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.
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.
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|Gao, Wei; Xu, Yongmei; Liu, Jian et al. (2016) Epitope mapping by a Wnt-blocking antibody: evidence of the Wnt binding domain in heparan sulfate. Sci Rep 6:26245|
|Miller, Colton M; Donner, Aaron J; Blank, Emma E et al. (2016) Stabilin-1 and Stabilin-2 are specific receptors for the cellular internalization of phosphorothioate-modified antisense oligonucleotides (ASOs) in the liver. Nucleic Acids Res 44:2782-94|
|Hsieh, Po-Hung; Thieker, David F; Guerrini, Marco et al. (2016) Uncovering the Relationship between Sulphation Patterns and Conformation of Iduronic Acid in Heparan Sulphate. Sci Rep 6:29602|
|Rasineni, Karuna; Penrice, Daniel D; Natarajan, Sathish Kumar et al. (2016) Alcoholic vs non-alcoholic fatty liver in rats: distinct differences in endocytosis and vesicle trafficking despite similar pathology. BMC Gastroenterol 16:27|
|Whelihan, Matthew F; Cooley, Brian; Xu, Yongmei et al. (2016) In vitro and in vivo characterization of a reversible synthetic heparin analog. Thromb Res 138:121-9|
|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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