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

Abstract

BackgroundStachybotrys microspora triprenyl phenols (SMTPs) are a novel family of small molecules that enhance both activation and fibrin-binding of plasminogen. While their effects on fibrinolysis have been characterized in vitro, little is known about their activity in vivo with respect to plasminogen activation and blood clot clearance.ResultsTo 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.ConclusionsOur 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.

Efficacy of SMTP‐7, a small‐molecule anti‐inflammatory thrombolytic, in embolic stroke in monkeys

“…These declines can be the consequences of systemic activation of plasminogen. The action of SMTP‐7 is to enhance endogenous fibrinolytic system; it is not a direct plasminogen activator but a modulator that relaxes plasminogen conformation . This could lead to plasminogen activation only where, when, and to the extent endogenous plasminogen activators are supplied .…”

“…SMTP was first discovered by a screening of microbial cultures for a compound that promoted plasminogen binding to fibrin, a crucial step of physiological fibrinolysis . SMTP‐7 (2,5‐bis[2‐[(3 E )‐4,8‐dimethylnona‐3,7‐dienyl]‐3,5‐dihydroxy‐2‐methyl‐7‐oxo‐4,9‐dihydro‐3 H ‐pyrano[2,3‐ e ]isoindol‐8‐yl]pentanoic acid), one of the most intensively studied SMTP congeners, relaxes plasminogen conformation and, thereby, enhances plasminogen‐fibrin binding and plasminogen activator‐catalyzed activation of plasminogen, leading to a promotion of thrombus clearance in vivo . On the other hand, SMTP‐7 exhibits anti‐inflammatory activities in vivo in disease models that are irrelevant to thromboembolism .…”

“…6 SMTP was first discovered by a screening of microbial cultures for a compound that promoted plasminogen binding to fibrin, a crucial step of physiological fibrinolysis. 6 activator-catalyzed activation of plasminogen, [7][8][9] leading to a promotion of thrombus clearance in vivo. 8,10 On the other hand, SMTP-7 exhibits anti-inflammatory activities in vivo in disease models that are irrelevant to thromboembolism.…”

Soluble epoxide hydrolase as an anti-inflammatory target of the thrombolytic stroke drug SMTP-7

“…Details of this interpretation are described under "Discussion." DISCUSSION SMTP-7 has a plasminogen modulation activity that leads to a thrombolytic enhancement as observed in several animal models (14,16,20). SMTP-7 effectively treats thrombotic and embolic stroke models (17,18,20), and the involvement of an additional mechanism that leads to anti-inflammation has been suggested (16,18,19,21).…”

“…SMTP-7 ( Fig. 1A), one of the SMTP family compounds with profound biological activities, enhances plasminogen activation by modulating plasminogen conformation (10,(13)(14)(15). SMTP-7 thus promotes plasmin formation and clot clearance in vivo (14,16), and it has been used to treat thrombotic and embolic strokes in experimental models in rodents and nonhuman primates (17)(18)(19)(20).…”