Apr 27, 2020

Targeting Thymidine Phosphorylase with Tipiracil Hydrochloride is a Safe and Effective Antithrombotic Therapy

BioRxiv : the Preprint Server for Biology
A. H. M. ZulfikerWei Li

Abstract

Rationale: Most of the current anti-platelet drugs inhibit platelet function permanently and have systemic side effects, including thrombocytopenia and hemorrhage. We previously found that thymidine phosphorylase (TYMP), a platelet cytoplasmic protein, facilitates multiple agonist-induced platelet activation and enhances thrombosis. A specific TYMP inhibitor, namely, tipiracil hydrochloride (TPI), has been approved by the U.S. Food and Drug Administration for clinical use as an auxiliary drug making it possible to be repositioned as an anti-platelet medicine. Objective: We aimed to test the hypothesis that TPI is a novel and safe anti-platelet drug by examining its role in platelet activation and thrombosis using both in vitro and in vivo studies. Methods and Results: By co-expression of TYMP and Lyn or Lyn-SH3 domain tagged with glutathione S-transferase, we showed the direct evidence that TYMP binds to the SH3 domain in its partners. TYMP haplodeficiency is sufficient to inhibit thrombosis in vivo regardless of gender. TPI treatment rapidly inhibited collagen- and ADP-induced platelet aggregation, which copied the phenotype of TYMP deficient platelets. Under both normal and hyperlipidemic conditions, treating wild type (WT) m...Continue Reading

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Mentioned in this Paper

Establishment and Maintenance of Localization
Diagnostic Radiology Modality
Patterns
Research
Electroencephalography
Magnetic Resonance Imaging
Spatial Distribution
Neuroma
Environment
Face

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