Efficient targeted anticoagulant with active RGD motif

Bi, Qun; Zhou, Xue; Cen, Xiaodong; Qu, Hong; Luo, Jingchu; Yong, Huang; Zhu, Shenggeng

doi:10.1016/j.thromres.2006.11.013

Cited by 4 publications

(1 citation statement)

References 24 publications

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“…Thus, recombinant proteins usually contain a single-binding-site, such as the RGD motif in NR3 7 . With the capability of interacting with platelet α IIb β 3 receptor, the RGD motif has been served as a useful binding unit for targeting activated platelets 19 20 . As a functional RGD motif forms a small loop exposed on the protein surface 21 22 , we appealed to investigate whether engineering multiple RGD motifs in one protein could improve its platelet targeting.…”

Section: Discussionmentioning

confidence: 99%

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

Zhu

Lin

et al. 2016

Sci Rep

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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 αIIbβ3. Molecular dynamics simulation demonstrated that NR4 has more opportunities to interact with αIIbβ3 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.

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