Design and synthesis of a kininogen-based selective inhibitor of thrombin-induced platelet aggregation.
Thrombin-induced platelet aggregation has been suggested to play an important role in reocclusion following thrombolytic therapy or angioplasty for treatment of myocardial infarction. We previously demonstrated that thrombin-induced platelet aggregation is indirectly mediated by intracellularly activated calpain expressed on the platelet surface through the cleavage of aggregin, a putative ADP-receptor, and that high molecular weight kininogen (HK), a naturally occurring thiol protease inhibitor, modulates thrombin-induced platelet aggregation. Considering the substrate specificity of calpain and the conserved sequence in HK, we studied selective inhibitors of thrombin-induced platelet aggregation by the affinity labeling approach with an S-3-nitro-2-pyridinesulfenyl (Npys) group. H-Phe-Gln-Val-Val-Cys (Npys)-Gly-NH2, which combines chemical and structural features of calpain substrate specificity and the conserved sequence in HK, selectively inhibited thrombin-induced platelet aggregation. It did not inhibit the aggregatory effects of other platelet agonists, and did not inhibit amidolytic activity of thrombin and thrombin-induced platelet shape change. The design and synthesis of such inhibitors could lead to the development of a new class of inhibitors that selectively block thrombin-induced platelet aggregation.
Matsueda
R
R
New Lead Research Laboratories, Sanko, Tokyo.
Umeyama
H
H
Puri
R N
RN
Bradford
H N
HN
Colman
R W
RW
D000595:Amino Acid Sequence; D002154:Calpain / Q000037:antagonists & inhibitors; D007704:Kininogens / Q000138:chemical synthesis* / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000494:pharmacology*
D007704:Kininogens; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C065586:3-nitro-2-pyridinesulfenyl; D013917:Thrombin; D002154:Calpain