(±) cis-bisamido epoxides: A novel series of potent FXIII-A inhibitors

Avery, Craig A.; Pease, Richard J.; Smith, Kerrie A.; Boothby, M.; Buckley, Helen M.; Grant, Peter J.; Fishwick, Colin W. G.

doi:10.1016/j.ejmech.2015.05.019

Cited by 14 publications

(9 citation statements)

References 16 publications

(18 reference statements)

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“…Analogues of this peptidic inhibitor offer insight into the mechanism of action and have potential as lead structures for development [215]. The novel inhibitors with a cis-bisamido epoxides pharmacore were shown to have an improved potency compared to a natural product inhibitor, cerulenin, although still lacked selectivity for FXIII over transglutaminase 2 [216]. ZED3197 has a Michael acceptor warhead which irreversibly blocks the active site cysteine and has recently been shown to restore blood flow in an in vivo rabbit model of venous stasis without affecting clotting time [217].…”

Section: Fxiii-a Replacement Therapy and Utility As A Drug Targetmentioning

confidence: 99%

Factor XIII-A: An Indispensable “Factor” in Haemostasis and Wound Healing

Alshehri

Whyte

Mutch

2021

IJMS

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Factor XIII (FXIII) is a transglutaminase enzyme that catalyses the formation of ε-(γ-glutamyl)lysyl isopeptide bonds into protein substrates. The plasma form, FXIIIA2B2, has an established function in haemostasis, with fibrin being its principal substrate. A deficiency in FXIII manifests as a severe bleeding diathesis emphasising its crucial role in this pathway. The FXIII-A gene (F13A1) is expressed in cells of bone marrow and mesenchymal lineage. The cellular form, a homodimer of the A subunits denoted FXIII-A, was perceived to remain intracellular, due to the lack of a classical signal peptide for its release. It is now apparent that FXIII-A can be externalised from cells, by an as yet unknown mechanism. Thus, three pools of FXIII-A exist within the circulation: plasma where it circulates in complex with the inhibitory FXIII-B subunits, and the cellular form encased within platelets and monocytes/macrophages. The abundance of this transglutaminase in different forms and locations in the vasculature reflect the complex and crucial roles of this enzyme in physiological processes. Herein, we examine the significance of these pools of FXIII-A in different settings and the evidence to date to support their function in haemostasis and wound healing.

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Section: Fxiii-a Replacement Therapy and Utility As A Drug Targetmentioning

confidence: 99%

Factor XIII-A: An Indispensable “Factor” in Haemostasis and Wound Healing

Alshehri

Whyte

Mutch

2021

IJMS

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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 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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“…Consequently, FXIIIa serves as an interesting target for the development of anticoagulants in order to circumvent the problem of undesired bleeding. So far, several small-molecule inhibitors such as cerulenin and alutacenoic acid A have been investigated for their inhibitory potential against FXIIIa [21][22][23][24]. However, many of these small-molecule inhibitors possess a low selectivity and/or halflife in plasma.…”

Section: Introductionmentioning

confidence: 99%

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

Schmitz

George

Nubbemeyer

et al. 2021

IJMS

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The saliva of blood-sucking leeches contains a plethora of anticoagulant substances. One of these compounds derived from Haementeria ghilianii, the 66mer three-disulfide-bonded peptide tridegin, specifically inhibits the blood coagulation factor FXIIIa. Tridegin represents a potential tool for antithrombotic and thrombolytic therapy. We recently synthesized two-disulfide-bonded tridegin variants, which retained their inhibitory potential. For further lead optimization, however, structure information is required. We thus analyzed the structure of a two-disulfide-bonded tridegin isomer by solution 2D NMR spectroscopy in a combinatory approach with subsequent MD simulations. The isomer was studied using two fragments, i.e., the disulfide-bonded N-terminal (Lys1–Cys37) and the flexible C-terminal part (Arg38–Glu66), which allowed for a simplified, label-free NMR-structure elucidation of the 66mer peptide. The structural information was subsequently used in molecular modeling and docking studies to provide insights into the structure–activity relationships. The present study will prospectively support the development of anticoagulant-therapy-relevant compounds targeting FXIIIa.

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(±) cis-bisamido epoxides: A novel series of potent FXIII-A inhibitors

Cited by 14 publications

References 16 publications

Factor XIII-A: An Indispensable “Factor” in Haemostasis and Wound Healing

Factor XIII-A: An Indispensable “Factor” in Haemostasis and Wound Healing

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

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

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