2. Academic Validation
  3. Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo

Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo

  • J Med Chem. 2024 Feb 26. doi: 10.1021/acs.jmedchem.3c02224.
Yang Zong 1,  Zhuo Lei 1,  Shang-Bo Yu 1,  Ling-Yu Zhang 2,  Yan Wu 2,  Ke Feng 1,  Qiao-Yan Qi 1,  Yamin Liu 2,  Yajie Zhu 1,  Peng Guo 1,  Wei Zhou 2,  Dan-Wei Zhang 2,  Zhan-Ting Li 1 2
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Chemistry, Fudan University, 2205 Songhu Road, Shanghai 200438, China.
PMID: 38407934 DOI: 10.1021/acs.jmedchem.3c02224
Abstract

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.

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