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Engineering Factor Xa Inhibitor with Multiple Platelet-Binding Sites Facilitates its Platelet Targeting.

ABSTRACT: Targeted delivery of antithrombotic drugs centralizes the effects in the thrombosis site and reduces the hemorrhage side effects in uninjured vessels. We have recently reported that the platelet-targeting factor Xa (FXa) inhibitors, constructed by engineering one Arg-Gly-Asp (RGD) motif into Ancylostoma caninum anticoagulant peptide 5 (AcAP5), can reduce the risk of systemic bleeding than non-targeted AcAP5 in mouse arterial injury model. Increasing the number of platelet-binding sites of FXa inhibitors may facilitate their adhesion to activated platelets, and further lower the bleeding risks. For this purpose, we introduced three RGD motifs into AcAP5 to generate a variant NR4 containing three platelet-binding sites. NR4 reserved its inherent anti-FXa activity. Protein-protein docking showed that all three RGD motifs were capable of binding to platelet receptor ?IIb?3. Molecular dynamics simulation demonstrated that NR4 has more opportunities to interact with ?IIb?3 than single-RGD-containing NR3. Flow cytometry analysis and rat arterial thrombosis model further confirmed that NR4 possesses enhanced platelet targeting activity. Moreover, NR4-treated mice showed a trend toward less tail bleeding time than NR3-treated mice in carotid artery endothelium injury model. Therefore, our data suggest that engineering multiple binding sites in one recombinant protein is a useful tool to improve its platelet-targeting efficiency.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC4949463 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Engineering Factor Xa Inhibitor with Multiple Platelet-Binding Sites Facilitates its Platelet Targeting.

Zhu Yuanjun Y Li Ruyi R Lin Yuan Y Shui Mengyang M Liu Xiaoyan X Chen Huan H Wang Yinye Y

Scientific reports 20160719

Targeted delivery of antithrombotic drugs centralizes the effects in the thrombosis site and reduces the hemorrhage side effects in uninjured vessels. We have recently reported that the platelet-targeting factor Xa (FXa) inhibitors, constructed by engineering one Arg-Gly-Asp (RGD) motif into Ancylostoma caninum anticoagulant peptide 5 (AcAP5), can reduce the risk of systemic bleeding than non-targeted AcAP5 in mouse arterial injury model. Increasing the number of platelet-binding sites of FXa in ...[more]

PMID: 27432161

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Project description:ObjectivePatients undergoing peripheral vascular intervention (PVI) (ie, endovascular revascularization) for symptomatic lower extremity peripheral artery disease remain at high risk for major adverse limb and cardiovascular events. High-quality evidence demonstrates the addition of a low-dose oral factor Xa inhibitor to single antiplatelet therapy, termed dual pathway inhibition (DPI), reduces the incidence of major adverse events in this population. This study aims to describe the longitudinal trends in factor Xa inhibitor initiation after PVI, identify patient and procedural characteristics associated with factor Xa inhibitor use, and describe temporal trends in antithrombic therapy post-PVI before vs after VOYAGER PAD.MethodsThis retrospective cross-sectional study was performed using data from the Vascular Quality Initiative PVI registry from January 2018 through June 2022. Multivariate logistic regression was utilized to determine predictors of factor Xa inhibitor initiation following PVI, reported as odds ratios (ORs) with 95% confidence intervals (CIs).ResultsA total of 91,569 PVI procedures were deemed potentially eligible for factor Xa inhibitor initiation and were included in this analysis. Overall rates of factor Xa inhibitor initiation after PVI increased from 3.5% in 2018 to 9.1% in 2022 (P < .0001). The strongest positive predictors of factor Xa inhibitor initiation after PVI were non-elective (OR, 4.36; 95% CI, 4.06-4.68; P < .0001) or emergent (OR, 8.20; 95% CI, 7.14-9.41; P < .0001) status. The strongest negative predictor was postoperative dual antiplatelet therapy prescription (OR, 0.20; 95% CI, 0.17-0.23; P < .0001), highlighting significant hesitation about use of DPI after PVI and limited translation of VOYAGER PAD findings into clinical practice. Antiplatelet medications remain the most common antithrombotic regimen after PVI, with almost 70% of subjects discharged on dual antiplatelet therapy and approximately 20% discharged on single antiplatelet therapy.ConclusionsFactor Xa inhibitor initiation after PVI has increased in recent years, although the absolute rate remains low, and most eligible patients are not prescribed this treatment.

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Engineering Factor Xa Inhibitor with Multiple Platelet-Binding Sites Facilitates its Platelet Targeting.

Publications

Engineering Factor Xa Inhibitor with Multiple Platelet-Binding Sites Facilitates its Platelet Targeting.

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