Division of Basic Pharmaceutical Sciences College of Pharmacy, Xavier University of Louisiana, New Orleans, LA, 70125, USA.
RCMI Cancer Research Center & Department of Chemistry, Xavier University of Louisiana, New Orleans, LA, 70125, USA.
ChemistryOpen. 2020 Nov 10;9(11):1161-1172. doi: 10.1002/open.202000277. eCollection 2020 Nov.
The inhibition of factor XIa (FXIa) is a trending paradigm for the development of new generations of anticoagulants without a substantial risk of bleeding. In this report, we present the discovery of a benzyl tetra-phosphonate derivative as a potent and selective inhibitor of human FXIa. Biochemical screening of four phosphonate/phosphate derivatives has led to the identification of the molecule that inhibited human FXIa with an value of ∼7.4 μM and a submaximal efficacy of ∼68 %. The inhibitor was at least 14-fold more selective to FXIa over thrombin, factor IXa, factor Xa, and factor XIIIa. It also inhibited FXIa-mediated activation of factor IX and prolonged the activated partial thromboplastin time of human plasma. In Michaelis-Menten kinetics experiment, inhibitor reduced the V of FXIa hydrolysis of a chromogenic substrate without significantly affecting its K suggesting an allosteric mechanism of inhibition. The inhibitor also disrupted the formation of FXIa - antithrombin complex and inhibited thrombin-mediated and factor XIIa-mediated formation of FXIa from its zymogen factor XI. Inhibitor has been proposed to bind to or near the heparin/polyphosphate-binding site in the catalytic domain of FXIa. Overall, inhibitor is the first benzyl tetraphosphonate small molecule that allosterically inhibits human FXIa, blocks its physiological function, and prevents its zymogen activation by other clotting factors under conditions. Thus, we put forward benzyl tetra-phosphonate as a novel lead inhibitor of human FXIa to guide future efforts in the development of allosteric anticoagulants.
因子 XIa（FXIa）的抑制作用是开发新一代抗凝剂的趋势，其出血风险较小。在本报告中，我们介绍了一种苯甲基四膦酸酯衍生物的发现，该衍生物是一种有效的、选择性的人 FXIa 抑制剂。对四种膦酸酯/磷酸酯衍生物的生化筛选导致了发现能以约 7.4μM 的 值和约 68%的亚最大功效抑制人 FXIa 的分子。抑制剂对 FXIa 的选择性至少比凝血酶、因子 IXa、因子 Xa 和因子 XIIIa 高 14 倍。它还抑制 FXIa 介导的因子 IX 的激活，并延长人血浆的活化部分凝血活酶时间。在 Michaelis-Menten 动力学实验中，抑制剂 降低了 FXIa 水解显色底物的 V ，而对其 K 没有显著影响，提示抑制作用是变构机制。抑制剂还破坏了 FXIa-抗凝血酶复合物的形成，并抑制了凝血酶介导的和因子 XIIa 介导的因子 XI 转化为 FXIa。抑制剂 被提议与 FXIa 催化域中的肝素/多聚磷酸盐结合位点结合或附近结合。总的来说，抑制剂 是第一个变构抑制人 FXIa、阻断其生理功能、并防止其在生理条件下被其他凝血因子激活的苯甲基四膦酸酯小分子。因此，我们提出苯甲基四膦酸酯 作为人 FXIa 的新型先导抑制剂，以指导开发变构抗凝剂的未来工作。
