Dual-target synergistic antithrombotic mechanism of a dabigatran etexilate analogue (HY023016).
Clin Exp Pharmacol Physiol
; 49(5): 567-576, 2022 05.
Article
em En
| MEDLINE
| ID: mdl-35147244
ABSTRACT
Thrombin has long been considered a desirable antithrombotic target, but anti-thrombin therapy without anti-platelet therapy has never achieved the ideal effect. HY023016, derived from dabigatran etexilate, exhibited a potent antithrombotic efficacy. In the present study, mechanisms underlying this effect were explored. HY023016 strongly decreased the binding of thrombin to recombinant GPIbα N-terminal sequence, which was confirmed by surface plasmon resonance. Flow cytometry revealed that HY023016 selectively decreased the binding of antibody to GPIbα and inhibited the washed human platelet aggregation induced by thrombin. Fluorescence experiment showed that HY023016 remarkably inhibited exosite II by a loss of affinity for the γ'-peptide of fibrinogen. Using intravital microscopy, we observed and recorded the dynamic process of thrombus formation and found that HY023016 effectively prevented thrombus formation in rat arteriovenous shunt thrombosis model. On the basis of these findings, we propose that HY023016 provides a novel insight into the antithrombotic mechanism, which exerts synergistic anticoagulant and antiplatelet effects through thrombin and GPIbα.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fibrinolíticos
/
Dabigatrana
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Clin Exp Pharmacol Physiol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China