Recombinant supercharged polypeptides for safe and efficient heparin neutralization

Tu, Jianfei; Liu, Qing; You, SangGuan; Meng, Zhuojun; Fang, Shiji; Yu, Binhong; Chen, Xumin; Zhou, Yu; Zeng, Lulu; Herrmann, Andreas; Chen, Gang; Shen, Jian; Zheng, Lifei; Ji, Jiansong

doi:10.1039/d3bm00628j

Cited by 2 publications

(1 citation statement)

References 53 publications

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“…In the past decade, a number of heparin antidotes have been developed, which include cationic macromolecules or polymers, − supramolecular polymers or frameworks, − peptides and proteins, − and various small molecules, including aminoquincarbamide surfen, sulfonated calix[ n ]arene, aromatic amide-derived foldamers, piperazine-derived arginine dimer PER977, spermine-derived library of amines, and γ-cyclodextrin-derived octacarboxylate . Compared with macromolecular and polymeric counterparts, small-molecule antidotes have single structures, which endow them with several advantages such as more controllable synthesis and quality, more predictable efficacy, higher storage stability, and easier analysis of distribution and metabolism in body.…”

Section: Introductionmentioning

confidence: 99%

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

Zong,

Lei,

et al. 2024

J. Med. Chem.

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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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