Thymidine Phosphorylase: a Novel Target of Antiplatelet Therapy

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Project Summary/Abstract Platelet activation and aggregation is a major component of thrombosis, an underlying cause of myocardial infarction, ischemic stroke, and severe COVID-19, a new viral respiratory illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Various antiplatelet drugs are used clinically to prevent thrombosis. These drugs block platelet activation and aggregation systemically and, thus, have side effects (e.g., thrombocytopenia and hemorrhage). Therefore, new molecular mechanism-mediated antiplatelet and antithrombotic therapies are urgently needed. We recently discovered that thymidine phosphorylase (TYMP), a highly expressed protein in platelet cytosol, facilitates multiple agonist-induced platelet activation. TYMP haploinsufficiency or inhibition with its inhibitors significantly attenuates arterial thrombosis without disturbing systemic hemostasis. Most importantly, TYMP is increased in COVID-19 patients in an acuity-dependent manner. Increased plasma TYMP in COVID-19 patients occurs earlier than the increase in C-reactive protein, a predictive factor for inflammation and future risk of cardiovascular events. Increased TYMP is also positively associated with plasma D-dimer and lactate dehydrogenase levels and the presence of pulmonary symptoms. These findings indicate that TYMP may play a critical role in the development of severe COVID-19, and modulation of TYMP activity could potentially be a systemically safe therapy against COVID-19. To this end, it is necessary to elucidate the detailed mechanistic pathways of TYMP in platelet activation and thrombosis. We have clarified the role of TYMP in the platelet signaling pathway mediated by platelet glycoprotein VI (GPVI). However, we still do not know how TYMP deficiency or inhibition attenuates G-protein coupled receptor (GPCR)-mediated platelet activation and what TYMP’s role is in the hyperthrombotic milieu of severe COVID- 19. We will address these questions in the proposed specific aims. In Aim1, we will clarify the function of TYMP in GPCR-mediated platelet activation using specific GPCR agonists and antagonists and test the hypothesis that a combination of low-dose TYMP inhibitor and GPCR antagonist represents a new, safe dual antiplatelet therapy. In Aim 2, we will determine whether the SARS-CoV-2 spike protein enhances TYMP expression and subsequent microthrombi formation in the COVID-19 milieu. We will also investigate if TYMP deficiency or inhibition attenuates SARS-CoV-2 spike protein-associated microthrombosis and reduces mortality in mice. Our ongoing study suggest that pharmacological inhibition of TYMP with tipiracil, a selective TYMP inhibitor and an FDA-approved medication, is a promising anti-thrombotic therapy without bleeding disorders. Successful completion of this R15 renewal will pave the way for repurposing tipiracil as an antiplatelet medication for patients with high thrombotic risks, especially COVID-19 patients.