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Potent anti-respiratory syncytial virus activity of a cholestanol-sulfated tetrasaccharide conjugate.

Journal article
Authors Anna Lundin
Tomas Bergström
Carla Regina Andrighetti-Fröhner
Loubna Bendrioua
Vito Ferro
Edward Trybala
Published in Antiviral research
Volume 93
Issue 1
Pages 101-9
ISSN 1872-9096
Publication year 2012
Published at Institute of Biomedicine, Department of Infectious Medicine
Pages 101-9
Language en
Links dx.doi.org/10.1016/j.antiviral.2011...
Keywords Animals, Antiviral Agents, pharmacology, Cell Line, Tumor, Dogs, Humans, Microbial Sensitivity Tests, Respiratory Syncytial Viruses, drug effects, Saponins, pharmacology
Subject categories Clinical Medicine

Abstract

A number of different viruses including respiratory syncytial virus (RSV) initiate infection of cells by binding to cell surface glycosaminoglycans and sulfated oligo- and polysaccharide mimetics of these receptors exhibit potent antiviral activity in cultured cells. We investigated whether the introduction of different lipophilic groups to the reducing end of sulfated oligosaccharides would modulate their anti-RSV activity. Our results demonstrate that the cholestanol-conjugated tetrasaccharide (PG545) exhibited ∼5- to 16-fold enhanced anti-RSV activity in cultured cells compared with unmodified sulfated oligosaccharides. Furthermore, PG545 displayed virus-inactivating (virucidal) activity, a feature absent in sulfated oligosaccharides. To inhibit RSV infectivity PG545 had to be present during the initial steps of viral infection of cells. The anti-RSV activity of PG545 was due to both partial inhibition of the virus attachment to cells and a more profound interference with some post-attachment steps as PG545 efficiently neutralized infectivity of the cell-adsorbed virus. The anti-RSV activity of PG545 was reduced when tested in the presence of human nasal secretions. Serial passages of RSV in the presence of increasing concentrations of PG545 selected for weakly resistant viral variants that comprised the F168S and the P180S amino acid substitutions in the viral G protein. Altogether we identified a novel and potent inhibitor of RSV, which unlike sulfated oligo- and polysaccharide compounds, could irreversibly inactivate RSV infectivity.

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