title: Sulfated polysaccharide, curdlan sulfate, efficiently prevents entry/fusion and restricts antibody-dependent enhancement of dengue virus infection in vitro: a possible candidate for clinical application.
abstract: Curdlan sulfate (CRDS), a sulfated 1→3-β-D glucan, previously shown to be a potent HIV entry inhibitor, is characterized in this study as a potent inhibitor of the Dengue virus (DENV). CRDS was identified by in silico blind docking studies to exhibit binding potential to the envelope (E) protein of the DENV. CRDS was shown to inhibit the DENV replication very efficiently in different cells in vitro. Minimal effective concentration of CRDS was as low as 0.1 µg/mL in LLC-MK2 cells, and toxicity was observed only at concentrations over 10 mg/mL. CRDS can also inhibit DENV-1, 3, and 4 efficiently. CRDS did not inhibit the replication of DENV subgenomic replicon. Time of addition experiments demonstrated that the compound not only inhibited viral infection at the host cell binding step, but also at an early post-attachment step of entry (membrane fusion). The direct binding of CRDS to DENV was suggested by an evident reduction in the viral titers after interaction of the virus with CRDS following an ultrafiltration device separation, as well as after virus adsorption to an alkyl CRDS-coated membrane filter. The electron microscopic features also showed that CRDS interacted directly with the viral envelope, and caused changes to the viral surface. CRDS also potently inhibited DENV infection in DC-SIGN expressing cells as well as the antibody-dependent enhancement of DENV-2 infection. Based on these data, a probable binding model of CRDS to DENV E protein was constructed by a flexible receptor and ligand docking study. The binding site of CRDS was predicted to be at the interface between domains II and III of E protein dimer, which is unique to this compound, and is apparently different from the β-OG binding site. Since CRDS has already been tested in humans without serious side effects, its clinical application can be considered.
authors: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Koji
authors: K
authors: Ichiyama
authors: Sindhoora Bhargavi
authors: SB
authors: Gopala Reddy
authors: Li Feng
authors: LF
authors: Zhang
authors: Wei Xin
authors: WX
authors: Chin
authors: Tegshi
authors: T
authors: Muschin
authors: Lars
authors: L
authors: Heinig
authors: Youichi
authors: Y
authors: Suzuki
authors: Haraprasad
authors: H
authors: Nanjundappa
authors: Yoshiyuki
authors: Y
authors: Yoshinaka
authors: Akihide
authors: A
authors: Ryo
authors: Nobuo
authors: N
authors: Nomura
authors: Eng Eong
authors: EE
authors: Ooi
authors: Subhash G
authors: SG
authors: Vasudevan
authors: Takashi
authors: T
authors: Yoshida
authors: Naoki
authors: N
authors: Yamamoto
mesh_terms: D000818:Animals; D019067:Antibody-Dependent Enhancement / Q000187:drug effects*; D002460:Cell Line; D003715:Dengue / Q000276:immunology*; D003716:Dengue Virus / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D008253:Macaca mulatta; D008854:Microscopy, Electron; D014779:Virus Replication / Q000187:drug effects*; D047071:beta-Glucans / Q000494:pharmacology*
chemical_list: D047071:beta-Glucans; C063130:curdlan sulfate
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