LB-1Treatment with Oral ALS-008176, a Nucleoside Analog, Rapidly Reduces RSV Viral Load and Clinical Disease Severity in a Healthy Volunteer Challenge Study

2017

Virus Research

The paramyxo- and pneumoviruses are members of the order Mononegavirales, a group of viruses with non-segmented, negative strand RNA genomes. The polymerases of these viruses are multi-functional complexes, capable of transcribing subgenomic capped and polyadenylated mRNAs and replicating the genome. Although there is no native structure available for any complete paramyxo- or pneumovirus polymerase, functional and structural studies of a fragment of a pneumovirus polymerase protein and mutation analyses and resistance profiling of small-molecule inhibitors have generated a wealth of mechanistic information. This review integrates these data with the structure of a related polymerase, identifying similarities, differences, gaps in knowledge, and avenues for antiviral drug development.

Section: Inhibitors Of Rsv Polymerase Activitymentioning

confidence: 99%

Polymerases of paramyxoviruses and pneumoviruses

Fearns

2017

Virus Research

“…By contrast, ALS-8176 is a nucleoside analog that competitively inhibits the RSV RdRp complex [16]. Both candidates decreased viral load and disease symptoms in challenge studies [17]. In this review, we will discuss the current state and future of RSV drug development.…”

Section: Current Therapy and Developmental Status Of Anti-rsv Thementioning

confidence: 99%

“…In contrast, ALS-8176, a newly developed nucleoside analog, is currently in phase II clinical trials for use against RSV infection [17]. ALS-8176 was well tolerated in initial trials and significantly reduced viral load when administered at the onset of infection [17], but the toxicity profile in particular for pediatric use is unclear at present.…”

Section: Targeting the Rsv Rdrp Complex: Nucleoside And Nucleotidmentioning

confidence: 99%

“…ALS-8176 was well tolerated in initial trials and significantly reduced viral load when administered at the onset of infection [17], but the toxicity profile in particular for pediatric use is unclear at present. Nevertheless, these findings are promising and offer proof-of-concept for the clinical benefit of competitive polymerase inhibitors for RSV therapy.…”

Section: Targeting the Rsv Rdrp Complex: Nucleoside And Nucleotidmentioning

confidence: 99%

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

Cox

Expert Opinion on Drug Discovery

2016

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. Areas Covered 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. Expert Opinion In this review, we discuss the current status of the mechanism of action of RSV entry inhibitors, 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.

“…The nucleoside compound ALS-8176 is a competitive inhibitor of the RSV RNAdependent RNA polymerase (RdRp) complex (Wang et al, 2015), while Gilead's compound GS-5806 functions as an allosteric blocker of the fusion (F) protein, preventing viral entry (Devincenzo et al, 2014;Mackman et al, 2015). Both candidates decreased the viral load and disease symptoms when administered in challenge studies to healthy adult volunteers, although the rate of virus load reduction by ALS-8176 seemed to exceed that of GS-5806 (Devincenzo et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Blocking Respiratory Syncytial Virus Entry: A Story with Twists

Weisshaar

Cox

2015

DNA and Cell Biology

Respiratory syncytial virus (RSV) is responsible for majority of infant hospitalizations due to viral infections. Despite its clinical importance, no vaccine against RSV or effective antiviral therapy is available. Several structural classes of small-molecule RSV entry inhibitor have been described and one compound has advanced to clinical testing. Mutations in either one of two resistance hot spots in the F protein mediate unusual pan-resistance to all of these inhibitor classes. Based on the biochemical characterization of resistant viruses and structural insight into the RSV F trimer, we propose a kinetic escape model as the origin of pan-resistance. Since a resistant RSV remained pathogenic in the mouse model, pan-resistance mutations could emerge rapidly in circulating RSV strains. We evaluate clinical implications and discuss consequences for the design of future RSV drug discovery campaigns.