Exposed
collagen on the diseased vessel wall is crucial for arterial
thrombosis. The currently developed antithrombotic drugs mostly target
blood components such as platelets and suffer from the risk of bleeding.
Therefore, anticollagen therapy of covering the collagen surface was
proposed as an alternative in our previous study, and an antithrombotic
peptide LWWNSYY was designed and validated. However, its application
was hindered due to the poor water solubility. In the present study,
in order to develop a novel antithrombotic peptide with enhanced water
solubility, redesigning of LWWNSYY to LEKNSTY using the EK pattern
was proposed. Improved solubility was obtained for LEKNSTY. Moreover,
the binding of LEKNSTY on the collagen surface was confirmed by molecular
docking, molecular dynamics simulations, and experimental validation.
A K
d of 0.91 ± 0.44 μM was
observed. The effective inhibition of platelet adhesion on the collagen
surface by LEKNSTY was demonstrated at an IC50 of 2.48
± 0.59 μg/mL. Therefore, the successful design of the antithrombotic
peptide LEKNSTY was confirmed, which would facilitate the research
into the interface involving thrombus and the development of antithrombotic
agents.
The
development of antithrombotic peptides targeting collagen was
proven effective, and an effective antithrombotic peptide LEKNSTY
was obtained in part I. However, the plasma stability of LEKNSTY was
found to be not good enough. In this part, the LEKNSTY was further
optimized for improvement in plasma stability by substitution using d-amino acid residues. Two novel antithrombotic peptides LekNStY
and lEKnsTy were designed, where lowercase letters represent d-amino acid residues. Improvements in plasma stability of both LekNStY
and lEKnsTy were experimentally
confirmed. Moreover, good binding of these antithrombotic peptides
on the collagen surface was confirmed by molecular dynamics simulation
and experimental validation. For example, a K
d of only 0.75 ± 0.10 μM was observed for lEKnsTy.
Moreover, LekNStY and lEKnsTy were found to inhibit platelet adhesion
on the collagen surface more effectively than LEKNSTY, and the IC
50 of lEKnsTy was only 2/5 of that of LEKNSTY.
These results confirmed the successful design of LekNStY and lEKnsTy
that had good plasma stability and could effectively inhibit arterial
thrombosis, which would be helpful for the research into interfaces
involved in thrombus formation and the development of antithrombotic
nanomedicine.
Binding of platelets on vascular endothelia at the damaged site using von Willebrand factor (vWF) as a bridge is of great significance for platelet adhesion and subsequent arterial thrombosis. Molecular...
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