SARUPLASE - BACKGROUND AND BIOCHEMISTRY

Prourokinase, also termed single-chain urokinase-type plasminogen acti vator (scu-PA), is the natural precursor of the two-chain plasminogen activator urokinase (tcu-PA). Prourokinase was first described in 1973 . The remarkable properties of scu-PA, such as increased fibrinolytic activity ii treated with plasmin, persistency of its activity in plasm a, and its ability of fibrin-specific action, raised interest in its u se as a thrombolytic agent. Since natural sources are not suitable for commercial exploitation, production of scu-PA requires the use of rec ombinant gene technology. In contrast to prourokinase from natural sou rces, scu-PA from recombinant bacteria is unglycosylated and was named 'saruplase'. The protein structure of saruplase complies with that of natural scu-PA. It consists of a single peptide chain of 411 amino ac ids (MW: 46344 Da) arranged in three protein domains. Saruplase is con verted to the fully active two-chain proteinase (tcu-PA) by a single p eptide cleavage catalyzed, for example, by plasmin. Although structura lly related, saruplase differs from other plasminogen activators, such as natural urokinase or tissue-type plasminogen activators, in functi onally relevant details. It generates plasmin by a positive feedback c ycle which can be triggered by minute initial activities and may contr ibute to fast action. It combines properties of a proenzyme and an enz yme, as it is not inhibited in plasma but appears to be active enough to trigger plasmin generation. The ability to lyse clots without syste mic fibrinogen breakdown has been confirmed in various pharmacological models. The fibrin-selectivity of saruplase must be different from th at of tissue-type plasminogen activators, since scu-PA does not bind t o fibrin. This property of scu-PA is explained by its preference for a ctivation of fibrin-bound over plasmatic plasminogen, probably support ed by deficient inhibitor capacity at the fibrin clot site. if rapid a nd complete clot lysis is to be achieved, e.g., in treatment of acute myocardial infarction (AMI), saruplase doses are required which can le ad to systemic fibrinogen degradation. This is considered to reflect a n acceleration of overall plasminogen activation rather than a loss of saruplase's preference of action. The paradigm of fibrin selectivity has not met all its claims in practice. There is no proof of a correla tion between bleeding and fibrinogen decrease. Further, binding to fib rin may affect the thrombolytic activity of a plasminogen activator, s ince it prevents penetration into the clot matrix. In conclusion, saru plase is a recombinant fibrinolytic agent which is related to other pl asminogen activators, but is unique in its structure and properties. T his justifies regarding saruplase as a promising modern thrombolytic a gent.