"Mirror image" antagonists of thrombin-induced platelet activation based on thrombin receptor structure.
Platelet activation by thrombin plays a critical role in hemostasis and thrombosis. Based on structure-activity studies of a cloned platelet thrombin receptor, we designed two "mirror image" antagonists of thrombin and thrombin receptor function. First, "uncleavable" peptides mimicking the receptor domain postulated to interact with thrombin were found to be potent thrombin inhibitors. Second, proteolytically inactive mutant thrombins designed to bind but not cleave the thrombin receptor were found to be specific antagonists of receptor activation by thrombin. The effectiveness of these designed antagonists in blocking thrombin-induced platelet activation suggests a model for thrombin-receptor interaction and possible strategies for the development of novel antithrombotic agents.
Hung
D T
DT
Department of Medicine, University of California, San Francisco 94143.
Vu
T K
TK
Wheaton
V I
VI
Charo
I F
IF
Nelken
N A
NA
Esmon
N
N
Esmon
C T
CT
Coughlin
S R
SR
D000595:Amino Acid Sequence; D001665:Binding Sites; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D015539:Platelet Activation / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000187:drug effects*; D018179:Receptors, Thrombin; D011994:Recombinant Proteins / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D005343:Fibrinolytic Agents; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; D011994:Recombinant Proteins; D013917:Thrombin