Thromb Haemost 2020; 120(10): 1432-1441
DOI: 10.1055/s-0040-1714215
Cellular Haemostasis and Platelets

Conformation-Specific Blockade of αIIbβ3 by a Non-RGD Peptide to Inhibit Platelet Activation without Causing Significant Bleeding and Thrombocytopenia

Chuanbin Shen*
1  Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan, China
2  KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
,
Ming Liu*
3  Department of Molecular and Cell Biology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
,
Huiwen Tian*
4  Department of Zoology, Life Sciences College of Nanjing Agricultural University, Nanjing, Jiangsu, China
,
Jiameng Li
4  Department of Zoology, Life Sciences College of Nanjing Agricultural University, Nanjing, Jiangsu, China
,
Runjia Xu
1  Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan, China
2  KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
,
James Mwangi
1  Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan, China
2  KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
5  Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China
,
Qiumin Lu
1  Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan, China
2  KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
,
Xue Hao
1  Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan, China
2  KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
,
Ren Lai
1  Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan, China
2  KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
4  Department of Zoology, Life Sciences College of Nanjing Agricultural University, Nanjing, Jiangsu, China
6  Sino-African Joint Research Center, CAS, Kunming Institute of Zoology, Kunming, Yunnan, China
› Author Affiliations
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).

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.


Supplementary Material



Publication History

Received: 26 July 2019

Accepted: 04 June 2020

Publication Date:
27 July 2020 (online)

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