Bradykinin analogs as selective thrombin inhibitors
AssigneeThe Regents of the University of Michigan
InventorsAlvin H. Schmaier, Ahmed A. K. Hasan
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Abstract
Thrombin-induced and ADP-induced platelet and other cell activation is inhibited without affecting thrombin's other proteolytic activity by administration of a bradykinin sequence related analogous peptide. Bradykinin analogs are peptides to which substitutions, additions or deletions have been made to the first four amino acids of the amino acid sequence of native bradykinin. The bradykinin analogs described inhibit .alpha.-thrombin-induced and ADP-induced platelet activation and secretion, inhibit .alpha.-thrombin-induced calcium mobilization, and prevent .alpha.-thrombin from cleaving its platelet receptor. The bradykinin analogs may comprise single- or multiple-chain peptides.
Claims33
A method of inhibiting thrombin-induced cell activation mediated by a thrombin receptor by inhibiting cleavage of the thrombin receptor on said cells comprising administering to an individual in need of such treatment an effective amount of a peptide, wherein said peptide has an amino acid sequence of the formula:
- X.sub.1 -Arg-Pro-Pro-Gly-X.sub.2
- wherein:
- X.sub.1 is zero amino acids or the segment Gly-Met-Ile-Ser-Leu-Met-Lys (SEQ ID NO:23), or an N-terminal truncation fragment of said segment;
- and
- X.sub.2 is zero amino acids or the segment Phe-Ser-Pro-Phe-Arg-Ser-Ser-Arg-lle (SEQ ID NO:24), or a C-terminal truncation fragment of said segment;
- provided that the peptide is not native bradykinin.
A method of inhibiting thrombin-induced cell activation mediated by a thrombin receptor comprising administering to an individual in need of such treatment an effective amount of a peptide, wherein the peptide has an amino acid sequence (D-Arg)-Arg-Pro-Hyp-Gly-Thi-Ser-(D-Tic)-Oic-Arg.
A method of inhibiting thrombin-induced cell activation mediated by a thrombin receptor by inhibiting cleavage of the thrombin receptor on said cells comprising administering to an individual in need of such treatment an effective amount of a peptide, wherein said peptide is comprised of one or more segments having the amino acid sequence X.sub.1 -Arg-Pro-Pro-Gly-X.sub.2 and the peptide has the formula:
- L-(X.sub.1 -Arg-Pro-Pro-Gly-X.sub.2).sub.n
- wherein:
- L is a linker comprising a covalent bond or chemical group;
- X.sub.1, which may be the same or different in each segment, is zero amino acids or the sub-segment Gly-Met-lle-Ser-Leu-Met-Lys (SEQ ID NO:23), or an N-terminal truncation fragment of said sub-segment;
- X.sub.2, which may be the same or different in each segment, is zero amino acids or the sub-segment Phe-Ser-Pro-Phe-Arg-Ser-Ser-Arg-lle (SEQ ID NO:24), or a C-terminal truncation fragment of said sub-segment;
- and
- n is an integer from two to twenty.
A method for preventing thrombin-induced platelet aggregation by inhibiting cleavage of a thrombin receptor on said platelets comprising administering to an individual in need of such treatment an effective amount of a peptide, wherein said peptide has an amino acid sequence of the formula:
- X.sub.1 -Arg-Pro-Pro-Gly-X.sub.2
- wherein:
- X.sub.1 is zero amino acids or the segment Gly-Met-Ile-Ser-Leu-Met-Lys (SEQ ID NO:23), or an N-terminal truncation fragment of said segment;
- and
- X.sub.2 is zero amino acids or the segment Phe-Ser-Pro-Phe-Arg-Ser-Ser-Arg-lle (SEQ ID NO:24), or a C-terminal truncation fragment of said segment;
- provided that the peptide is not native bradykinin.
A method for preventing thrombin-induced platelet aggregation by inhibiting cleavage of a thrombin receptor on said platelets comprising administering to an individual in need of such treatment an effective amount of a peptide, wherein said peptide is comprised of one or more segments having the amino acid sequence X.sub.1 -Arg-Pro-Pro-Gly-X.sub.2 and the peptide has the formula:
- L-(X.sub.1 -Arg-Pro-Pro-Gly-X.sub.2).sub.n
- wherein:
- L is a linker comprising a covalent bond or chemical group;
- X.sub.1, which may be the same or different in each segment, is zero amino acids or the sub-segment Gly-Met-lle-Ser-Leu-Met-Lys (SEQ ID NO:23), or an N-terminal truncation fragment of said subsegment;
- X.sub.2, which may be the same or different in each segment, is zero amino acids or the sub-segment Phe-Ser-Pro-Phe-Arg-Ser-Ser-Arg-lle (SEQ ID NO:24), or a C-terminal truncation fragment of said sub-segment;
- and
- n is an integer from two to twenty.
A compound having the formula:
- ##STR7## wherein the glutamic acid and lysine residues of said peptide are bonded through their respective side chains.
A compound having the formula:
- ##STR8##
A method for preventing platelet aggregation comprising administering to an individual in need of such treatment an effective amount of the peptide:
A method of inhibiting thrombin-induced cell activation mediated by a thrombin receptor comprising administering to an individual in need of such treatment an effective amount of a peptide selected from the group consisting of Arg-Pro-Pro-Gly-Phe (SEQ ID NO:20);
- Met-lle-Ser-Leu-Met-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-Ser (SEQ ID NO:12);
- Met-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-Ser-Ser (SEQ ID NO:
- 13);
- and
- Met-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-Ser-Ser-Arg-lle-Gly (SEQ ID NO:14).
A method of inhibiting thrombin-induced cell activation mediated by a thrombin receptor comprising administering to an individual in need of such treatment an effective amount of the peptide:
- ##STR9##
Dependencies are inferred from the claim text.