Abstract
Nucleolin (NCL) has been reported as a cellular receptor for the human respiratory syncytial virus (RSV). We studied the effects of re-purposing AS1411, an anti-cancer compound that binds cell surface NCL, as a possible novel strategy for RSV therapy in vitro and in vivo. AS1411 was administered to RSV-infected cultures of non-polarized (HEp-2) and polarized (MDCK) epithelial cells and to virus-infected mice and cotton rats. Results of in vitro experiments showed that AS1411, used in micromolar concentrations, was associated with decreases in the number of virus-positive cells. Intranasal administration of AS1411 (50 mg/kg) to RSV-infected mice and cotton rats was associated with partial reductions in lung viral titers, decreased virus-associated airway inflammation, and decreased IL-4/IFN-γ ratios when compared to untreated, infected animals. In conclusion, our findings indicate that therapeutic use of AS1411 has modest effects on RSV replication and host response. While the results underscore the challenges of targeting cell surface NCL as a potential novel strategy for RSV therapy, they also highlight the potential of cell surface NCL as a therapeutic target.
Highlights
The respiratory syncytial virus (RSV, or human orthopneumovirus due to a recent name change [1]), an enveloped, single-stranded RNA Pneumovirus which affects all age groups worldwide and causes serious lower respiratory infections such as bronchiolitis and pneumonia [2].Despite considerable efforts made since the 1960s to develop a safe and effective RSV vaccine, no licensed vaccine is available, and the recent failure of a phase III clinical trial of a vaccine candidate exemplifies the longstanding difficulties experienced in this area [3]
The results of this study show that AS1411 treatment is effective at reducing levels of RSV
Observed in three different model systems: HEp-2 cell cultures, MDCK cell cultures, and replicating observed in three different model systems: HEp-2 cell cultures, MDCK cell cultures, and replicating virus isolated from the lungs of mice and cotton rats
Summary
The respiratory syncytial virus (RSV, or human orthopneumovirus due to a recent name change [1]), an enveloped, single-stranded RNA Pneumovirus which affects all age groups worldwide and causes serious lower respiratory infections such as bronchiolitis and pneumonia [2].Despite considerable efforts made since the 1960s to develop a safe and effective RSV vaccine, no licensed vaccine is available, and the recent failure of a phase III clinical trial of a vaccine candidate exemplifies the longstanding difficulties experienced in this area [3]. Palivizumab, an antibody that binds to the RSV fusion (F) protein (a viral envelope protein involved in initial viral entry into cells and cell-to-cell spread of infection), is used for RSV prophylaxis in selected “high-risk” patients, and there are reports of RSV resistance developing with respect to this drug [4,5,6,7]. Treatment of RSV infections has predominantly focused on targeting viral components such as the F protein [8] or the polymerase enzyme involved in viral nucleic acid replication [9]. Targeting viral components confers selection pressure for the emergence of drug-resistant viruses [5,10,11].
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