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

A novel class of potent FXIII-A inhibitors containing a (±) cis-bisamido epoxide pharmacophore is described. The compounds display highly potent inhibition of FXIII-A (IC50 = 5-500 nM) in an in vitro assay. In contrast to other types of previously described covalent transglutaminase inhibitors, the bis-amido epoxides exhibited no measurable reactivity with glutathione, therefore possibly rendering this class of compounds suitable for future in vivo investigations.

The activation peptide cleft exposed by thrombin cleavage of FXIII-A(2) contains a recognition site for the fibrinogen α chain.

Formation of a stable fibrin clot is dependent on interactions between factor XIII and fibrin. We have previously identified a key residue on the αC of fibrin(ogen) (Glu396) involved in binding activated factor XIII-A(2) (FXIII-A(2)*); however, the functional role of this interaction and binding site(s) on FXIII-A(2)* remains unknown. Here we (1) characterized the functional implications of this interaction; (2) identified by liquid-chromatography-tandem mass spectrometry the interacting residues on FXIII-A(2)* following chemical cross-linking of fibrin(ogen) αC389-402 peptides to FXIII-A(2)*; and (3) carried out molecular modeling of the FXIII-A(2)*/peptide complex to identify contact site(s) involved.