Heparosan-Derived Heparan Sulfate/Heparin-Like Compounds: One Kind of Potential Therapeutic Agents

Institute of Biochemical and Biotechnological Drug & National Glycoengineering Research Center, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
Medicinal Research Reviews (Impact Factor: 8.43). 05/2013; 33(3). DOI: 10.1002/med.21263
Source: PubMed


Heparan sulfate (HS) is a highly sulfated glycosaminoglycan and exists in all animal tissues. HS and heparin are very similar, except that heparin has higher level of sulfation and higher content of iduronic acid. Despite the fact that it is a century-old drug, heparin remains as a top choice for treating thrombotic disorders. Pharmaceutical heparin is derived from porcine intestine or bovine lung via a long supply chain. This supply chain is vulnerable to the contamination of animal pathogens. Therefore, new methods for manufacturing heparin or heparin-like substances devoid of animal tissues have been explored by many researchers, among which, modifications of heparosan, the capsular polysaccharide of Escherichia coli K5 strain, is one of the promising approaches. Heparosan has a structure similar to unmodified backbone of natural HS and heparin. It is feasible to obtain HS or heparin derivatives by modifying heparosan with chemical or enzymatic methods. These derivatives display different biological activities, such as anticoagulant, anti-inflammatory, anticancer, and antiviral activities. This review focuses on the recent studies of synthesis, activity, and structure-activity relationship of HS/heparin-like derivatives prepared from heparosan. © 2012 Wiley Periodicals, Inc. Med. Res. Rev., 00, No. 00, 1-28, 2012.

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Available from: Fengshan Wang, Jul 21, 2014
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    • "A health crisis in 2008, involving the adulteration of heparin produced from hogs in China, led to the death of ~100 Americans and resulted in a demand for heparin from non-animal sources [4]. In addition, recent studies suggest that heparin may have significant antineoplastic activity, separate and distinct from its anticoagulant activity [5] [6] [7] [8] [9], while other studies indicate a role for heparin in treating inflammation, infertility, and infectious disease [10] [11] [12] [13] [14]. These observations point to a potential demand for tailored heparin and heparin-like molecules with specific structural and functional properties. "
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    ABSTRACT: Heparin is the most widely used anticoagulant drug in the world today. Heparin is currently produced from animal tissues, primarily porcine intestines. A recent contamination crisis motivated development of a non-animal-derived source of this critical drug. We hypothesized that Chinese hamster ovary (CHO) cells could be metabolically engineered to produce a bioengineered heparin, equivalent to current pharmaceutical heparin. We previously engineered CHO-S(®) cells to overexpress two exogenous enzymes from the heparin/heparan sulfate biosynthetic pathway, increasing the anticoagulant activity ∼100-fold and the heparin/heparan sulfate yield ∼10-fold. Here, we explored the effects of bioprocess parameters on the yield and anticoagulant activity of the bioengineered GAGs. Fed-batch shaker-flask studies using a proprietary, chemically-defined feed, resulted in ∼two-fold increase in integrated viable cell density and 70% increase in specific productivity, resulting in nearly three-fold increase in product titer. Transferring the process to a stirred-tank bioreactor increased the productivity further, yielding a final product concentration of ∼90 μg/mL. Unfortunately, the product composition still differs from pharmaceutical heparin, suggesting that additional metabolic engineering will be required. However, these studies clearly demonstrate bioprocess optimization, in parallel with metabolic engineering refinements, will play a substantial role in developing a bioengineered heparin to replace the current animal-derived drug. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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    • "Studies have proved that HBV infection of hepatocytes uses HSPGs as lowaffinity receptor, and HBV infection can be inhibited by heparin and other high-sulfated polymers, by interfering with the binding of HBV surface protein (HBsAg) to HSPGs (Leistner, Gruen-Bernhard, & Glebe, 2008; Schulze et al., 2007). Further studies found that two positively charged residues R122 and K141 positioned in an antigenic loop in the HBV envelope proteins could bind with HS through electrostatic interactions (Sureau & Salisse, 2013). Therefore, we suspect that the reason why CS3 showed weaker inhibitory effect than heparin sodium is mainly due to the lower sulfur content than that of heparin sodium, that is, lower sulfur content, weaker binding affinity with HBV particles. "
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