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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2f1cc945ff084274a10fe99842cf9bb1
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spelling	oai:doaj.org-article:2f1cc945ff084274a10fe99842cf9bb12021-12-02T15:56:41ZIn vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα10.1038/s41598-021-91165-82045-2322https://doaj.org/article/2f1cc945ff084274a10fe99842cf9bb12021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91165-8https://doaj.org/toc/2045-2322Abstract 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.Benjamin Xiaoyi LiXiangrong DaiXiaohong Ruby XuReheman AdiliMiguel Antonio Dias NevesXi LeiChuanbin ShenGuangheng ZhuYiming WangHui ZhouYan HouTiffany NiYfke PasmanZhongqiang YangFang QianYanan ZhaoYongxiang GaoJing LiuMaikun TengAlexandra H. MarshallEric G. CerenziaMandy Lokyee LiHeyu NiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα
description	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.
format	article
author	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
author_facet	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
author_sort	Benjamin Xiaoyi Li
title	In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα
title_short	In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα
title_full	In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα
title_fullStr	In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα
title_full_unstemmed	In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα
title_sort	in vitro assessment and phase i randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet gpibα
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2f1cc945ff084274a10fe99842cf9bb1
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In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα

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