Development of anticoagulant sulfated glycans

Sulfated glycan 8-mer is a carbohydrate-based compound with anticoagulant activity. The goal of this project is to replace animal-sourced low-molecular weight heparin (LMWH) with the 8- mer. LMWHs are partially depolymerized natural products of heparin, which are isolated from porcine intestine. A worldwide distribution of contaminated heparin in 2007 was associated with 85 deaths in the US, which is impacted the supply of LMWH. LMWHs are complex mixtures, having average molecular masses of 3500-6000 Daltons, corresponding to 12-20 saccharide units. The production of homogeneous LMWHs has not been possible due to difficulties in the synthesis. Glycan Therapeutics proposes to use an innovative chemoenzymatic approach to prepare synthetic heparin to substitute animal-sourced LMWH. The 8-mer product possesses following properties compared with other candidates: relative short synthesis, fast clearance property and low risk for heparin-induced thrombocytopenia. Two specific aims are proposed. Aim 1 is to scale up the synthesis of 8-mer by 10-fold in the phase I funding period and 100-fold in the phase II funding period. Aim 2 is to conduct the pharmacodynamic analysis of 8-mer and enoxaparin in advanced animal models using the quantitative LC-MS/MS method. In phase I funding period, the focus is on method development for analyzing 8-mer and enoxaparin in a mouse model. In the phase II funding period, we will analyze the pharmacodynamics of 8-mer and enoxaparin in a nonhuman primate model. The completion of this project will modernize this century-old drug with improved safety and anticoagulant properties.