Characterization of a Small Molecule Inhibitor of Plasminogen Activator Inhibitor Type 1 That Accelerates the Transition into the Latent Conformation

Fjellström, Ola; Deinum, Johanna; Sjögren, Tove; Johansson, Christina; Geschwindner, Stefan; Nerme, V.; Legnehed, A.; McPheat, Jane; Olsson, Karolina; Bodin, Cristian; Paunovic, Amalia; Gustafsson, David

doi:10.1074/jbc.m112.371732

Cited by 27 publications

(35 citation statements)

References 61 publications

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“…Directed mutagenesis showed that annonacinone binds to the pocket between s2A, hD and hE similarly to other small molecule PAI-1 inhibitors such as tiplaxtinin, AZ3976 and embelin141517. Molecular dynamics is in agreement with site directed mutagenesis results.…”

Section: Discussionsupporting

confidence: 75%

“…Docking studies together with mutagenesis localized its binding site in the region of helices D and E close to the vitronectin binding site14. Three crystal structures of latent PAI-1 cocrystallized with compound AZ397615 and active PAI-1 cocrystallized with compound CDE-09616 and Embelin17 were also reported. They show different binding site on PAI-1 and different mechanism of action.…”

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confidence: 98%

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

Pautus

Alami

Adam

et al. 2016

Sci Rep

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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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Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 98%

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

Pautus

Alami

Adam

et al. 2016

Sci Rep

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“…(B), comparison of the AZ3976 (56) binding site in ligand bound and free latent PAI-1. From Fjellstrom et al [97]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)…”

Section: Embelin (57)mentioning

confidence: 97%

Small molecules inhibitors of plasminogen activator inhibitor-1 – An overview

Rouch

Vanucci-Bacqué

Bedos‐Belval

et al. 2015

European Journal of Medicinal Chemistry

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“…Physiologically, this regulation is achieved by binding to the cell adhesion factor vitronectin, leading to an ∼50% increase in the active state t 1/2 (3). Because high levels of active PAI-1 are associated both with poor prognoses for some cancers, presumably due to interactions with vitronectin, and with cardiovascular diseases (1), PAI-1 inhibitors that accelerate the latency transition are under development (1,4,5). However, drug design efforts are hampered by the lack of detailed molecular mechanisms for PAI-1 conformational changes.…”

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confidence: 99%

Serpin latency transition at atomic resolution

Cazzolli

Wang

Beccara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Protease inhibition by serpins requires a large conformational transition from an active, metastable state to an inactive, stable state. Similar reactions can also occur in the absence of proteases, and these latency transitions take hours, making their time scales many orders of magnitude larger than are currently accessible using conventional molecular dynamics simulations. Using a variational path sampling algorithm, we simulated the entire serpin active-to-latent transition in all-atom detail with a physically realistic force field using a standard computing cluster. These simulations provide a unifying picture explaining existing experimental data for the latency transition of the serpin plasminogen activator inhibitor-1 (PAI-1). They predict a long-lived intermediate that resembles a previously proposed, partially loop-inserted, prelatent state; correctly predict the effects of PAI-1 mutations on the kinetics; and provide a potential means to identify ligands able to accelerate the latency transition. Interestingly, although all of the simulated PAI-1 variants readily access the prelatent intermediate, this conformation is not populated in the active-to-latent transition of another serpin, α 1 -antitrypsin, which does not readily go latent. Thus, these simulations also help elucidate why some inhibitory serpin families are more conformationally labile than others. T he serpin plasminogen activator inhibitor 1 (PAI-1) negatively regulates blood clot clearance (fibrinolysis) by mechanically inhibiting important serine proteases, including tissue type plasminogen activator and urokinase type plasminogen activator (1). Suicide inhibition, initiated by proteolytic cleavage of the PAI-1 reactive center loop (RCL), requires insertion of the cleaved RCL into the central β-sheet (sheet A). This process expands sheet A, inhibits the covalently attached protease by mechanical disruption of the active site (2), and results in a thermodynamically stable serpin conformation. Alternatively, PAI-1 can spontaneously deactivate by inserting its intact, uncleaved RCL into sheet A, resulting in the more stable but inactive latent conformation (1) (Fig. 1).The latency transition provides a facile way to regulate PAI-1 activity. Physiologically, this regulation is achieved by binding to the cell adhesion factor vitronectin, leading to an ∼50% increase in the active state t 1/2 (3). Because high levels of active PAI-1 are associated both with poor prognoses for some cancers, presumably due to interactions with vitronectin, and with cardiovascular diseases (1), PAI-1 inhibitors that accelerate the latency transition are under development (1, 4, 5). However, drug design efforts are hampered by the lack of detailed molecular mechanisms for PAI-1 conformational changes. Numerous studies have identified mutations that either accelerate or retard the conformational transition, as well as antibodies that can accelerate latency. Despite these efforts, the molecular details of the latency transition and the residues involved in the key i...

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Characterization of a Small Molecule Inhibitor of Plasminogen Activator Inhibitor Type 1 That Accelerates the Transition into the Latent Conformation

Cited by 27 publications

References 61 publications

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

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

Small molecules inhibitors of plasminogen activator inhibitor-1 – An overview

Serpin latency transition at atomic resolution

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