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.

KEYWORDS:

• Respiratory syncytial virus
• small molecule antiviral
• viral replication
• RNA-dependent RNA-polymerase
• virus entry

Article highlights

• RSV infection is the foremost cause of infant mortality from viral respiratory disease

• The development of novel antiviral therapeutics for prevention or improved management of RSV disease is urgently needed

• All currently available RSV entry inhibitor classes considered for human use are sensitive to viral escape from inhibition through resistance mutations in the same microdomains

• An RSV strain carrying a signature pan-resistance mutation remained fully pathogenic in a small animal model of RSV infection

• The development of next-generation RSV therapeutics must focus on overcoming pan-resistance through proactive design of drug screening campaigns and/or therapeutic targeting of post-entry steps of the virus replication cycle

Rapidly expanding structural insight into the organization and function of the RSV polymerase complex identified novel candidate druggable target sites and provides a tangible basis for the design of drug screening campaigns

This box summarizes key points contained in the article.

Declaration of interest

This work was supported, in part, by Public Health Service grants AI071002 and HD079327 from the National Institutes of Health (NIH)/ National Institute of Allergy and Infectious Diseases (NIAID) and NIH/National Institute of Child Health and Human Development (NICHD) (to RK Plemper). RK Plemper is an inventor on a disclosure filing describing the use of small-molecule inhibitors of anti-paramyxovirus therapy and the generation of recombinant reporter viruses. This study could affect his personal financial status as he is listed inventor on these filings and entitled to royalties should the technology go to commercialization. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.