Enzymatic Synthesis of Chondroitin Sulfate E to Attenuate Bacteria Lipopolysaccharide-Induced Organ Damage

• Published in: ACS central science Vol. 6; no. 7; pp. 1199 - 1207
• Main Authors: Li, Jine, Sparkenbaugh, Erica M, Su, Guowei, Zhang, Fuming, Xu, Yongmei, Xia, Ke, He, Pen, Baytas, Sultan, Pechauer, Shannon, Padmanabhan, Anand, Linhardt, Robert J, Pawlinski, Rafal, Liu, Jian
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22.07.2020
• ISSN: 2374-7943; 2374-7951
• DOI: 10.1021/acscentsci.0c00712

Chondroitin sulfate E (CS-E) is a sulfated polysaccharide that contains repeating disaccharides of 4,6-disulfated N-acetylgalactosamine and glucuronic acid residues. Here, we report the enzymatic synthesis of three homogeneous CS-E oligosaccharides, including CS-E heptasaccharide (CS-E 7-mer), CS-E tridecasaccharide (CS-E13-mer), and CS-E nonadecasaccharide (CS-E 19-mer). The anti-inflammatory effect of CS-E 19-mer was investigated in this study. CS-E 19-mer neutralizes the cytotoxic effect of histones in a cell-based assay and in mice. We also demonstrate that CS-E 19-mer treatment improves survival and protects against organ damage in a mouse model of endotoxemia induced by bacterial lipopolysaccharide (LPS). CS-E19-mer directly interacts with circulating histones in the plasma from LPS-challenged mice. CS-E 19-mer does not display anticoagulant activity nor react with heparin-induced thrombocytopenia antibodies isolated from patients. The successful synthesis of CS-E oligosaccharides provides structurally defined carbohydrates for advancing CS-E research and offers a potential therapeutic agent to treat life-threatening systemic inflammation.