2. Academic Validation
  3. Discovery of a Piperazine-Based Quaternary Ammonium Macrocycle as a Universal Reversal Agent for Heparin Anticoagulants

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

  • J Med Chem. 2026 Jan 22;69(2):1752-1765. doi: 10.1021/acs.jmedchem.5c03525.
Shi-Xian Gan 1,  Yajie Zhu 2,  Congying Guo 1,  Jiangshan Zhang 1,  Haodong Fang 2,  Haofeng Zhu 3,  Ru-Lei Zhang 1,  Xiaoyun Dong 1,  Qiao-Yan Qi 2,  Hui Wang 1,  Wei Zhou 1,  Gang Zhao 3 4,  Dan-Wei Zhang 1,  Zhan-Ting Li 1 2,  Shang-Bo Yu 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Fudan University, 2205 Songhu Road, Shanghai 200438, China.
  • 2 State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
  • 3 Shinewin Pharmaceuticals, 108 Yuxin Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
  • 4 School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, China.
PMID: 41498425 DOI: 10.1021/acs.jmedchem.5c03525
Abstract

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.

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