title: Novel diversity-oriented synthesis-derived respiratory syncytial virus inhibitors identified via a high throughput replicon-based screen.
abstract: Respiratory syncytial virus (RSV) infections affect millions of children and adults every year. Despite the significant disease burden, there are currently no safe and effective vaccines or therapeutics. We employed a replicon-based high throughput screen combined with live-virus triaging assays to identify three novel diversity-oriented synthesis-derived scaffolds with activity against RSV. One of these small molecules is shown to target the RSV polymerase (L protein) to inhibit viral replication and transcription; the mechanisms of action of the other small molecules are currently unknown. The compounds described herein may provide attractive inhibitors for lead optimization campaigns.
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA 02142, United States.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Duvall
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA 02142, United States.
authors.forename: Lynn
authors.initials: L
authors.lastname: VerPlank
authors.affiliation: Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ludeke
authors.affiliation: AstraZeneca R&D Boston, Infection Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: McLeod
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA 02142, United States.
authors.forename: Maurice D
authors.initials: MD
authors.lastname: Lee
authors.affiliation: AstraZeneca R&D Boston, Early Clinical Development, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Karthick
authors.initials: K
authors.lastname: Vishwanathan
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA 02142, United States.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Mulrooney
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA 02142, United States.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Le Quement
authors.affiliation: AstraZeneca R&D Boston, Infection Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA 02142, United States.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Palmer
authors.affiliation: AstraZeneca R&D Boston, Infection Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Fleming
authors.affiliation: Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Fearns
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA 02142, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Foley
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA 02142, United States. Electronic address: cscherer@alum.mit.edu.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Scherer
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods*; D056945:Hep G2 Cells; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008826:Microbial Sensitivity Tests; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D012093:Replicon / Q000187:drug effects*; D018357:Respiratory Syncytial Virus Infections / Q000628:therapy / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D014764:Viral Proteins / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase
keywords: Diversity-oriented synthesis; Replicon; Respiratory syncytial virus