Carbajo Daniel, Pérez Yolanda, Castelo Gabriela F, Prats Eva, Bujons Jordi, Alfonso Ignacio
Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia, IQAC-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain.
NMR Facility, Institute for Advanced Chemistry of Catalonia, IQAC-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain.
ACS Pharmacol Transl Sci. 2025 Apr 29;8(5):1333-1346. doi: 10.1021/acsptsci.4c00747. eCollection 2025 May 9.
Fondaparinux is a highly anionic synthetic heparinoid pentasaccharide used as an anticoagulant for specific clinical conditions and surgeries. As a non-natural small-molecule drug, it presents pharmacokinetic and pharmacodynamic advantages, as well as high stability and low immunogenicity, when compared with different forms of heparin. However, its broader usage is hampered by different factors like price, existence of alternative anticoagulants, or, specifically in this case, the lack of an effective antidote that is highly recommendable for avoiding uncontrolled bleeding. In this work, we describe two synthetic small molecules derived from spermine (3AC and 3FF) that efficiently revert the anticoagulant activity of fondaparinux. In an enzymatic assay related to blood coagulation, the spermine derivatives show potent activity as fondaparinux antidotes, with higher activity than ciraparantag (a small molecule in the clinical phase as an anticoagulant antidote) and much higher activity than protamine, the only approved antidote for unfractioned heparin but inefficient against fondaparinux. Remarkably, naked-eye tests demonstrated their efficacy in freshly extracted mice blood. Mechanistic studies show that both small molecules strongly bind fondaparinux in buffered water, as detected by fluorescence and NMR spectroscopy and confirmed by molecular dynamics simulations. Thus, these spermine derivatives are promising reversal agents against heparinoid anticoagulants with a wide range of molecular weights, overcoming the drawbacks of those antidotes based on biomacromolecules.
磺达肝癸钠是一种高度阴离子化的合成类肝素五糖，用于特定临床病症和手术的抗凝治疗。作为一种非天然小分子药物，与不同形式的肝素相比，它具有药代动力学和药效学优势，以及高稳定性和低免疫原性。然而，其更广泛的应用受到多种因素的阻碍，如价格、替代抗凝剂的存在，或者在这种情况下，尤其缺乏一种高度推荐用于避免出血失控的有效解毒剂。在这项研究中，我们描述了两种源自精胺的合成小分子（3AC和3FF），它们能有效逆转磺达肝癸钠的抗凝活性。在一项与血液凝固相关的酶学检测中，精胺衍生物显示出作为磺达肝癸钠解毒剂的强大活性，其活性高于西帕曲班（一种处于临床阶段的小分子抗凝解毒剂），且远高于鱼精蛋白（唯一获批用于普通肝素的解毒剂，但对磺达肝癸钠无效）。值得注意的是，肉眼测试证明了它们在新鲜提取的小鼠血液中的有效性。机理研究表明，通过荧光和核磁共振光谱检测并经分子动力学模拟证实，这两种小分子在缓冲水中都能与磺达肝癸钠强烈结合。因此，这些精胺衍生物有望成为针对各种分子量类肝素抗凝剂的逆转剂，克服了那些基于生物大分子的解毒剂的缺点。
