Abstract
This study demonstrated that the λ- and ι-carrageenans, sulfated polysaccharides containing linear chains of galactopyranosyl residues, are potent inhibitors of dengue virus type 2 (DENV-2) and 3 (DENV-3) multiplication in Vero and HepG2 cells, with values of effective concentration 50% from 0.14 to 4.1 μg/ml. This activity was assayed by plaque reduction, virus yield inhibition and antigen expression tests, and was independent of the input multiplicity of infection in the range 0.001–1. The inhibitory action of the λ-carrageenan, an heparan sulfate (HS)-imitative compound, was exerted by a dual interference with virus adsorption and internalization of nucleocapsid into the cytoplasm. Although virus particles may enter the cell when compound was added after DENV-2 adsorption, as shown by intracellular uptake of radiolabeled DENV-2 particles and quantitative RT-PCR, infectious center and virion uncoating assays have shown that carrageenan-treated virions cannot be released from the endosomes. Viral protein synthesis, the first step of macromolecular synthesis after DENV entry to the host cell, was not affected by the carrageenan. Furthermore, no inhibition of virus multiplication was detected when the entry process was bypassed through DENV-2 RNA transfection into the cell. The dual sites of action of an HS-like molecule suggest that, at least in monkey kidney and human hepatic cells, the HS residues in the cell membrane appear to act as mediators for DENV-2 entry, an interesting alternative target for flavivirus therapy.
Highlights
Dengue virus (DENV), a member of family Flaviviridae genus Flavivirus, is the agent of the most prevalent arthropodborne viral disease in humans
The values of effective concentration 50% (EC50) for λ-carrageenan calculated from data in Figs. 1A and C were in the range 0.15–0.39 μg/ml against dengue virus type 2 (DENV-2) and 1.40–2.28 μg/ml against DENV-3, respectively
Studies reported here have proved that λ- and ι-carrageenans, sulfated polysaccharides containing linear chains of galactopyranosyl residues, are potent inhibitors of DENV-2 and DENV-3 multiplication in cells of monkey and human origin, with values of selectivity indices in the range > 244–> 7143
Summary
Dengue virus (DENV), a member of family Flaviviridae genus Flavivirus, is the agent of the most prevalent arthropodborne viral disease in humans. It is estimated that the virus is endemic in more than 100 countries, producing about 50 million infections each year (Gubler, 2002). Most primary infections are asymptomatic, the four serotypes can cause dengue fever (DF), a mild febrile illness that in a minority of cases progresses to the severe and life-threatening dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). The genome is translated into three structural proteins (the capsid protein C, a small nonglycosylated membrane protein M and the envelope glycoprotein E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5)
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