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DOI: 10.1055/s-0040-1714215
Conformation-Specific Blockade of αIIbβ3 by a Non-RGD Peptide to Inhibit Platelet Activation without Causing Significant Bleeding and Thrombocytopenia
Funding This work was supported by funding from the Chinese Academy of Sciences (XDB31000000, Y802B81201, and XDA12020334), Youth Innovation Promotion Association of the Chinese Academy of Sciences (QYZDJ-SSW-SMC012), the National Science Foundation of China (331372208, 31640071, 31770835, and 31801975), Yunnan Province (2015HA023), and Biological Resources Program, Chinese Academy of Sciences (KFJ-BRP-008).![](https://www.thieme-connect.de/media/10.1055-s-00035024/202010/lookinside/thumbnails/10-1055-s-0040-1714215_190446-1.jpg)
Abstract
Bleeding and thrombocytopenia to readministration are the most serious side effects of clinical integrin αIIbβ3 antagonists such as RGD-containing peptides. Here we show that a non-RGD peptide ZDPI, identified from skin secretions of Amolops loloensis, inhibited platelet aggregation induced by agonists, such as adenosine diphosphate, collagen, arachidonic acid, PAR1AP, and integrin αIIbβ3 allosteric activator, and reduces soluble fibrinogen binding to activated platelets without perturbing adhesion numbers on immobilized fibrinogen. Further study showed that ZDPI preferred to bind to the active conformation of integrin αIIbβ3, and thus inhibited c-Src-mediated integrin signaling transduction. In contrast to currently used clinical blockers of integrin αIIbβ3, which are all conformation-unspecific blockers, ZDPI conformation specifically binds to activated integrin αIIbβ3, subsequently suppressing platelet spreading. In vivo study revealed that ZDPI inhibited carotid arterial thrombosis with limited bleeding and thrombocytopenia. A non-RGD peptide which targets the active conformation of integrin αIIbβ3, such as ZDPI, might be an excellent candidate or template to develop antithrombotics without significant bleeding and thrombocytopenia side effects.
Authors' Contributions
C.S., M.L., and H.T. performed the experiments, analyzed the data, and created the figures; J.L., R.X., and J.M. performed the experiments; X.H. performed the experiments and analyzed the data; R.L. designed the research, analyzed the data, and wrote the paper.
* These authors contributed equally to this work.
Publication History
Received: 26 July 2019
Accepted: 04 June 2020
Article published online:
27 July 2020
© 2020. Thieme. All rights reserved.
Georg Thieme Verlag KG
Stuttgart · New York
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