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Int. J. Mol. Sci. 2017, 18(2), 269;

Uridine Triphosphate Thio Analogues Inhibit Platelet P2Y12 Receptor and Aggregation

Department of Cardiology/Angiology, University Hospital Giessen, 35392 Giessen, Germany
Department of Neurology, University Hospital Giessen, 35392 Giessen, Germany
Department of Cardiology/Angiology, Hannover Medical School, 30625 Hannover, Germany
Department of Cardiology/Angiology, University Hospital Marburg, 35043 Marburg, Germany
Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, 35392 Giessen, Germany
Author to whom correspondence should be addressed.
Academic Editor: Denise Jackson
Received: 6 November 2016 / Revised: 23 January 2017 / Accepted: 23 January 2017 / Published: 29 January 2017
(This article belongs to the Special Issue Mechanisms of Platelet Thrombus Formation)
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Platelet P2Y12 is an important adenosine diphosphate (ADP) receptor that is involved in agonist-induced platelet aggregation and is a valuable target for the development of anti-platelet drugs. Here we characterise the effects of thio analogues of uridine triphosphate (UTP) on ADP-induced platelet aggregation. Using human platelet-rich plasma, we demonstrate that UTP inhibits P2Y12 but not P2Y1 receptors and antagonises 10 µM ADP-induced platelet aggregation in a concentration-dependent manner with an IC50 value of ~250 °µM. An eight-fold higher platelet inhibitory activity was observed with a 2-thio analogue of UTP (2S-UTP), with an IC50 of 30 µM. The 4-thio analogue (4S-UTP) with an IC50 of 7.5 µM was 33-fold more effective. A three-fold decrease in inhibitory activity, however, was observed by introducing an isobutyl group at the 4S- position. A complete loss of inhibition was observed with thio-modification of the γ phosphate of the sugar moiety, which yields an enzymatically stable analogue. The interaction of UTP analogues with P2Y12 receptor was verified by P2Y12 receptor binding and cyclic AMP (cAMP) assays. These novel data demonstrate for the first time that 2- and 4-thio analogues of UTP are potent P2Y12 receptor antagonists that may be useful for therapeutic intervention. View Full-Text
Keywords: 2S-UTP; 4S-UTP; P2Y12 receptor; ADP; platelet aggregation 2S-UTP; 4S-UTP; P2Y12 receptor; ADP; platelet aggregation

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Gündüz, D.; Tanislav, C.; Sedding, D.; Parahuleva, M.; Santoso, S.; Troidl, C.; Hamm, C.W.; Aslam, M. Uridine Triphosphate Thio Analogues Inhibit Platelet P2Y12 Receptor and Aggregation. Int. J. Mol. Sci. 2017, 18, 269.

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