title: Identification of Non-Nucleoside Inhibitors of the Respiratory Syncytial Virus Polymerase Complex.
abstract: Respiratory syncytial virus (RSV) represents a threat to infants, the elderly, and the immunocompromised. RSV entry blockers are in clinical trials, but escape mutations challenge their potential. In search of RSV inhibitors, we have integrated a signature resistance mutation into a recombinant RSV virus and applied the strain to high-throughput screening. Counterscreening of candidates returned 14 confirmed hits with activities in the nano- to low-micromolar range. All blocked RSV polymerase activity in minigenome assays. Compound 1a (GRP-74915) was selected for development based on activity (EC50= 0.21 μM, selectivity index (SI) 40) and scaffold. Resynthesis confirmed the potency of the compound, which suppressed viral RNA synthesis in infected cells. However, metabolic testing revealed a short half-life in the presence of mouse hepatocyte fractions. Metabolite tracking and chemical elaboration combined with 3D-quantitative structure-activity relationship modeling yielded analogues (i.e., 8n: EC50= 0.06 μM, SI 500) that establish a platform for the development of a therapeutic candidate.
authors.affiliation: Emory Institute for Drug Development, Emory University , Atlanta, Georgia 30329, United States.
authors.forename: Alberto
authors.initials: A
authors.lastname: Jiménez-Somarribas
authors.affiliation: Emory Institute for Drug Development, Emory University , Atlanta, Georgia 30329, United States.
authors.forename: Shuli
authors.initials: S
authors.lastname: Mao
authors.affiliation: Institute for Biomedical Sciences, Georgia State University , Atlanta, Georgia 30303, United States.
authors.forename: Jeong-Joong
authors.initials: JJ
authors.lastname: Yoon
authors.affiliation: Institute for Biomedical Sciences, Georgia State University , Atlanta, Georgia 30303, United States.
authors.forename: Marco
authors.initials: M
authors.lastname: Weisshaar
authors.affiliation: Institute for Biomedical Sciences, Georgia State University , Atlanta, Georgia 30303, United States.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Cox
authors.affiliation: Emory Institute for Drug Development, Emory University , Atlanta, Georgia 30329, United States.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Marengo
authors.affiliation: Emory Institute for Drug Development, Emory University , Atlanta, Georgia 30329, United States.
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Mitchell
authors.affiliation: Institute for Biomedical Sciences, Georgia State University , Atlanta, Georgia 30303, United States.
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Morehouse
authors.affiliation: Institute for Biomedical Sciences, Georgia State University , Atlanta, Georgia 30303, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Yan
authors.affiliation: Institute for Biomedical Sciences, Georgia State University , Atlanta, Georgia 30303, United States.
authors.forename: Ivan
authors.initials: I
authors.lastname: Solis
authors.affiliation: Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Dennis C
authors.identifier: 0000-0002-7736-7113
authors.initials: DC
authors.lastname: Liotta
authors.affiliation: Emory Institute for Drug Development, Emory University , Atlanta, Georgia 30329, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Natchus
authors.affiliation: Institute for Biomedical Sciences, Georgia State University , Atlanta, Georgia 30303, United States.
authors.forename: Richard K
authors.identifier: 0000-0003-2034-2107
authors.initials: RK
authors.lastname: Plemper
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D021281:Quantitative Structure-Activity Relationship; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D014764:Viral Proteins; D012321:DNA-Directed RNA Polymerases