Thromb Haemost 2020; 120(10): 1351
DOI: 10.1055/s-0040-1715898
T&H Insights

Antithrombotics from Frog Skin Secretions

Heyu Ni
1  Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science-Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
2  Toronto Platelet Immunobiology Group, Toronto, Ontario, Canada
3  Canadian Blood Services Centre for Innovation, Toronto, Ontario, Canada
4  Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
5  Department of Physiology, University of Toronto, Toronto, Ontario, Canada
6  Department of Medicine, University of Toronto, Toronto, Ontario, Canada
› Author Affiliations
Funding This study was funded by Canadian Institutes for Health Research (foundation grant: 389035) and Heart and Stroke Foundation of Canada (grant: G-17-0018663).

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

In this issue of Thrombosis and Haemostasis, Shen et al described a non-RGD 15-mer peptide isolated from skin secretions of the frog Amolops loloensis, which could selectively bind to activated platelet αIIbβ3 integrin and inhibit platelet aggregation induced either by physiological agonists or by an allosteric activator targeting the αIIb transmembrane domain (anti-αIIb TM). This peptide, named Zongdian platelet inhibitor (ZDPI) was able to reduce binding of activated platelets to soluble fibrinogen, and to suppress platelet spreading (but not adhesion) on immobilized fibrinogen. Importantly, ZDPI could inhibit carotid arterial thrombosis without inducing significant bleeding or thrombocytopenia in mice, making it a promising candidate or template to develop antithrombotics with reduced side effects.[1]

It is interesting that ZDPI (FRGCWLKNYSPRGCL-NH2) neither contains a RGD motif nor the key negatively charged “D,” which has been considered important for integrin recognition.[2] Consistently, RGD peptides could not inhibit its binding to αIIbβ3. The authors proposed it could bind to the fibrinogen and fibronectin recognition area on αIIbβ3 since it interfered with binding from these integrin ligands to platelets. Alternatively, it may bind to an area that regulates integrin conformation, such as the integrin PSI domain. We indeed recently demonstrated that integrin family PSI domains exerted endogenous thiol isomerase function and that targeting these could inhibit αIIbβ3–ligand interactions and thrombosis.[3] Since ZDPI has two cysteine residues, it would be interesting to explore whether disulfide bond exchange between ZDPI and PSI domain or other cysteine-rich domains of αIIbβ3 can occur, and whether this could subsequently downregulate αIIbβ3 affinity for its ligands. Although a promising antithrombotic candidate, ZDPI has a relatively short half-live in vivo and its efficacy is weaker than Integrilin, calling for further modifications toward drug development.



Publication History

Received: 04 August 2020

Accepted: 04 August 2020

Publication Date:
09 September 2020 (online)

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