Targeting RSV with Vaccines and Small Molecule Drugs

Abstract

Respiratory syncytial virus (RSV) is the most significant cause of pediatric respiratory infections. Palivizumab (Synagis®), a humanized monoclonal antibody, has been used successfully for a number of years to prevent severe RSV disease in at-risk infants. However, despite intense efforts, there is no approved vaccine or small molecule drug for RSV. As an enveloped virus, RSV must fuse its envelope with the host cell membrane, which is accomplished through the actions of the fusion (F) glycoprotein, with attachment help from the G glycoprotein. Because of their integral role in initiation of infection and their accessibility outside the lipid bilayer, these proteins have been popular targets in the discovery and development of antiviral compounds and vaccines against RSV. This review examines advances in the development of antiviral compounds and vaccine candidates.

Novel recombinant DNA vaccine candidates for human respiratory syncytial virus: Preclinical evaluation of immunogenicity and protection efficiency

“…41 The F protein, a type 1 viral protein, has long been considered the most promising target for developing DNA vaccine candidates against HRSV due to its conserved nature and its ability to activate both the humoral and cellular immune responses. 42 However, the use of the non-optimized F gene in DNA vaccination has provided unsatisfactory protection in The heatmaps were generated using the MORPHEUS software tool. The rows were sorted in ascending gene expression order and were processed for hierarchical clustering using one minus Pearson's correlation.…”

Respiratory Syncytial Virus Disease: Prevention and Treatment

“…When administered to RSV-infected mice, TMC-353121 reduced lung inflammation, as measured by chemokine and cytokine levels as well as by histopathology, and decreased RSV viral load. TMC-353121 binds to Y198, an amino acid in the central portion of the pre-triggered F-protein, and is associated with resistance mutations S398L, K394R, K399I, as well as D486 N, E487D, and D489Y (Costello et al 2012).…”

“…MBX-300 has been shown in animal models to be safe and efficacious in decreasing RSV viral load (Douglas 2004). Resistance mutations associated with MBX-300 occur across the entire G protein, and are noted in Table 2 (Costello et al 2012). An RSV receptor antagonist in development (AS-1411) is a oligodeoxynucleotide aptamer targeting nucleolin on cell surfaces (Mastrangelo et al 2012).…”

“…This agent appears to inhibit viral replication after mucosal entry in in vitro studies and has undergone testing in phase II clinical trials. RSV-604 associated resistance mutations include N105D, K107 N, I129L, and L139I (Costello et al 2012). AZ-27 (Astra-Zeneca, Waltham, MA) is a small molecule RSV polymerase inhibitor that has been shown in in vitro studies to have inhibition of viral replication in RSV subtype A and B clinical isolates (Tiong-Yip et al 2012).…”

“…Upon attachment of the viral membrane, the F glycoprotein undergoes a conformational change that allows the viral and cell membrane to fuse together and allow viral entry. The F-protein exists in a pretriggered state prior to attachment to a target cell, at which point it enters into a post-triggered conformational state that allows for membrane fusion between the target cell and virion (Costello et al 2012). Antibody responses to the F protein are broadly reactive across RSV strains while those to G tend to be group-or strainspecific (Johnson et al 1987).…”