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.
Resumen
Characterizes 3-disulfide-bonded isomers of leech-derived tridegin, a Factor XIIIa inhibitor — defines structure-activity for clot-stabilization inhibitor.
Por qué esto importa para la hirudoterapia
Este estudio caracterizó cinco isómeros diferentes con tres enlaces disulfuro de la tridegina, un inhibidor del factor XIIIa (FXIIIa) de 66 aminoácidos proveniente de la sanguijuela gigante amazónica Haementeria ghilianii, encontrando que la flexibilidad conformacional en la región N-terminal se correlacionó con la potencia inhibitoria, respaldada por estudios de dinámica molecular y acoplamiento. Para el dominio de la ASH, esto es directamente relevante como un estudio de relación estructura-actividad de un péptido anticoagulante derivado de sanguijuela dirigido al FXIIIa. Sin embargo, el trabajo es completamente estructural/computacional (péptidos sintéticos, ensayos enzimáticos, modelado) sin datos en animales ni en humanos, y la conectividad nativa de los enlaces disulfuro permanece sin resolverse. Se trata de química medicinal preliminar más que de un estudio terapéutico.
Citación
Distinct 3-disulfide-bonded isomers of tridegin differentially inhibit coagulation factor XIIIa.
Bäuml CA et al. · European journal of medicinal chemistry, 2020
Contexto clínico relacionado
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: 18 de junio de 2026