title: 3-O-sulfated glucuronide derivative as a potential anti-dengue virus agent.
abstract: 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 1mM. The EC(50) value (120 μM) 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.
authors: Department of Biochemistry, School of Pharmaceutical Sciences, Global COE Program for Innovation in Human Health Sciences, University of Shizuoka, Shizuoka 422-8526, Japan. hidari@u-shizuoka-ken.ac.jp
authors: Kazuya I P J
authors: KI
authors: Hidari
authors: Kiyoshi
authors: K
authors: Ikeda
authors: Ippei
authors: I
authors: Watanabe
authors: Tomoko
authors: T
authors: Abe
authors: Ayumi
authors: A
authors: Sando
authors: Yuji
authors: Y
authors: Itoh
authors: Hiroaki
authors: H
authors: Tokiwa
authors: Kouichi
authors: K
authors: Morita
authors: Takashi
authors: T
authors: Suzuki
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D003716:Dengue Virus / Q000187:drug effects* / Q000502:physiology; D020719:Glucuronides / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D013463:Sulfuric Acid Esters / Q000737:chemistry* / Q000494:pharmacology*; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors; D053585:Virus Attachment / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D020719:Glucuronides; D013463:Sulfuric Acid Esters; D014759:Viral Envelope Proteins; C072281:E protein TH Sman, Dengue virus