and a test compound;
- and
- (b) assessing the ability of the test compound to moderate the interaction of the protein tyrosine kinases Syk and/or ZAP-70 with their substrate compared with the interaction resulting in the absence of the test compound.
An assay to identify an inhibitor to ZAP-70 and/or Syk comprising
- (a) incubating the ZAP-70 protein and/or the Syk protein with a compound of formula I, adenosine 5′-triphosphate (ATP), and a test compound;
- and
- (b) assessing the ability of the test compound to moderate the interaction of the protein tyrosine kinases Syk and/or ZAP-70 with their substrate compared with the interaction resulting in the absence of the test compound.
Dependencies are inferred from the claim text.