title: A G-quartet oligonucleotide blocks glycoprotein Ib-mediated platelet adhesion and aggregation under flow conditions.
abstract: Platelets arrest bleeding by adhering to and aggregating on the subendothelium exposed at the site of vessel injury. This process is initiated by the interaction between the subendothelium von Willebrand factor (VWF) and the glycoprotein (GP) Ib-IX-V complex on platelets. However, the same interaction also results in thrombosis at the site of a ruptured atherosclerotic plaque. Reagents regulating the GP Ib-VWF interaction will therefore have direct impact on haemostasis and thrombosis. We have characterised an oligonucleotide G-quartet (T30923) that specifically blocks VWF binding to GP Ibalpha, the VWF-binding subunit of the GP Ib-IX-V complex. We evaluated the potential interactions of T30923 with GP Ibalpha and VWF A1 domain by computer simulated molecular dockings, which identified four T30923 docking sites in the beta-sheets of the N-terminal region of GP Ibalpha (E14-D18, S39, D63-S64, and D83-S85). Experimentally, T30923 bound GP Ibalpha and dose-dependently blocked platelet aggregation induced by ristocetin and thrombin, but not by botrocetin, collagen, TRAP, and ADP. It also blocked shear-induced platelet aggregation and thrombus formation on immobilised VWF under arterial shear stress. These results demonstrate that T30923 may have therapeutic potentials to regulate the GP Ibalpha-VWF interaction.
authors.affiliation: Section of Thrombosis Research, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.forename: Aubrey
authors.initials: A
authors.lastname: Bernardo
authors.forename: Qiqing
authors.initials: Q
authors.lastname: Zhu
authors.forename: Yongli
authors.initials: Y
authors.lastname: Guan
authors.forename: Wensheng
authors.initials: W
authors.lastname: Sun
authors.forename: Jose A
authors.initials: JA
authors.lastname: Lopez
authors.forename: Naijie
authors.initials: N
authors.lastname: Jing
authors.forename: Jing-fei
authors.initials: JF
authors.lastname: Dong
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006023:Glycoproteins / Q000737:chemistry*; D006801:Humans; D008968:Molecular Conformation; D009841:Oligonucleotides / Q000737:chemistry* / Q000494:pharmacology; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013314:Stress, Mechanical; D014841:von Willebrand Factor / Q000737:chemistry
chemical_list: D006023:Glycoproteins; D009841:Oligonucleotides; D019038:Platelet Glycoprotein GPIb-IX Complex; C545001:T30923; D014841:von Willebrand Factor