In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα.

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.

• Authors: Benjamin Xiaoyi Li, Xiangrong Dai, Xiaohong Ruby Xu, Reheman Adili, Miguel Antonio Dias Neves, Xi Lei, Chuanbin Shen, Guangheng Zhu, Yiming Wang, Hui Zhou, Yan Hou, Tiffany Ni, Yfke Pasman, Zhongqiang Yang, Fang Qian, Yanan Zhao, Yongxiang Gao, Jing Liu, Maikun Teng, Alexandra H Marshall, Eric G Cerenzia, Mandy Lokyee Li, Heyu Ni
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 11663 (06 03 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34083615 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Crotalid Venoms
• Fibrinolytic Agents
• Lectins, C-Type
• Platelet Glycoprotein GPIb-IX Complex
• Snake Venoms
• adhesion receptor
• von Willebrand Factor
• Ristocetin
• agkisacucetin protein, Agkistrodon acutus
• Thrombin

Topics

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