Development of the Antithrombotic Peptide LEKNSTY Targeting the Collagen Surface: I. Design and Validation.

Abstract

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 Kd 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.