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，由于持续存在的出血风险而变得复杂。降低这种风险的改进治疗策略将产生巨大的临床影响。中和和抑制聚磷酸盐 (polyP) 的抗血栓形成剂可能是实现这一目标的有效方法。在这里，我们报告了一种针对 polyP 抑制的设计概念，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。通过对在生理 pH 下具有低电荷密度但在与 polyP 结合后电荷增加的分子进行文库筛选来鉴定先导抗血栓形成候选物，从而提供一种提高其活性和选择性的智能方法。领先的 MPI 候选药物在血栓形成的小鼠模型中表现出抗血栓活性，不会引起出血，即使在非常高的剂量下，小鼠也能很好地耐受。开发的抑制剂有望在没有出血风险的情况下开辟预防血栓形成的途径，这是目前疗法尚未解决的挑战。