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Homogeneous low-molecular-weight heparins with reversible anticoagulant activity

Nature Chemical Biology volume 10, pages 248–250 (2014)Cite this article

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Abstract

Low-molecular-weight heparins (LMWHs) are carbohydrate-based anticoagulants clinically used to treat thrombotic disorders, but impurities, structural heterogeneity or functional irreversibility can limit treatment options. We report a series of synthetic LMWHs prepared by cost-effective chemoenzymatic methods. The high activity of one defined synthetic LMWH against human factor Xa (FXa) was reversible in vitro and in vivo using protamine, demonstrating that synthetically accessible constructs can have a critical role in the next generation of LMWHs.

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Figure 1: Targeted structures and schematic synthesis of synthetic LMWHs.
Figure 2: Determination of the clearance, anti-FXa activity and sensitivity to protamine neutralization of synthetic LMWHs.

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Acknowledgements

We thank J.E. Rogers for helpful discussions. This work is supported in part by US National Institutes of Health grants HL094463 (to J.L.), GM102137 (to J.L.), HL62244 (to R.J.L.), HL096972 (to R.J.L.), GM38060 (to R.J.L.) HL096679 (to R.P.) and HL117659 (to N.S.K. and R.P.). E.M.S. is supported by a US National Institutes of Health Research Training Grant (T32-HL007149). K.C. is a recipient of a Royal Thai Government fellowship.

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Authors and Affiliations

  1. Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA

    Yongmei Xu, Kasemsiri Chandarajoti, Po-Hung Hsieh, Truong Q Pham & Jian Liu

  2. Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA

    Chao Cai, Lingyun Li & Robert J Linhardt

  3. Division of Hematology/Oncology, Department of Medicine, McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA

    Erica M Sparkenbaugh, Nigel S Key & Rafal Pawlinski

  4. Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Science, Shandong University, Jinan, China

    Juzheng Sheng

  5. Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA

    Edward N Harris

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  1. Yongmei Xu
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Contributions

Y.X. synthesized synthetic LMWHs and analyzed in vitro anti-FXa activity and protamine neutralization. C.C. conducted 1D and 2D NMR analysis. K.C. and E.M.S. determined the reversibility of LMWH anti-FXa activity and performed tail bleeding experiments. P.-H.H. conducted NMR analysis. L.L. did the high-resolution MS analysis. T.Q.P. expressed and purified enzymes. N.S.K. and R.P. designed and analyzed the ex vivo protamine neutralization. R.P. designed the tail bleeding experiment. J.S. helped develop synthetic routes. E.N.H. determined the metabolic pathways for synthetic LMWHs. R.J.L. did data analysis and wrote the manuscript. J.L. designed the project and wrote the manuscript. All authors participated in discussions and critically read the manuscript.

Corresponding authors

Correspondence to Robert J Linhardt or Jian Liu.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Tables 1 and 2, Supplementary Note and Supplementary Figures 1–36. (PDF 8681 kb)

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Xu, Y., Cai, C., Chandarajoti, K. et al. Homogeneous low-molecular-weight heparins with reversible anticoagulant activity. Nat Chem Biol 10, 248–250 (2014). https://doi.org/10.1038/nchembio.1459

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