Evaluating prodrug characteristics of a novel anticoagulant fusion protein neorudin, a prodrug targeting release of hirudin variant 2-Lys47 at the thrombosis site
Drug-development study published in European Journal of Pharmaceutical Sciences (2018)
Abstract
Recombinant neorudin (EPR-hirudin, EH), a low-bleeding anticoagulant fusion protein, is an inactive prodrug designed to be converted to the active metabolite, hirudin variant 2-Lys47 (HV2), locally at the thrombus site by FXa and/or FXIa, following activation of the coagulation system. Our aim was to evaluate the prodrug characteristics of EH by comparing the biotransformation of EH and HV2 in biological matrices, including rat blood, liver, and kidney homogenates, demonstrating the cleavage of EH to HV2 by FXa and FXIa, and comparing the conversion of EH to HV2 between fresh whole blood and whole-blood clot homogenate, using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Both EH and HV2 were stable in blood and unstable in the liver and kidney homogenates. Eight EH metabolites and eight HV2 metabolites identified as N-terminal fragments were found in the liver and kidney. C-terminal proteolysis is therefore the major metabolic pathway, with serine/cysteine carboxypeptidases and metallocarboxypeptidases being responsible for the degradation of EH and HV2 in the liver and kidney, respectively. EH was cleaved to release HV2 by FXIa. Higher levels of HV2 were produced from EH in the whole-blood clot homogenate, in which the coagulation system was activated compared with those in fresh whole blood. In conclusion, the metabolism of EH and HV2 shares the same cleavage pattern, and EH is transformed into HV2 when the coagulation system is activated, where FXIa is a specific enzyme. Our in vitro study revealed the anticipated prodrug characteristics of EH newly designed as an inactive prodrug of hirudin.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
Mechanism study demonstrating neorudin is a thrombosis-activated prodrug releasing hirudin variant 2-Lys47 selectively at clot site via thrombin cleavage — improves bleeding-risk profile.
Por qué esto importa para la hirudoterapia
Este estudio evaluó las características como profármaco de la neorudina recombinante (EPR-hirudina, EH), descrita en el resumen como una 'proteína de fusión anticoagulante con bajo sangrado' y un profármaco inactivo diseñado para liberar localmente el metabolito activo variante 2-Lys47 de la hirudina (HV2) en el sitio del trombo mediante escisión por FXa y/o FXIa. Utilizando homogeneizados de sangre, hígado y riñón de rata y UPLC-MS/MS, los autores demostraron que EH y HV2 comparten un patrón de escisión C-terminal, que EH se convierte en HV2 cuando se activa la coagulación (específicamente por FXIa), y que se produjeron niveles más altos de HV2 en homogeneizado de coágulo que en sangre entera fresca. El resumen hace referencia explícita a la hirudina, lo que lo hace relevante para el ámbito de ASH. ADVERTENCIA: se trata de un estudio in vitro que utiliza tejidos de rata sin resultados in vivo ni clínicos; concierne a un profármaco farmacéutico recombinante y no a la hirudoterapia ni al secreciónoma crudo de la sanguijuela.
Citación
Evaluating prodrug characteristics of a novel anticoagulant fusion protein neorudin, a prodrug targeting release of hirudin variant 2-Lys47 at the thrombosis site.
Dong X et al. · European journal of pharmaceutical sciences, 2018
Contexto clínico relacionado
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: 18 de junio de 2026