Strategies for development of novel antithrombotics: modulating thrombin's procoagulant and anticoagulant properties.
Thrombin is a serine proteinase that can interact with a large number of diverse macromolecular substrates, which results in either a procoagulant or anticoagulant effect. These divergent properties are physiologically regulated by the endogenous protein thrombomodulin. This review summarizes recent work on a variety of methods used to exploit the allosteric nature of the enzyme. The procoagulant and anticoagulant functions of thrombin can be modulated by sodium binding, site-directed mutagenesis, and a small synthetic molecule. Modulation of thrombin's intrinsic properties represents a novel approach to the development of unique antithrombotic agents.
Hall
S W
SW
Department of Medicine, Stanford University Medical School, California 94305-5112, USA.
Gibbs
C S
CS
Leung
L L
LL
D000494:Allosteric Regulation; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry*; D000990:Antithrombin III / Q000494:pharmacology; D000991:Antithrombins / Q000737:chemistry*; D005343:Fibrinolytic Agents / Q000737:chemistry*; D006801:Humans; D011487:Protein Conformation; D015202:Protein Engineering; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000737:chemistry*; D018180:Thrombomodulin / Q000502:physiology
D000925:Anticoagulants; D000991:Antithrombins; D005343:Fibrinolytic Agents; D018180:Thrombomodulin; D000990:Antithrombin III; D013917:Thrombin