Characterization of the Annonaceous Acetogenin, Annonacinone, a Natural Product Inhibitor of Plasminogen Activator Inhibitor-1

Overview

Journal Sci Rep

Specialty Science

Date 2016 Nov 24

PMID 27876785

Citations 4

Authors

Stephane Pautus

Mouad Alami

Frederic Adam

Guillaume Bernadat

Daniel A Lawrence

Allan de Carvalho

Gilles Ferry

Alain Rupin

Abdallah Hamze

Pierre Champy

Natacha Bonneau

Philippe Gloanec

Jean-Louis Peglion

Jean-Daniel Brion

Elsa P Bianchini

Delphine Borgel

Affiliations

Soon will be listed here.

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.

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