THROMBOLYTIC AGENTS IN DEVELOPMENT

The quest continues for thrombolytic agents with a higher thrombolytic potency, specific thrombolytic activity and/or a better fibrin select ivity. Several lines of research towards improvement of thrombolytic a gents are being explored, including the construction of mutants and va riants of plasminogen activators (PAs), chimaeric PAs, conjugates of P As with monoclonal antibodies, and PAs from animal or bacterial origin . Some of these new thrombolytic agents have shown promise in animal m odels of venous or arterial thrombosis and in pilot clinical studies. Such molecules include numerous mutants of tissue-type PA (t-PA) with prolonged in vivo half-life and/or resistance to protease inhibitors, and chimaeric PAs consisting of different regions of t-PA and of uroki nase-type PA (u-PA). Several molecular forms of the thrombolytic subst ance in the saliva of the vampire bat have been characterised and clon ed. Vampire bat PA exhibits 85% homology to human t-PA but lacks kring le 2 and the plasmin-sensitive cleavage site. A thrombolytic enzyme of 203 amino acids is present in the venom of a southern copperhead snak e. This polypeptide, termed fibrolase, is now produced by recombinant technology. Fibrolase does not activate plasminogen or protein C, but directly degrades the a and beta chains of fibrin and fibrinogen. Reco mbinant staphylokinase is not an enzyme, but it forms a 1 : 1 stoichio metric complex with plasminogen, which becomes active after conversion of plasminogen to plasmin. It is a potent and highly fibrin specific thrombolytic agent in animals and patients.