Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1

Abstract

Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of the tissue type and urokinase type plasminogen activators. High levels of PAI-1 are correlated with an increased risk of thrombotic events and several other pathologies. Despite several compounds with in vitro activity being developed, none of them are currently in clinical use. In this study, we evaluated a novel PAI-1 inhibitor, annonacinone, a natural product from the Annonaceous acetogenins group. Annonacinone was identified in a chromogenic screening assay and was more potent than tiplaxtinin. Annonacinone showed high potency ex vivo on thromboelastography and was able to potentiate the thrombolytic effect of tPA in vivo in a murine model. SDS-PAGE showed that annonacinone inhibited formation of PAI-1/tPA complex via enhancement of the substrate pathway. Mutagenesis and molecular dynamics allowed us to identify annonacinone binding site close to helix D and E and β-sheets 2A.

The safety and tolerability of Annona muricata leaf extract: a systematic review

“…Of the three studies which investigated A. muricata leaf extract in renal effect, two studies demonstrated a nephroprotective effect, while one demonstrated a nephrotoxic effect with no substantial differences in the dose, formulation or route of administration. There were limited data reported on the cardiac ( n = 1), haematological ( n = 2) and reproductive ( n = 1) effect of A. muricata leaf extract.…”

Antithrombotic Natural Products That Inhibit Plasminogen Activator Inhibitor 1 (PAI-1)

“…Annonacinone inhibited formation of PAI-1/tPA complex. 45) There are no PAI-1 activity inhibitor currently used in clinical situation. However, clinical applications of drugs that inhibit the binding of PAI-1 to t-PA and drugs that inactivate PAI-1 by changing the three-dimensional structure are considered.…”

Serpins in Hemostasis as Therapeutic Targets for Bleeding or Thrombotic Disorders

“…Annonacinone is more potent than tiplaxtinin in inhibiting PAI-1 in vitro , with IC 50 values of 9 and 28 μM, respectively, in a chromogenic assay. Annonacinone promotes fibrinolysis in plasma (as assessed by thromboelastography) and potentiates tPA-induced thrombolysis in a murine model of FeCl 3 -induced venule occlusion ( 50 ). However, the compound's highly challenging chemical synthesis and lack of efficacy against vitronectin-bound PAI-1 have not warranted the clinical development of annonacinone.…”