Sulfated, low-molecular-weight lignins are potent inhibitors of plasmin, in addition to thrombin and factor Xa: Novel opportunity for controlling complex pathologies

Brian L. Henry; May Abdel Aziz; Qibing Zhou; Umesh R. Desai

doi:10.1160/TH09-07-0454

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 103(03): 507-515
DOI: 10.1160/TH09-07-0454

Theme Issue Article

Schattauer GmbH

Sulfated, low-molecular-weight lignins are potent inhibitors of plasmin, in addition to thrombin and factor Xa: Novel opportunity for controlling complex pathologies

Brian L. Henry

¹Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA

²Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, USA

,

May Abdel Aziz

¹Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA

²Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, USA

,

Qibing Zhou

³Department of Chemistry, Virginia Commonwealth University, Richmond, Virginia

,

Umesh R. Desai

¹Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA

²Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, USA

› Author Affiliations

Abstract

Summary

Recently we prepared sulfated, low-molecular-weight lignins (LMWLs) to mimic the biological activities of heparin and heparan sulfate. Chemo-enzymatically prepared sulfated LMWLs represent a library of diverse non-sugar, aromatic molecules with structures radically different from the heparins, and have been found to potently inhibit thrombin and factor Xa. To assess their effect on the fibrinolytic system, we studied the interaction of LMWLs with human plasmin. Enzyme inhibition studies indicate that the three sulfated LMWLs studied inhibit plasmin with IC50 values in the range of 0.24 and 1.3 μM, which are marginally affected in the presence of antithrombin. Similarly, plasmin degradation of polymeric fibrin is also inhibited by sulfated LMWLs. Michaelis-Menten kinetic studies indicate that maximal velocity of hydrolysis of chromogenic substrates decreases nearly 70% in the presence of LMWLs, while the effect on Michaelis constant is dependent on the nature of the substrate. Competitive binding studies indicate that the sulfated LMWLs compete with full-length heparin. Comparison with thrombin-heparin crystal structure identifies an anionic region on plasmin as a plausible sulfated LMWL binding site. Overall, the chemoenzymatic origin coupled with coagulation and fibrinolysis inhibition properties of sulfated LMWLs present novel opportunities for designing new pharmaceutical agents that regulate complex pathologies in which both systems are known to play important roles such as disseminated intravascular coagulation.

Keywords

Plasmin - lignins - heparin mimetics - enzyme inhibition - allostery - anticoagulant - anti-fibrinolytic agent

Full Text

References

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