title: High-throughput screening-based identification of paramyxovirus inhibitors.
abstract: Several members of the paramyxovirus family constitute major human pathogens that, collectively, are responsible for major morbidity and mortality worldwide. In an effort to develop novel therapeutics against measles virus (MV), a prominent member of the paramyxovirus family, the authors report a high-throughput screening protocol that uses a nonrecombinant primary MV strain as targets. Implementation of the assay has yielded 60 hit candidates from a 137,500-entry library. Counterscreening and generation of dose-response curves narrows this pool to 35 compounds with active concentrations < or =15.3 microM against the MV-Alaska strain and specificity indices ranging from 36 to >500. Library mining for structural analogs of several confirmed hits combined with retesting of identified candidates reveals a high accuracy of primary hit identification. Eleven of the confirmed hits interfere with viral entry, whereas the remaining 24 compounds target postentry steps of the viral life cycle. Activity testing against selected members of the paramyxovirus family reveals 3 patterns of activity: 1) exclusively MV-specific blockers, 2) inhibitors of MV and related viruses of the same genus, and 3) broader range inhibitors with activity against a different Paramyxovirinae genus. Representatives of the last class may open avenues for the development of broad-range paramyxovirus inhibitors through hit-to-lead chemistry.
authors.affiliation: Division of Pediatric Infectious Diseases, Department of Pediatrics, Emory Children's Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Jeong-Joong
authors.initials: JJ
authors.lastname: Yoon
authors.forename: Dhruv
authors.initials: D
authors.lastname: Chawla
authors.forename: Tanja
authors.initials: T
authors.lastname: Paal
authors.forename: Maina
authors.initials: M
authors.lastname: Ndungu
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.forename: Serdar
authors.initials: S
authors.lastname: Kurtkaya
authors.forename: Aiming
authors.initials: A
authors.lastname: Sun
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Richard K
authors.initials: RK
authors.lastname: Plemper
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001331:Automation; D002522:Chlorocebus aethiops; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation* / Q000379:methods*; D006801:Humans; D008956:Models, Chemical; D018098:Paramyxovirinae / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism; D012984:Software; D014162:Transfection; D014709:Vero Cells
chemical_list: D000890:Anti-Infective Agents; D000998:Antiviral Agents; D012367:RNA, Viral