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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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-91165-8 |
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doaj-2f1cc945ff084274a10fe99842cf9bb1 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| 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 |
| spellingShingle |
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 Scientific Reports |
| 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 Publishing Group |
| series |
Scientific Reports |
| issn |
2045-2322 |
| publishDate |
2021-06-01 |
| 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. |
| url |
https://doi.org/10.1038/s41598-021-91165-8 |
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doaj-2f1cc945ff084274a10fe99842cf9bb12021-06-06T11:38:04ZengNature Publishing GroupScientific Reports2045-23222021-06-0111111710.1038/s41598-021-91165-8In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbαBenjamin Xiaoyi Li0Xiangrong Dai1Xiaohong Ruby Xu2Reheman Adili3Miguel Antonio Dias Neves4Xi Lei5Chuanbin Shen6Guangheng Zhu7Yiming Wang8Hui Zhou9Yan Hou10Tiffany Ni11Yfke Pasman12Zhongqiang Yang13Fang Qian14Yanan Zhao15Yongxiang Gao16Jing Liu17Maikun Teng18Alexandra H. Marshall19Eric G. Cerenzia20Mandy Lokyee Li21Heyu Ni22Lee’s Pharmaceutical Holdings LimitedLee’s Pharmaceutical Holdings LimitedDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoZhaoke Pharmaceutical Co. LimitedZhaoke Pharmaceutical Co. LimitedWannan Medical College First Affiliated Hospital, Yijishan HospitalSchool of Life Sciences, University of Science and Technology of ChinaSchool of Life Sciences, University of Science and Technology of ChinaSchool of Life Sciences, University of Science and Technology of ChinaDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoLee’s Pharmaceutical Holdings LimitedDepartment of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health TorontoAbstract 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.https://doi.org/10.1038/s41598-021-91165-8 |