The proposal is aimed to improve the pharmacological effects of low-molecular weight heparins (LMWH). This project is a collaborative effort of four research groups, including Dr. Jian Liu (University of North Carolina) Dr. Robert Linhardt (Rensselaer Polytechnic Institute), Dr. Edward Harris (University of Nebraska, Lincoln) and Dr. Jawed Fareed (Loyola University Medical Center). LWMH is a widely used anticoagulant drug to treat thrombotic disorders. The currently marketed LMWH drugs are a mixture of sulfated poly-/oligo-saccharides, which are vulnerable to contamination and batch-to-batch variability. We plan to synthesize structurally homogeneous LMWH to eliminate the structural heterogeneity. The new LMWH constructs should display consistent anticoagulant activity, improved sensitivity to protamine neutralization, and controlled metabolic pathway. The synthesis of homogeneous LMWH will be completed using a chemo enzymatic approach. The pharmacological effects of the products will be evaluated in mouse and primate models. The success of this project will optimize the structures of heparin-based drugs with improved safety and efficacy.

Public Health Relevance

Low-molecular weight heparin is a commonly used anticoagulant drug. Currently, low-molecular weight heparin is prepared from the degradation of heparin that is isolated from animal tissues. It has been known that animal-sourced heparin is vulnerable to contamination. This project is aimed to design and synthesize structurally homogeneous low-molecular weight heparins to improve its pharmacological effects as well as eliminate the need for animal-sourced heparin.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL094463-05
Application #
8578129
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Sarkar, Rita
Project Start
2009-02-13
Project End
2017-05-31
Budget Start
2013-08-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$390,190
Indirect Cost
$90,426
Name
University of North Carolina Chapel Hill
Department
None
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Cai, Chao; Dickinson, Demetria M; Li, Lingyun et al. (2014) Fluorous-assisted chemoenzymatic synthesis of heparan sulfate oligosaccharides. Org Lett 16:2240-3
Fu, Li; Li, Lingyun; Cai, Chao et al. (2014) Heparin stability by determining unsubstituted amino groups using hydrophilic interaction chromatography mass spectrometry. Anal Biochem 461:46-8
Sterner, Eric; Li, Lingyun; Paul, Priscilla et al. (2014) Assays for determining heparan sulfate and heparin O-sulfotransferase activity and specificity. Anal Bioanal Chem 406:525-36
Liu, Zhangguo; Zhang, Fuming; Li, Lingyun et al. (2014) Compositional analysis and structural elucidation of glycosaminoglycans in chicken eggs. Glycoconj J 31:593-602
Xu, Yongmei; Cai, Chao; Chandarajoti, Kasemsiri et al. (2014) Homogeneous low-molecular-weight heparins with reversible anticoagulant activity. Nat Chem Biol 10:248-50
Liu, Chunhui; Sheng, Juzheng; Krahn, Juno M et al. (2014) Molecular mechanism of substrate specificity for heparan sulfate 2-O-sulfotransferase. J Biol Chem 289:13407-18
Chandarajoti, Kasemsiri; Xu, Yongmei; Sparkenbaugh, Erica et al. (2014) De novo synthesis of a narrow size distribution low-molecular-weight heparin. Glycobiology 24:476-86
Hsieh, Po-Hung; Xu, Yongmei; Keire, David A et al. (2014) Chemoenzymatic synthesis and structural characterization of 2-O-sulfated glucuronic acid-containing heparan sulfate hexasaccharides. Glycobiology 24:681-92
Gasimli, Leyla; Glass, Charles A; Datta, Payel et al. (2014) Bioengineering murine mastocytoma cells to produce anticoagulant heparin. Glycobiology 24:272-80
Liu, Jian; Linhardt, Robert J (2014) Chemoenzymatic synthesis of heparan sulfate and heparin. Nat Prod Rep 31:1676-85

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