The development of a novel antagonist for the treatment of cardiovascular disease
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The binding of VWF to GpIb-α is a critical step for maintaining normal haemostasis. The interaction between VWF with GpIb initiates the adhesion and aggregation of platelets at an injury site in the blood vessel wall. This binding is specific to high shear conditions that are typically found in small arterioles where the shear rates vary between 500-5000 s-1 . However, excessive binding of GpIb-α and VWF under normal conditions can cause stroke or myocardial infarction (MI). The purpose behind blocking GpIb is to stop the initial adhesion and stimulation of platelets under high shear conditions. There have been several attempts to generate GpIb-α inhibitors, such as the monoclonal antibody H6B4, OS-1 peptide, and the snake venom anfibatide. However, only anfibatide has successfully reached the clinical trials. In this project, we aimed to design a novel GpIb inhibitor for the treatment of cardiovascular disease. We performed both high-throughput docking as well as pharmacophore based screening to identify lead compounds for development. We then performed platelet aggregation assays, high shear flow experiments to assess their function ex vivo, and ELISA assays to investigate the binding interaction between the tested compounds and GpIb. A pharmacophore was generated based on GpIb-α crystal structure and published mutagenic data. The cyclic peptide GKYFG from the pharmacophore screening inhibited the interaction between VWF and GpIb-α under high shear conditions at a concentration of 0.1 mM (P