Centre for Blood Research, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
Department of Chemistry, University of British Columbia, Vancouver, BC, Canada.
Nat Commun. 2023 Apr 26;14(1):2177. doi: 10.1038/s41467-023-37709-0.
Current treatments to prevent thrombosis, namely anticoagulants and platelets antagonists, remain complicated by the persistent risk of bleeding. Improved therapeutic strategies that diminish this risk would have a huge clinical impact. Antithrombotic agents that neutralize and inhibit polyphosphate (polyP) can be a powerful approach towards such a goal. Here, we report a design concept towards polyP inhibition, termed macromolecular polyanion inhibitors (MPI), with high binding affinity and specificity. Lead antithrombotic candidates are identified through a library screening of molecules which possess low charge density at physiological pH but which increase their charge upon binding to polyP, providing a smart way to enhance their activity and selectivity. The lead MPI candidates demonstrates antithrombotic activity in mouse models of thrombosis, does not give rise to bleeding, and is well tolerated in mice even at very high doses. The developed inhibitor is anticipated to open avenues in thrombosis prevention without bleeding risk, a challenge not addressed by current therapies.
目前预防血栓形成的治疗方法，即抗凝剂和血小板拮抗剂，仍然存在持续出血的风险。减少这种风险的改进治疗策略将具有巨大的临床影响。能够中和和抑制多聚磷酸盐（polyP）的抗血栓形成剂可能是实现这一目标的一种有效方法。在这里，我们报告了一种针对 polyP 抑制的设计理念，称为大分子聚阴离子抑制剂（MPI），具有高结合亲和力和特异性。通过对具有生理 pH 下低电荷密度但与 polyP 结合时增加其电荷的分子进行文库筛选，确定了有前途的抗血栓形成候选物，为提高其活性和选择性提供了一种巧妙的方法。先导 MPI 候选物在血栓形成的小鼠模型中表现出抗血栓形成活性，不会引起出血，即使在非常高的剂量下，在小鼠中也具有良好的耐受性。预计开发的抑制剂将在没有出血风险的情况下开辟血栓形成预防的途径，这是当前治疗方法无法解决的挑战。
