Sideroxylonal C, a New Inhibitor of Human Plasminogen Activator Inhibitor Type-1, from the Flowers of <i>Eucalyptus albens</i>

Neve, Juliette Ellen; Leone, Priscila de Almeida; Carroll, Anthony Richard; Moni, Roger W.; Paczkowski, Natalii J.; Pierens, Greg; Björquist, Petter; Deinum, Johanna; Ehnebom, J.; Inghardt, Tord; Guymer, Gordon P; Grimshaw, Paul; Quinn, Ronald J.

doi:10.1021/np980286+

Cited by 31 publications

(22 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These associations have made PAI-1 an attractive pharmaceutical target. However, despite extensive studies, only a few small molecule inhibitors have been identified thus far (7)(8)(9)(10)(11)(12)(13)(14)(15)(16), and the majority of these are poor pharmaceutical candidates as they have relatively low affinity for PAI-1 and are unable to inactivate PAI-1 bound to its plasma cofactor vitronectin.…”

mentioning

confidence: 99%

Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1

Reinke

Sanders

et al. 2013

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

View full text Add to dashboard Cite

Plasminogen activator inhibitor type-1 (PAI-1) is a member of the serine protease inhibitor (serpin) family. Excessive PAI-1 activity is associated with human disease, making it an attractive pharmaceutical target. However, like other serpins, PAI-1 has a labile structure, making it a difficult target for the development of small molecule inhibitors, and to date, there are no US Food and Drug Administration-approved small molecule inactivators of any serpins. Here we describe the mechanistic and structural characterization of a high affinity inactivator of PAI-1. This molecule binds to PAI-1 reversibly and acts through an allosteric mechanism that inhibits PAI-1 binding to proteases and to its cofactor vitronectin. The binding site is identified by X-ray crystallography and mutagenesis as a pocket at the interface of β-sheets B and C and α-helix H. A similar pocket is present on other serpins, suggesting that this site could be a common target in this structurally conserved protein family.fibrinolysis | thrombolysis | fibrosis | cancer P lasminogen activator inhibitor type 1 (PAI-1) is a serine protease inhibitor (serpin) implicated in numerous pathological processes, including coronary heart disease, chronic fibrotic and inflammatory diseases, and tumor invasion and metastasis (1-6). These associations have made PAI-1 an attractive pharmaceutical target. However, despite extensive studies, only a few small molecule inhibitors have been identified thus far (7-16), and the majority of these are poor pharmaceutical candidates as they have relatively low affinity for PAI-1 and are unable to inactivate PAI-1 bound to its plasma cofactor vitronectin.PAI-1 is the most potent physiologic inhibitor of tissue-type and urokinase-type plasminogen activators (tPA and uPA, respectively) (17). Like other serpins, PAI-1 has a solvent-exposed, reactive center loop (RCL) that contains an amino acid sequence that confers protease target specificity. The serpin inhibitory mechanism is a multistep process of coordinated conformational changes that are necessary to trap a target protease (18). The first step is the formation of a noncovalent Michaelis complex, followed by the initial steps of a typical serine protease catalytic attack leading to the covalent acyl-enzyme complex (19). However, before the protease can dissociate from the serpin, a dramatic conformational change occurs [termed the stressed to relaxed (S to R) transition], in which the cleaved RCL inserts into the central β-sheet A, translocating the covalently-bound protease 70 Å to the base of β-sheet A (20). This conformational change results in distortion of the protease active site (21,22) and thereby prevents the deacylation reaction, inactivating the protease. Should this conformational change be interrupted, the protease can complete its cleavage of the serpin RCL, remaining active and leaving the serpin in a cleaved, inactive, loop-inserted state (23).PAI-1 is unique among serpins in that it readily autoinactivates into a so-called latent form, where the PAI-1 ...

show abstract

mentioning

confidence: 99%

Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1

Reinke

Sanders

et al. 2013

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

View full text Add to dashboard Cite

show abstract

“…Small-molecule synthetic antagonists of PAI-1 have been described previously (Charlton et al, 1996;Friederich et al, 1997;Neve et al, 1999;Gils et al, 2002;Einholm et al, 2003;Elokdah et al, 2004;Liang et al, 2005;Gorlatova et al, 2007). The metastable conformation of PAI-1 along with the intricacies of the pathway by which PAI-1 inhibits tPA affords numerous potential opportunities whereby a PAI-1 inhibitor could block PAI-1 activity.…”

mentioning

confidence: 99%

Neutralization of Plasminogen Activator Inhibitor I (PAI-1) by the Synthetic Antagonist PAI-749 via a Dual Mechanism of Action

Gardell¹,

Krueger²,

Antrilli³

et al. 2007

Mol Pharmacol

View full text Add to dashboard Cite

PAI-749 is a potent and selective synthetic antagonist of plasminogen activator inhibitor 1 (PAI-1) that preserved tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) activities in the presence of PAI-1 (IC 50 values, 157 and 87 nM, respectively). The fluorescence (Fl) of fluorophore-tagged PAI-1 (PAI-NBD119) was quenched by PAI-749; the apparent K d (254 nM) was similar to the IC 50 (140 nM) for PAI-NBD119 inactivation. PAI-749 analogs displayed the same potency rank order for neutralizing PAI-1 activity and perturbing PAI-NBD119 Fl; hence, binding of PAI-749 to PAI-1 and inactivation of PAI-1 activity are tightly linked. Exposure of PAI-1 to PAI-749 for 5 min (sufficient for full inactivation) followed by PAI-749 sequestration with Tween 80 micelles yielded active PAI-1; thus, PAI-749 did not irreversibly inactivate PAI-1, a known metastable protein. Treatment of PAI-1 with a PAI-749 homolog (producing less assay interference) blocked the ability of PAI-1 to displace p-aminobenzamidine from the uPA active site. Consistent with this observation, PAI-749 abolished formation of the SDS-stable tPA/PAI-1 complex. PAI-749-mediated neutralization of PAI-1 was associated with induction of PAI-1 polymerization as assessed by native gel electrophoresis. PAI-749 did not turn PAI-1 into a substrate for tPA; however, PAI-749 promoted plasmin-mediated degradation of PAI-1. In conclusion, PAI-1 inactivation by PAI-749 using purified components can result from a dual mechanism of action. First, PAI-749 binds directly to PAI-1, blocks PAI-1 from accessing the active site of tPA, and abrogates formation of the SDS-stable tPA/PAI-1 complex. Second, binding of PAI-749 to PAI-1 renders PAI-1 vulnerable to plasmin-mediated proteolytic degradation.Plasminogen activator inhibitor 1 (PAI-1) is a rapidly acting inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) (Dellas and Loskutoff, 2005). PAI-1 is a member of the serpin class of serine protease inhibitors that characteristically produce SDS-stable complexes with their cognate protease targets (Silverman et al., 2001). Formation of the acyl-enzyme adduct between PAI-1 and the protease involves initial formation of a Michaelis-type noncovalent complex without significant conformational change, followed by reversible acylation and irreversible reactive loop conformational changes that trap the protease in a covalent complex (Olson et al., 2001). Two other conformation states of PAI-1 are known. First, the acyl-enzyme adduct between PAI-1 and tPA (or uPA) can be hydrolyzed to form cleaved (inactive) PAI-1 and regenerate active plasminogen activator (PA) (Declerck et al., 1992). Second, active PAI-1 can undergo a spontaneous large conformation change that gives rise to an inactive (latent) state of the inhibitor (Levin and Santell, 1987;Mottonen et al., 1992).PAI-1 plays a pivotal role in a myriad of physiological processes that involve activation of plasminogen (Dellas and Loskutoff, 2005). High ...

show abstract

“…The sideroxylonals A-C (24-26) test showed the inhibition of PAI-1 (IC50 = 3.3, 5.3 and 4.7 μM, respectively). Other phloroglucinols with PAI-1 acitivities, euglobal IA2 (27), [57] euglobal IIC (28) [58] and robustadial A (29) [59] (IC50 = 138, 700 and 152 μM, respectively), were also isolated.…”

Section: Phenolic Acidsmentioning

confidence: 99%

“…Another phenolic acid, Rosmarinic acid, showed a mild antithrombotic effect. [55] In 1993, Zou et al [56] revealed that (25) and Sideroxylonal C (26), were isolated from the flowers of Eucalyptus albens [57] in 1998 ( Figure 5). The sideroxylonals A-C (24-26) test showed the inhibition of PAI-1 (IC50 = 3.3, 5.3 and 4.7 μM, respectively).…”

Section: Phenolic Acidsmentioning

confidence: 99%

Natural Products Phenols as Novel Antithrombotic Agents

Zhou¹,

Guo²

2018

Med. Res.

View full text Add to dashboard Cite

Sideroxylonal C, a New Inhibitor of Human Plasminogen Activator Inhibitor Type-1, from the Flowers of Eucalyptus albens

Cited by 31 publications

References 9 publications

Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1

Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1

Neutralization of Plasminogen Activator Inhibitor I (PAI-1) by the Synthetic Antagonist PAI-749 via a Dual Mechanism of Action

Natural Products Phenols as Novel Antithrombotic Agents

Contact Info

Product

Resources

About