Abstract
Plasmin (Plm), a trypsin-like serine protease, is responsible for fibrinolysis pathway and pathologic events, such as angiogenesis, tumor invasion, and metastasis, and alters the expression of cytokines. A growing body of data indicates that a Plm inhibitor is a potential candidate as an anti-inflammatory and anti-cancer agent. A class of active site-directed plasmin inhibitors containing tranexamic acid residue has been designed. As evidenced by docking studies, the inhibitor binds to the active site not to the lysine binding site (LBS) in plasmin, thus preventing plasmin from digesting the substrate. Further optimization of the series, concerning both activity and selectivity, led to the second generation of inhibitors. This review focuses on the Plm inhibitory activity-structure relationship of Plm inhibitors with the goal of realizing their design and clinical application.
Highlights
Plasmin (Plm), a trypsin-like serine protease, plays a critical role in the fibrinolysis pathway, in which Plm removes intra- and extra-vascularly formed thrombi by degrading fibrin clots
Plm circulates in the blood in its zymogen form, plasminogen (Plg), which is a single-chain glycoprotein of 92 kDa [1]
The C-terminal area of fibrin monomers that are rich in lysine residues facilitates binding to the lysine binding sites (LBS)
Summary
Plasmin (Plm), a trypsin-like serine protease, plays a critical role in the fibrinolysis pathway, in which Plm removes intra- and extra-vascularly formed thrombi by degrading fibrin clots. The two agents are surrogates of the amino acid, lysine, and bind to the lysine binding site (LBS) on the kringle domains of Plg, but not to the active site (AS) of Plm. Fibrinolysis is effectively suppressed, as seen in enzyme assays using TXA (IC50 = 50 μM), while fibrinogenolysis and amidolysis are hardly suppressed (IC50 = 10 mM and Ki = 40 mM, respectively) [19]. Development of Plm inhibitors, YO-2 and its derivatives, are described They showed the Plm inhibitory activity against a chromogenic substrate, demonstrating that they interacted to AS not LBS, in spite of having a TXA moiety in the molecule. This review highlights functional and structural aspects of the YO-related compounds
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