3-O-sulfated glucuronide derivative as a potential anti-dengue virus agent

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• 作者：Kazuya I.P.J. Hidari ; Kiyoshi Ikeda ; Ippei Watanabe ; Tomoko Abe ; Ayumi S ; o ; Yuji Itoh ; Hiroaki Tokiwa ; Kouichi Morita ; Takashi Suzuki
• 关键词：DENV ; dengue virus ; NS ; non-structural ; GlcA ; glucuronic acid ; CS ; chondroitin sulfate ; CSE ; chondroitin sulfate E ; SOS ; sucrose octasulfate
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 出版时间：3 August, 2012
• 年：2012
• 卷：424
• 期：3
• 页码：573-578
• 全文大小：489 K

文摘

A series of 12 carbohydrate compounds were synthesized by introduction of a sulfated group at specific positions and evaluated for their activities against dengue virus (DENV) infection as well as binding to BHK-21 cells. 3-O-sulfated GlcA was active against DENV infection, whereas 2-O-sulfated GlcA and 3,6-di-O-sulfated Glc showed negligible activity. Persulfated compounds did not inhibit DENV infection. These results provided a rationale for designing sulfated carbohydrate compounds with low molecular mass as anti-DENV agents targeting E protein functions. 3-O-Sulfated GlcA showed no significant cytotoxicity at 1 mM. The EC₅₀ value (120 ¦ÌM) was lower than that of sucrose octasulfate (SOS), a small molecular weight inhibitor of DENV infection. Two negatively charged groups, 3-O-sulfate and 6-C-carboxylic acid, appear to be essential for anti-DENV activity. We performed docking study to investigate the binding potential of 3-O-sulfated GlcA with respect to DENV E protein. The docking study showed that distance and conformation of these negative charges on the carbohydrate may be suitable for association with three amino acid residues of E protein critically involved in virus adsorption (Lys295, Ser145, and Gly159). This interaction may competitively prevent functional DENV binding to receptor(s) on host cells. In conclusion, 3-O-sulfated GlcA is a chemical probe that may facilitate exploration of the molecular mechanisms underlying manifestations of dengue diseases.