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.