Novel inhibitor ZED3197 as potential drug candidate in anticoagulation targeting coagulation FXIIIa (F13a)

Abstract

Background: Factor XIII (FXIII) is the final enzyme of the coagulation cascade. While the other enzymatic coagulation factors are proteases, FXIII belongs to the transglutaminase family. FXIIIa covalently crosslinks the fibrin clot and represents a promising target for drug development to facilitate fibrinolysis. However, no FXIII-inhibiting compound has entered clinical trials. Here, we introduce the features of a peptidomimetic inhibitor of FXIIIa (ZED3197) as a potential drug candidate. Methods:The potency of ZED3197 against FXIIIa and the selectivity against other human transglutaminases were characterized using transamidation and isopeptidase assays. The inhibition of fibrin crosslinking was evaluated by biochemical methods and thromboelastometry. Further, the pharmacology of the compound was explored in a rabbit model of venous stasis and reperfusion.Results: ZED3197 proved to be a potent and selective inhibitor of human FXIIIa. Further, the compound showed broad inhibitory activity against cellular FXIIIA from various animal species. Rotational thromboelastometry in whole human blood indicated that the inhibitor, in a dose-dependent manner, prolonged clot formation, reduced clot firmness, and facilitated clot lysis without affecting the clotting time, indicating minimal impact on hemostasis. In vivo, the novel FXIIIa inhibitor effectively decreased the weight of clots and facilitated flow restoration without prolongation of the bleeding time.Conclusions: ZED3197 is the first drug-like potent compound targeting FXIIIa, a yet untapped target in anticoagulation. Due to the function of FXIII downstream of thrombin the approach provides minimal impact on hemostasis. In vivo data imply that the inhibitor dissociates an antithrombotic effect from increased bleeding tendency.

Extracellular Histones Inhibit Fibrinolysis through Noncovalent and Covalent Interactions with Fibrin

“…23 Recently developed small-molecule inhibitors of FXIIIa have shown promise in animal models, reducing clot weight without prolonging bleeding in models of venous stasis. 44 Our results show that histones can be added to the list of FXIIIa substrates that inhibit fibrinolysis, which includes α 2 -antiplasmin, TAFI, and PAI-2. 19 In these cases, crosslinking is proposed to localize antifibrinolytic activity to the fibrin surface and contribute to fibrin stability, and we find that crosslinked histones have a similar effect.…”

Factor XIII and Fibrin Clot Properties in Acute Venous Thromboembolism

“…A similar effect was achieved using low-molecular-weight heparin (LMWH) to inhibit the histone-fibrin crosslinking and improve fibrinolysis [ 44 ]. Recently, a novel specific inhibitor, ZED3197, has been described as a potential drug candidate in anticoagulation targeting FXIIIa for at least short-term therapy to modulate clot structure and enhance fibrinolysis [ 45 ]. ZED3197 is a potent and selective peptidomimetic inhibitor of FXIIIa, covalently and irreversibly binding FXIIIa [ 45 ].…”

“…Recently, a novel specific inhibitor, ZED3197, has been described as a potential drug candidate in anticoagulation targeting FXIIIa for at least short-term therapy to modulate clot structure and enhance fibrinolysis [ 45 ]. ZED3197 is a potent and selective peptidomimetic inhibitor of FXIIIa, covalently and irreversibly binding FXIIIa [ 45 ]. However, clinical studies are needed to corroborate the therapeutic strategy based on modulation of FXIIIa.…”

NMR-Based Structural Characterization of a Two-Disulfide-Bonded Analogue of the FXIIIa Inhibitor Tridegin: New Insights into Structure–Activity Relationships

“…Thus, the development of these inhibitors has not been pursued further. Nowadays, the main focus is directed toward peptidic and allosteric FXIIIa inhibitors, such as the peptidomimetic inhibitor ZED3197 and glucosaminoglycan-derived inhibitors, e.g., NSGM 13 (non-saccharide glucosaminoglycan mimetics), introduced by Al-Horani et al [ 23 , 24 , 25 , 26 ]. Furthermore, the peptidic inhibitor tridegin, a 66mer peptide, first isolated from the giant Amazon leech Haementeria ghilianii in 1997, has been investigated for its high inhibitory potential against FXIIIa [ 23 , 27 ].…”