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 #
5R01HL094463-06
Application #
8711536
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
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$374,845
Indirect Cost
$66,825
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Purushothaman, Anurag; Bandari, Shyam Kumar; Liu, Jian et al. (2016) Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions. J Biol Chem 291:1652-63

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