State of the Art in Respiratory Syncytial Virus Drug Discovery and Development

Abstract

Respiratory syncytial virus (RSV) is a globally prevalent viral infection with limited treatment options which hospitalizes millions each year. Treatment options have been limited to palivizumab, a monoclonal antibody, approved for prophylaxis in high-risk infants and ribavirin with very limited efficacy and significant safety concerns. This Perspective surveys the range of direct acting antiviral agents (DAAs) that target key steps in the viral life cycle. A number of approaches to DAAs have produced landmark clinical studies over the past few years, notably in fusion and nucleoside inhibitors, and an update of the clinical status of these compounds is provided. Non-nucleoside inhibitors of replication are reviewed in addition to inhibitors of other mechanisms, notably the RSV N and G proteins. This article will provide an informative perspective of the current status of drug discovery targeted at providing an effective therapy for RSV infection.

Structure of the Respiratory Syncytial Virus Polymerase Complex

“…Nucleoside analogs that terminate RNA chain synthesis have been identified (Clarke et al, 2015;Deval et al, 2015;Wang et al, 2015), and one such compound, ALS-8176, has shown efficacy in RSV-infected adults (DeVincenzo et al, 2015). Several non-nucleoside small-molecule inhibitors have also been identified (Cockerill et al, 2019;Fearns and Deval, 2016), and although some (for example, BI-compound D) are known to disrupt RNA cap addition (Liuzzi et al, 2005), there are additional inhibitor classes for which the mechanism of action is not well understood (Duvall et al, 2016;McCutcheon et al, 2015). P serves as an essential polymerase cofactor that tethers L to the nucleoprotein-RNA complex (García et al, 1993;Grosfeld et al, 1995;Yu et al, 1995).…”

Targeting the Respiratory Syncytial Virus N 0 -P Complex with Constrained α-Helical Peptides in Cells and Mice

“…Based on these predictions, we decided to stabilize the transient -helix of P (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Given that at least 16 to 18 residues are usually required to successfully stabilize an -helix in aqueous solution (22), and that Phe28 appeared to fit well into the helical wheel representation, we decided to focus on P (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). A stapled peptide scan of P (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)…”

“…Given that at least 16 to 18 residues are usually required to successfully stabilize an -helix in aqueous solution (22), and that Phe28 appeared to fit well into the helical wheel representation, we decided to focus on P (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). A stapled peptide scan of P (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) was performed by inserting the all-hydrocarbon cross-link at the hydrophilic face of the helix, the presumed non interacting face of the helix. (19).…”

Generation of neutralizing and non-neutralizing monoclonal antibodies against H7N9 influenza virus

“…Therapeutic monoclonal antibodies (mAbs) have become a prospective part of infectious diseases due to their specificity, limited off-target effects, and favourable safety profile. Primary examples of mAbs as treatment are palivizumab against respiratory syncytial virus and ZMapp against Ebola virus [17,18].…”