RGD-hirudin-based low molecular weight peptide prevents blood coagulation via subcutaneous injection
Pharmacology study published in Acta Pharmacologica Sinica (2020)
Abstract
Thromboembolic disease is a common cardio-cerebral vascular disease that threatens human life and health. Thrombin not only affects the exogenous coagulation pathway, but also the endogenous pathway. Thus, it becomes one of the most important targets of anticoagulant drugs. RGD-hirudin is an anticoagulant drug targeting thrombin, but it can only be administered intravenously. We designed a low molecular weight peptide based on RGD-hirudin that could prevent blood clots. We first used NMR to identify the key amino acid residues of RGD-hirudin that interacted with thrombin. Then, we designed a novel direct thrombin inhibitor peptide (DTIP) based on the structure and function of RGD-hirudin using homology modeling. Molecular docking showed that the targeting and binding of DTIP with thrombin were similar to those of RGD-hirudin, suggesting DTIP interacted directly with thrombin. The active amino acids of DTIP were identified by alanine scanning, and mutants were successfully constructed. In blood clotting time tests in vitro, we found that aPTT, PT, and TT in the rat plasma added with DTIP were greatly prolonged than in that added with the mutants. Subcutaneous injection of DTIP in rats also could significantly prolong the clotting time. Thrombelastography analysis revealed that DTIP significantly delayed blood coagulation. Bio-layer interferometry study showed that there were no significant differences between DTIP and the mutants in thrombin affinity constants, suggesting that it might bind to other sites of thrombin rather than to its active center. Our results demonstrate that DTIP with low molecular weight can prevent thrombosis via subcutaneous injection.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
Direct thrombin inhibitor peptide (DTIP) modeled from RGD-hirudin maintained anticoagulant action via subcutaneous (not just IV) administration, significantly prolonging aPTT/PT/TT in rats — first orally-tolerated hirudin-based peptide.
Por qué esto importa para la hirudoterapia
Este estudio diseñó un péptido inhibidor directo de trombina de bajo peso molecular (DTIP) basado en la estructura de RGD-hirudina, utilizando RMN, modelado por homología y acoplamiento molecular para identificar los residuos clave que interactúan con la trombina. In vitro, el DTIP prolongó significativamente el aPTT, el PT y el TT en plasma de rata en comparación con los mutantes; la inyección subcutánea en ratas prolongó significativamente el tiempo de coagulación, y la tromboelastografía confirmó retraso de la coagulación, aunque la interferometría de biocapa no mostró diferencias significativas en la afinidad por la trombina entre el DTIP y los mutantes, lo que sugiere unión a sitios no correspondientes al centro activo. Para ASH, esto es relevante ya que deriva de la hirudina, el anticoagulante distintivo de la sanguijuela, y aborda la limitación clínica de la administración exclusivamente intravenosa. ADVERTENCIA: Se trata de un estudio preclínico en ratas y ensayos in vitro sin datos en humanos; los tamaños muestrales, los métodos estadísticos y la comparación directa con anticoagulantes estándar no se detallan en el resumen.
Citación
RGD-hirudin-based low molecular weight peptide prevents blood coagulation via subcutaneous injection.
Li YR et al. · Acta Pharmacologica Sinica, 2020
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: 18 de junio de 2026