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Sci Rep ; 11(1): 11663, 2021 06 03.
Article in English | MEDLINE | ID: mdl-34083615

ABSTRACT

The interaction of platelet GPIbα with von Willebrand factor (VWF) is essential to initiate platelet adhesion and thrombosis, particularly under high shear stress conditions. However, no drug targeting GPIbα has been developed for clinical practice. Here we characterized anfibatide, a GPIbα antagonist purified from snake (Deinagkistrodon acutus) venom, and evaluated its interaction with GPIbα by surface plasmon resonance and in silico modeling. We demonstrated that anfibatide interferds with both VWF and thrombin binding, inhibited ristocetin/botrocetin- and low-dose thrombin-induced human platelet aggregation, and decreased thrombus volume and stability in blood flowing over collagen. In a single-center, randomized, and open-label phase I clinical trial, anfibatide was administered intravenously to 94 healthy volunteers either as a single dose bolus, or a bolus followed by a constant rate infusion of anfibatide for 24 h. Anfibatide inhibited VWF-mediated platelet aggregation without significantly altering bleeding time or coagulation. The inhibitory effects disappeared within 8 h after drug withdrawal. No thrombocytopenia or anti-anfibatide antibodies were detected, and no serious adverse events or allergic reactions were observed during the studies. Therefore, anfibatide was well-tolerated among healthy subjects. Interestingly, anfibatide exhibited pharmacologic effects in vivo at concentrations thousand-fold lower than in vitro, a phenomenon which deserves further investigation.Trial registration: Clinicaltrials.gov NCT01588132.


Subject(s)
Blood Platelets/drug effects , Blood Platelets/metabolism , Crotalid Venoms/therapeutic use , Fibrinolytic Agents/therapeutic use , Lectins, C-Type/therapeutic use , Platelet Glycoprotein GPIb-IX Complex/antagonists & inhibitors , Snake Venoms/therapeutic use , Animals , Blood Coagulation/drug effects , Crotalid Venoms/chemistry , Crotalid Venoms/isolation & purification , Crotalid Venoms/pharmacokinetics , Crotalinae , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/isolation & purification , Fibrinolytic Agents/pharmacokinetics , Healthy Volunteers , Humans , Lectins, C-Type/chemistry , Lectins, C-Type/isolation & purification , Models, Molecular , Platelet Adhesiveness/drug effects , Platelet Aggregation/drug effects , Platelet Count , Platelet Glycoprotein GPIb-IX Complex/chemistry , Protein Binding , Protein Conformation , Ristocetin/pharmacology , Snake Venoms/chemistry , Snake Venoms/isolation & purification , Snake Venoms/pharmacokinetics , Structure-Activity Relationship , Thrombin/pharmacology , Thrombosis/prevention & control , von Willebrand Factor/chemistry , von Willebrand Factor/metabolism
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