Foster Holly, Wilson Clare, Gauer Julia S, Xu Rui-Gang, Howard Mark J, Manfield Iain W, Ariëns Robert, Naseem Khalid, Vidler Lewis R, Philippou Helen, Foster Richard
School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), School of Medicine, University of Leeds, Leeds LS2 9JT, U.K.
ACS Med Chem Lett. 2022 Jan 20;13(2):171-181. doi: 10.1021/acsmedchemlett.1c00414. eCollection 2022 Feb 10.
The GPVI platelet receptor was recently validated as a safe antiplatelet target for the treatment of thrombosis using several peptidic modulators. In contrast, few weakly potent small-molecule GPVI antagonists have been reported. Those that have been published often lack evidence for target engagement, and their biological efficacy cannot be compared because of the natural donor variability associated with the assays implemented. Herein, we present the first side-by-side assessment of the reported GPVI small-molecule modulators. We have characterized their functional activities on platelet activation and aggregation using flow cytometry as well as light transmission and electrical impedance aggregometry. We also utilized microscale thermophoresis (MST) and saturation transfer difference (STD) NMR to validate GPVI binding and have used this along with molecular modeling to suggest potential binding interactions. We conclude that of the compounds examined, losartan and compound are currently the most viable GPVI modulators.
糖蛋白VI（GPVI）血小板受体最近被证实是一种安全的抗血小板靶点，可使用多种肽类调节剂来治疗血栓形成。相比之下，报道的弱效小分子GPVI拮抗剂很少。已发表的那些拮抗剂往往缺乏靶点结合的证据，并且由于所实施检测方法中存在的天然供体变异性，无法对它们的生物学功效进行比较。在此，我们对已报道的GPVI小分子调节剂进行了首次并列评估。我们使用流式细胞术以及光透射和电阻抗聚集测定法，对它们在血小板活化和聚集中的功能活性进行了表征。我们还利用微量热泳动（MST）和饱和转移差（STD）核磁共振来验证GPVI结合，并将此与分子建模一起用于推测潜在的结合相互作用。我们得出结论，在所研究的化合物中，氯沙坦和化合物目前是最可行的GPVI调节剂。
