Distinct 3-disulfide-bonded isomers of tridegin differentially inhibit coagulation factor XIIIa
Structural biology published in European Journal of Medicinal Chemistry (2020)
Abstract
Tridegin is a 66mer cysteine-rich coagulation factor XIIIa (FXI-IIa) inhibitor from the giant amazon leech Haementeria ghilianii of yet unknown disulfide connectivity. This study covers the structural and functional characterization of five different 3-disulfide-bonded tridegin isomers. In addition to three previously identified isomers, one isomer containing the inhibitory cystine knot (ICK, knottin) motif, and one isomer with the leech antihemostatic protein (LAP) motif were synthesized in a regioselective manner. A fluorogenic enzyme activity assay revealed a positive correlation between the constriction of conformational flexibility in the N-terminal part of the peptide and the inhibitory potential towards FXI-IIa with clear differences between the isomers. This observation was supported by molecular dynamics (MD) simulations and subsequent molecular docking studies. The presented results provide detailed structure-activity relationship studies of different tridegin disulfide isomers towards FXI-IIa and reveal insights into the possibly existing native linkage compared to non-native disulfide tridegin species.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Zusammenfassung
Characterizes 3-disulfide-bonded isomers of leech-derived tridegin, a Factor XIIIa inhibitor — defines structure-activity for clot-stabilization inhibitor.
Warum dies für die Hirudotherapie relevant ist
This study characterized five different three-disulfide-bonded isomers of tridegin, a 66-mer factor XIIIa (FXIIIa) inhibitor from the giant Amazon leech Haementeria ghilianii, finding that conformational flexibility in the N-terminal region correlated with inhibitory potency, supported by molecular dynamics and docking studies. For ASH's domain, this is directly relevant as a structure-activity study of a leech-derived anticoagulant peptide targeting FXIIIa. However, the work is entirely structural/computational (synthetic peptides, enzyme assays, modeling) with no animal or human data, and the native disulfide connectivity remains unresolved. It is preliminary medicinal chemistry rather than a therapy study.
Zitation
Distinct 3-disulfide-bonded isomers of tridegin differentially inhibit coagulation factor XIIIa.
Bäuml CA et al. · European journal of medicinal chemistry, 2020
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