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Structure-guided design of small-molecule therapeutics against RSV disease

ABSTRACT Introduction: In the United States, respiratory syncytial virus (RSV) is responsible for the majority of infant hospitalizations resulting from viral infections, as well as a leading source of pneumonia and bronchiolitis in young children and the elderly. In the absence of vaccine prophylaxis or an effective antiviral for improved disease management, the development of novel anti-RSV therapeutics is critical. Several advanced drug development campaigns of the past decade have focused on blocking viral infection. These efforts have returned a chemically distinct panel of small-molecule RSV entry inhibitors, but binding sites and molecular mechanism of action appeared to share a common mechanism, resulting in comprehensive cross-resistance and calling for alternative druggable targets such as viral RNA-dependent RNA-polymerase complex. Areas Covered: In this review, the authors discuss the current status of the mechanism of action of RSV entry inhibitors. They also provide the recent structural insight into the organization of the polymerase complex that have revealed novel drug targets sites, and outline a path towards the discovery of next-generation RSV therapeutics. Expert opinion: Considering the tremendous progress experienced in our structural understanding of RSV biology in recent years and encouraging early results of a nucleoside analog inhibitor in clinical trials, there is high prospect that new generations of much needed effective anti-RSV therapeutics will become available for clinical use in the foreseeable future.