State Key Laboratory of Organometallic Chemistry, Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Department of Chemistry, Fudan University, 2205 Songhu Road, Shanghai 200438, China.
J Med Chem. 2024 Mar 14;67(5):3860-3873. doi: 10.1021/acs.jmedchem.3c02224. Epub 2024 Feb 26.
Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) are widely applied for surgical procedures and extracorporeal therapies, which, however, suffer bleeding risk. Protamine, the only clinically approved antidote, can completely neutralize UFH, but only partially neutralizes LMWHs, and also has a number of safety drawbacks. Here, we show that caltrop-like multicationic small molecules can completely neutralize both UFH and LMWHs. In vitro and ex vivo assays with plasma and whole blood and in vivo assays with mice and rats support that the lead compound is not only superior to protamine by displaying higher neutralization activity and broader therapeutic windows but also biocompatible. The effective neutralization dose and the maximum tolerated dose of the lead compound are determined to be 0.4 and 25 mg/kg in mice, respectively, suggesting good promise for further preclinical studies.
未分级肝素 (UFH) 和低分子肝素 (LMWHs) 广泛应用于外科手术和体外治疗，但存在出血风险。鱼精蛋白是唯一被临床批准的解毒剂，可完全中和 UFH，但仅部分中和 LMWHs，并且存在许多安全隐患。在这里，我们表明，类似菱角的多阳离子小分子可以完全中和 UFH 和 LMWHs。使用血浆和全血进行的体外和离体实验以及使用小鼠和大鼠进行的体内实验表明，该先导化合物不仅通过显示更高的中和活性和更宽的治疗窗口优于鱼精蛋白，而且具有生物相容性。在小鼠中，该先导化合物的有效中和剂量和最大耐受剂量分别确定为 0.4 和 25mg/kg，这表明其具有很好的进一步临床前研究前景。
