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High-Throughput Screening—Based Identification of Paramyxovirus InhibitorsDivision of Pediatric Infectious Diseases, Department of Pediatrics, Emory Children's Center, Emory University School of Medicine, Atlanta, Georgia
Division of Pediatric Infectious Diseases, Department of Pediatrics, Emory Children's Center, Emory University School of Medicine, Atlanta, Georgia
Division of Pediatric Infectious Diseases, Department of Pediatrics, Emory Children's Center, Emory University School of Medicine, Atlanta, Georgia
Department of Chemistry, Emory University, Atlanta, Georgia
Department of Pharmacology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, Georgia
Department of Chemistry, Emory University, Atlanta, Georgia
Department of Chemistry, Emory University, Atlanta, Georgia
Department of Chemistry, Emory University, Atlanta, Georgia
Division of Pediatric Infectious Diseases, Department of Pediatrics, Emory Children's Center, Emory University School of Medicine, Atlanta, Georgia, rplempe{at}emory.edu
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
Key Words: high-throughput screening • drug discovery • paramyxovirus • anti-infective drugs
This version was published on August
1, 2008 Journal of Biomolecular Screening, Vol. 13, No. 7,
591-608 (2008) |
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15.3 µM 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. ( Journal of Biomolecular Screening 2008:591-608)