Discovery of a Piperazine-Based Quaternary Ammonium Macrocycle as a Universal Reversal Agent for Heparin Anticoagulants

The development of a biocompatible antidote that can efficiently neutralize the anticoagulation activity of both unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) represents an unmet medical need. Here, we report that a piperazine-derived tetracationic macrocycle can efficiently neutralize both UFH and LMWHs, including dalteparin, enoxaparin, and nadroparin. In vitro and in vivo assays reveal that the compound outperforms protamine, exhibiting significantly improved neutralization activity, a broad therapeutic window for all heparins, and high biocompatibility, which is confirmed by its very low coagulation and hemolysis effect, as well as a high therapeutic index (20.5), defined as the ratio of the maximum tolerated dose to the effective therapeutic dose. Molecular dynamics simulations indicate that binding may occur through interlocked threading and direct contact patterns, which are stabilized by intermolecular hydrogen bonding and ion-pair electrostatic attraction.