SMTP (Stachybotrys microspora triprenyl phenol) enhances clot clearance in a pulmonary embolism model in rats

To select a potent SMTP congener for the evaluation of its action in vitro and in vivo, we tested several SMTP congeners with distinct structural properties for their effects on plasminogen activation. As a result, SMTP-7 (orniplabin) was found to have distinguished activity. Several lines of biochemical evidence supported the idea that SMTP-7 acted as a plasminogen modulator. SMTP-7 elevated plasma level of plasmin-α2-antiplasmin complex, an index of plasmin formation in vivo, 1.5-fold in mice after the intravenous injections at doses of 5 and 10 mg kg-1. In a rat pulmonary embolism model, SMTP-7 (5 mg kg-1) enhanced the rate of clot clearance ~3-fold in the absence of exogenous plasminogen activator. Clot clearance was enhanced further by 5 mg kg-1 of SMTP-7 in combination with single-chain urokinase-type plasminogen activator.Our results show that SMTP-7 is a superior plasminogen modulator among the SMTP family compounds and suggest that the agent enhances plasmin generation in vivo, leading to clearance of thrombi in a model of pulmonary embolism.The plasminogen/plasmin system plays a central role in blood clot lysis [1,2]. Plasminogen is a single-chain glycoprotein consisting of an N-terminal PAN domain, five homologous kringle domains, and a trypsin-like serine protease domain. Plasminogen is converted to the active enzyme plasmin by the specific cleavage of the Arg561-Val562 bond by tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). The binding of plasminogen to fibrin and cell surfaces, mediated by kringle domains in plasminogen, localizes fibrinolytic activity on fibrin and cell surfaces [3]. Plasminogen adopts a tight conformation due to an intramolecular interaction between a lysine residue (Lys50 and/or Lys62) in the PAN domain and a lysine binding site in the fifth kringle domain [4,5]. The tight conformation of the plasminogen molecule attenuates its activation and interaction with fibrin and cellular receptors [3,