INHIBITION OF HUMAN RESPIRATORY SYNCYTIAL VIRUS INFECTIVITY BY A DENDRIMERIC HEPARAN SULPHATE-BINDING PEPTIDE.
Respiratory syncytial virus (RSV) interacts with cell surface heparan sulphate proteoglycans (HSPGs) to initiate infection. The interaction of RSV with HSPGs thus presents an attractive target for the development of novel inhibitors of RSV infection. In the present study, a minilibrary of linear, dimeric and dendrimeric peptides containing clusters of basic amino acids was screened with the aim of identifying peptides able to bind HSPGs and thus block RSV attachment and infectivity. Of the hit compounds identified, the dendrimer SB105-A10 was the most potent inhibitor of RSV infectivity, with IC50 values equal to 0.35 μM and 0.25 μM measured in Hep-2 and A549 cells, respectively. SB105-A10 was found to bind to both cell types via HSPGs, suggesting that its antiviral activity was indeed exerted by competing with RSV for binding to cell-surface HSPGs. SB105-A10 prevented RSV infection when added before the viral inoculum, in line with its proposed HSPG-binding mechanism of action; moreover, antiviral activity was also exhibited when added post-infection, being able to reduce the cell-to-cell spread of the virus. The antiviral potential of SB105-A10 was further assessed using human-derived tracheal/bronchial epithelial cells cultured to form a pseudo-stratified, highly differentiated model of the epithelial tissue of the human respiratory tract. SB105-A10 strongly reduced RSV infectivity in this model and presented no signs of cytotoxicity or pro-inflammatory effects. Together, these features render SB105-A10 an attractive candidate for further development as a RSV inhibitor to be administered by aerosol delivery.
Antiviral assay, Bronchiolitis, Immunohistochemistry, Interleukin 8 (IL-8), Lactate dehydrogenase (LDH), Lower respiratory tract infections, Pneumonia, Pneumovirus, Respiratory syncytial virus (RSV), Transepithelial electric resistance (TEER)
Dendrimeric peptide SB105A10, Human Respiratory syncytial virus (RSV)
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