This application is submitted in response to the announcement of PAS-15-168, entitled ?New Directions in Hematology Research (Shine-II) (R01). The primary goal of this proposal is to develop a synthetic form of ultra-low molecular weight heparin (sULMWH) to substitute animal sourced heparin. Heparin is a commonly used medicine to treat thrombotic disorders. It is isolated from porcine intestine through a long and unreliable supply chain. Heparin and its depolymerized product, known as low-molecular weight heparin (LMWH) are a mixture of structurally complex sulfated carbohydrates. The structural heterogeneity in nature makes heparin vulnerable to contamination. A worldwide distribution of contaminated heparin in 2007 was associated with 254 deaths in the US, demonstrating that US public needs a safer and more reliable supply chain of heparin. In 2016, US congress expresses concerns over the safety of heparin supply chains and urges US Food and Drug Administration to intensify its efforts to eliminate the risk of contamination and adulteration. In this proposal, we propose to investigate a heparin octasaccharide (8-mer) and a heparin heptasaccharide (7-mer). Chemical synthesis of heparin oligosaccharides larger than hexasaccharides is very difficult. Both the 8-mer and 7-mer, designated sULMWHs, will be synthesized with the innovative chemoenzymatic method developed by Professor Jan Liu (University of North Carolina). The chemoenzymatic method is a high efficient method to prepare heparin oligosaccharides, offering the possibility to prepare sULMWH in large scale and the competitive price. In addition, unlike previously reported heparin oligosaccharides, the 8-mer displays a fast clearance rate in both rat and mouse animal models. The fast clearance anticoagulant is in demand in clinics as such property is expected to reduce the bleeding side effect. We propose to investigate sULMWH from synthesis to biology and pharmacology using a multi-disciplinary approach. The results from our proposed studies will lead to a new and safe form of heparin.
Heparin and low molecular weight are commonly used anticoagulant drugs. A synthetic heparin should be the next generation of anticoagulant because the synthetic oligosaccharides will eliminate the needs for animal- sourced materials and improve the safety of heparin drug. In this proposal, we will investigate the synthesis and conduct pharmacological evaluation of two synthetic ultra-low molecular weight heparins.