Novel diversity-oriented synthesis-derived respiratory syncytial virus inhibitors identified via a high throughput replicon-based screen

Duvall, Jeremy R.; VerPlank, Lynn; Lüdeke, Barbara; McLeod, Sarah M.; Lee, Maurice D.; Vishwanathan, Karthick; Mulrooney, Carol A.; Quement, Sebastian Le; Yu, Qian; Palmer, Michelle; Fleming, Paul R.; Fearns, Rachel; Foley, Michael A.; Scherer, Christina

doi:10.1016/j.antiviral.2016.03.015

Cited by 11 publications

(5 citation statements)

References 31 publications

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“…180,182 The Pictet-Spengler-derived spirocycles 40 and 44 show antimalarial and antiviral activity, respectively. 178,183 Other compounds shown are described in more detail in the vignettes in the main text. Properties relevant to their value as probes are discussed in Box 2.…”

Section: Figure 1 |mentioning

confidence: 99%

Chemical probes and drug leads from advances in synthetic planning and methodology

Gerry

Schreiber

2018

Nat Rev Drug Discov

208

164

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Screening of small-molecule libraries is a productive method for identifying both chemical probes of disease-related targets and potential starting points for drug discovery. In this article, we focus on strategies such as diversity-oriented synthesis that aim to explore novel areas of chemical space efficiently by populating small-molecule libraries with compounds containing structural features that are typically under-represented in commercially available screening collections. Drawing from more than a decade's worth of examples, we highlight how the design and synthesis of such libraries have been enabled by modern synthetic chemistry, and we illustrate the impact of the resultant chemical probes and drug leads in a wide range of diseases.

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Section: Figure 1 |mentioning

confidence: 99%

Chemical probes and drug leads from advances in synthetic planning and methodology

Gerry

Schreiber

2018

Nat Rev Drug Discov

208

164

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“…Our initial characterization of the AVG-233 class revealed that the inhibitor does not block phosphodiester bond formation per se but disturbs initiation of viral RNA synthesis at the promoter ( 24 ). This inhibition pattern may reflect pharmacological interference with a predicted conformational rearrangement of the polymerase complex during initiation ( 43 , 44 ). Three lines of experimental evidence support this view: the AVG class resistance profile, the mechanism of action (MOA) characterization in biochemical RdRP assays, and the photoaffinity labeling–based mapping of the target site.…”

Section: Discussionmentioning

confidence: 99%

Orally efficacious lead of the AVG inhibitor series targeting a dynamic interface in the respiratory syncytial virus polymerase

et al. 2022

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Respiratory syncytial virus (RSV) is a leading cause of lower respiratory infections in infants and the immunocompromised, yet no efficient therapeutic exists. We have identified the AVG class of allosteric inhibitors of RSV RNA synthesis. Here, we demonstrate through biolayer interferometry and in vitro RNA-dependent RNA polymerase (RdRP) assays that AVG compounds bind to the viral polymerase, stalling the polymerase in initiation conformation. Resistance profiling revealed a unique escape pattern, suggesting a discrete docking pose. Affinity mapping using photoreactive AVG analogs identified the interface of polymerase core, capping, and connector domains as a molecular target site. A first-generation lead showed nanomolar potency against RSV in human airway epithelium organoids but lacked in vivo efficacy. Docking pose-informed synthetic optimization generated orally efficacious AVG-388, which showed potent efficacy in the RSV mouse model when administered therapeutically. This study maps a druggable target in the RSV RdRP and establishes clinical potential of the AVG chemotype against RSV disease.

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“…BRD3969 (19-2) was shown to inhibit viral replication, no RSV-B subtype activity was observed. 24 The BRD9259 (19-3) scaffold type, however, did show activity against both subtypes but was less explored in terms of published SAR. (T1-3).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…This system has had SH, G, and F proteins removed and replaced by an antibiotic resistance selection marker . They described the use of this screen against the AstraZeneca million compound library but reported no tractable hits. , A subsequent collaboration with the Broad Institute (Cambridge, MA) described the screening of the Broad Institute diversity oriented synthesis library and subsequent filtering of hits using whole virus CPE assays with both RSV-A and RSV-B subtypes . In addition, the Broad/AstraZeneca team utilized a transient minigenome assay, a system that contains only proteins necessary for replication and can be engineered to allow uncoupling of replication and transcription. , The output from this screen is discussed later (section ).…”

Section: The Rsv Small-molecule Discovery Processmentioning

confidence: 99%

“…Scaffolds emanating from the Broad Institute/AstraZeneca collaboration described earlier have produced moderate potency hits with variable subtype activity. BRD3969 ( 19 - 2 ) was shown to inhibit viral replication, no RSV-B subtype activity was observed . The BRD9259 ( 19 - 3 ) scaffold type, however, did show activity against both subtypes but was less explored in terms of published SAR.…”

Section: Preclinical Rsv Inhibitor Programsmentioning

confidence: 99%

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

2018

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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.

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Novel diversity-oriented synthesis-derived respiratory syncytial virus inhibitors identified via a high throughput replicon-based screen

Cited by 11 publications

References 31 publications

Chemical probes and drug leads from advances in synthetic planning and methodology

Chemical probes and drug leads from advances in synthetic planning and methodology

Orally efficacious lead of the AVG inhibitor series targeting a dynamic interface in the respiratory syncytial virus polymerase

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

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