Abstract
Stachybotrys microspora triprenyl phenol (SMTP) is a large family of small molecules derived from the fungus S. microspora. SMTP acts as a zymogen modulator (specifically, plasminogen modulator) that alters plasminogen conformation to enhance its binding to fibrin and subsequent fibrinolysis. Certain SMTP congeners exert anti-inflammatory effects by targeting soluble epoxide hydrolase. SMTP congeners with both plasminogen modulation activity and anti-inflammatory activity ameliorate various aspects of ischemic stroke in rodents and primates. A remarkable feature of SMTP efficacy is the suppression of hemorrhagic transformation, which is exacerbated by conventional thrombolytic treatments. No drug with such properties has been developed yet, and SMTP would be the first to promote thrombolysis but suppress disease-associated bleeding. On the basis of these findings, one SMTP congener is under clinical study and development. This review summarizes the discovery, mechanism of action, pharmacological activities, and development of SMTP.
Highlights
Hydrolase on Thrombolysis, The hemostatic system is finely regulated to achieve continuous blood circulation and prevent blood loss based on the balance between blood coagulation and fibrinolysis [1,2,3]
Therapy is a powerful approach to treat ischemic when within 4.5 h of onset (a); clinical outcome is poor when administered beyond this time window (b). type plasminogen activator (t-plasminogen activators (PAs)) therapy is associated with a significant increase in intracranial hemorrhage [153,163]. This can be explained by the following: (i) large amounts of pharmacological t-PA promote plasminogen activation in fibrin clots and in plasma; (ii) the latter induces the exhaustion of key hemostatic proteins such as plasminogen, α2 -antiplasmin, and fibrinogen, resulting in increased bleeding risk; (iii) t-PA exhibits non-fibrinolytic action affecting neutrophils, vascular endothelial cells, microglia, and astrocytes to induce production/release of reactive oxygen species (ROS), matrix metalloproteinases (MMPs), growth factors, and high-mobility group box protein 1 (HMGB1), which cause neuronal damage, inflammation, vascular remodeling, and blood–brain barrier (BBB) disruption [163]; and (iv) the systemic bleeding tendency in combination with the non-fibrinolytic action of t-PA increases the risk of hemorrhagic transformation
A remarkable feature of Stachybotrys microspora triprenyl phenol (SMTP) efficacy is the suppression of hemorrhagic transformation, which is exacerbated by conventional thrombolytic treatments
Summary
Hydrolase on Thrombolysis, The hemostatic system is finely regulated to achieve continuous blood circulation and prevent blood loss based on the balance between blood coagulation and fibrinolysis (blood clot degradation) [1,2,3]. The zymogens in this system contribute to autonomous regulation through spatiotemporal activation in response to physiological demands or stimuli [4,5]. We review the discovery, mechanism of action, pharmacological activity, and development of SMTP
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