Exploration of Active Site-Directed Plasmin Inhibitors: Beyond Tranexamic Acid

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.

Synthesis and Hemostatic Activity of New Amide Derivatives

“…Research on new, safer plasmin inhibitors has not yet provided satisfactory results. Studies on the interactions between plasmin active sites and potential inhibitors (including peptide-type substances) are only at the preliminary stages of in vitro tests or in silico prediction [ 45 ]. Another trend in recent research on new natural and synthetic substances with antifibrinolytic agents is the allosteric modulation of plasmin activity [ 46 ].…”

Urokinase plasminogen activator as an anti-metastasis target: inhibitor design principles, recent amiloride derivatives, and issues with human/mouse species selectivity

“…Hydrophobic interactions were formed between the cyclohexane ring and two cysteines (Cys191 and Cys219) as well as with Gly216 (Wu et al 2019). YO-2 20 (IC50 3.99 μM) and PSI-112 21 (IC50 > 25 μM) are derivatives of TXA 19 that inhibited uPA in the micromolar range (Law et al 2017;Tsuda et al 2021). YO-2 20 is more active than PSI-112 21 due to interaction of Tyr60 in uPA with the pyridine ring of YO-2 20, while it seemed to sterically clash with the quinoline moiety in PSI-112 21 together with the side chain of Arg35.…”

Special Issue: Advances of Peptide Engineering

“…From the field of the protease inhibitor, Y. Tsuda et al [9] presented a novel class of active site-directed plasmin (Plm) inhibitors containing tranexamic acid, which generally binds to the lysine binding site (LBS), not to the active site. Along with the elucidation of X-ray crystal structure of the new type inhibitors in the complex with µPlm, the further optimization of the series for both activity and selectivity led to the second-generation inhibitors.…”