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

Autor: Sindhoora Bhargavi Gopala Reddy, Wei Xin Chin, Nobuo Nomura, Youichi Suzuki, Yoshiyuki Yoshinaka, Haraprasad Nanjundappa, Subhash G. Vasudevan, LiFeng Zhang, Takashi Yoshida, Akihide Ryo, Lars Heinig, Tegshi Muschin, Eng Eong Ooi, Koji Ichiyama, Naoki Yamamoto
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Zdroj: PLoS Neglected Tropical Diseases
PLoS Neglected Tropical Diseases, Vol 7, Iss 4, p e2188 (2013)
ISSN: 1935-2735
1935-2727
Popis: 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.
Author Summary There is no specific approved antiviral and vaccine for treatment or prevention of dengue, an acute mosquito-transmitted viral disease that affects more than 50 million people each year. Dengue virus (DENV) entry is a critical step that establishes the infection and enables virus replication. Curdlan sulfate (CRDS) is known to inhibit the entry and propagation of HIV-1 in the laboratory. Here we applied a computational binding site identification strategy, which suggested that CRDS could be a probable entry inhibitor of the viral surface E protein. CRDS potently blocked DENV infection at an early stage of the virus lifecycle in vitro. In addition, CRDS prevented antibody dependent enhancement, which is considered to be one of the most important clinical observations in DENV-infected patients. CRDS shows a favorable selectivity index against all serotypes of DENV. Further computational docking indicates that the compound binds to a pocket on the DENV E protein. Since CRDS has already been tested in humans without serious side effects, it can be a good candidate for clinical application.
Databáze: OpenAIRE
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