Pharmacokinetic studies of a novel 1,2,4-thiadiazole derivative, inhibitor of Factor XIIIa, in the rabbit by a validated HPLC method

Novaković, Jasmina; Wodzinska, Jolanta; Tesoro, Angelo; Thiessen, Jake J.; Spino, Michael

doi:10.1016/j.jpba.2004.12.032

Cited by 6 publications

(5 citation statements)

References 14 publications

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“…The FXIII complex has always presented a structural functional challenge to researchers owing to its dynamic nature and association with various other proteins like fibrinogen in its physiological and biochemical life-cycle. The absence of an all atom basis for this complex further limits interpretation of pathomolecular mechanisms, as well as the development of drugs/inhibitors to bind both complexed and isolated FXIII-A(45–48). Indirect evidence in the context of inter-domain interactions exists, but does not have a visual/structural basis(1).…”

Section: Discussionmentioning

confidence: 99%

The plasma Factor XIII heterotetrameric complex structure: unexpected unequal pairing within a symmetric complex

Singh

Nazabal²,

Kaniyappan

et al. 2019

Preprint

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Factor XIII (FXIII) is a predominant determinant of clot stability, strength, and composition. Plasma FXIII circulates as a pro-transglutaminase with 2 catalytic A subunits and 2 carrierprotective B subunits in a heterotetramer (FXIII-A 2 B 2 ). FXIII-A 2 and -B 2 subunits are synthesized separately and then assembled in plasma. Following proteolytic activation by thrombin and calcium-mediated dissociation of the B-subunits, activated FXIII (FXIIIa) covalently cross-links fibrin, promoting clot stability. The zymogen and active states of the FXIII-A subunits have been structurally characterized; however, the structure of FXIII-B subunits and the FXIII-A 2 B 2 complex have remained elusive. Using integrative hybrid approaches including atomic force microscopy, cross-linking mass spectrometry, and computational approaches, we have constructed the first all-atom model of the FXIII-A 2 B 2 complex. We also used molecular dynamic simulations in combination with isothermal titration calorimetry to characterize FXIII-A 2 B 2 assembly, activation, and dissociation. Our data reveal unequal pairing of individual subunit monomers in an otherwise symmetric complex, and suggest this unusual structure is critical for both assembly and activation of this complex. Our findings enhance understanding of mechanisms associating FXIII-A 2 B 2 mutations with disease and have important implications for the rational design of molecules to alter FXIII assembly and/or activity to reduce bleeding and thrombotic complications.

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Section: Discussionmentioning

confidence: 99%

The plasma Factor XIII heterotetrameric complex structure: unexpected unequal pairing within a symmetric complex

Singh

Nazabal²,

Kaniyappan

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The FXIII complex has always presented a structural functional challenge to researchers owing to its dynamic nature and association with various other proteins such as fibrinogen in its physiological and biochemical life cycle. The interpretation of pathomolecular mechanisms is further limited by the absence of an all atom basis for this complex, as well as the development of drugs and inhibitors to bind both complexed and isolated FXIII-A [45][46][47][48]. Indirect evidence, in the context of interdomain interactions, exists but does not have a visual and structural basis [1].…”

Section: Ih Approaches Reveal a Unique Fxiii Complex Structurementioning

confidence: 99%

The Plasma Factor XIII Heterotetrameric Complex Structure: Unexpected Unequal Pairing within a Symmetric Complex

Singh

Nazabal²,

Kaniyappan

et al. 2019

Biomolecules

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Factor XIII (FXIII) is a predominant determinant of clot stability, strength, and composition. Plasma FXIII circulates as a pro-transglutaminase with two catalytic A subunits and two carrierprotective B subunits in a heterotetramer (FXIII-A 2 B 2 ). FXIII-A 2 and -B 2 subunits are synthesized separately and then assembled in plasma. Following proteolytic activation by thrombin and calcium-mediated dissociation of the B subunits, activated FXIII (FXIIIa) covalently cross links fibrin, promoting clot stability. The zymogen and active states of the FXIII-A subunits have been structurally characterized; however, the structure of FXIII-B subunits and the FXIII-A 2 B 2 complex have remained elusive. Using integrative hybrid approaches including atomic force microscopy, cross-linking mass spectrometry, and computational approaches, we have constructed the first all-atom model of the FXIII-A 2 B 2 complex. We also used molecular dynamics simulations in combination with isothermal titration calorimetry to characterize FXIII-A 2 B 2 assembly, activation, and dissociation. Our data reveal unequal pairing of individual subunit monomers in an otherwise symmetric complex, and suggest this unusual structure is critical for both assembly and activation of this complex. Our findings enhance understanding of mechanisms associating FXIII-A 2 B 2 mutations with disease and have important implications for the rational design of molecules to alter FXIII assembly or activity to reduce bleeding and thrombotic complications.

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“…Due to the lack of selectivity and potency along with short plasma half‐lives of only a few minutes, these inhibitors were solely considered as pharmacological tools but not as prospective drug candidates . The pharmacokinetic profile of an irreversibly acting inhibitor carrying a thiadiazole warhead was studied in rabbits in order to support and facilitate the design and selection of drug candidates . Further, medicinal chemists reported cyclopropenone derivatives from fungi and synthetic analogues as potent FXIIIa inhibitors .…”

Section: Introductionmentioning

confidence: 99%

“…18 The pharmacokinetic profile of an irreversibly acting inhibitor carrying a thiadiazole warhead was studied in rabbits in order to support and facilitate the design and selection of drug candidates. 19 Further, medicinal chemists reported cyclopropenone derivatives from fungi and synthetic analogues as potent FXIIIa inhibitors. 20 In both cases, from a drug discovery perspective, the low potency of the compounds disqualifies them for further development.…”

Section: Introductionmentioning

confidence: 99%

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

Pasternack¹,

Büchold²,

Jähnig³

et al. 2020

Journal of Thrombosis and Haemostasis

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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.

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Pharmacokinetic studies of a novel 1,2,4-thiadiazole derivative, inhibitor of Factor XIIIa, in the rabbit by a validated HPLC method

Cited by 6 publications

References 14 publications

The plasma Factor XIII heterotetrameric complex structure: unexpected unequal pairing within a symmetric complex

The plasma Factor XIII heterotetrameric complex structure: unexpected unequal pairing within a symmetric complex

The Plasma Factor XIII Heterotetrameric Complex Structure: Unexpected Unequal Pairing within a Symmetric Complex

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

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