title: Genomic-based high throughput screening identifies small molecules that differentially inhibit the antiviral and immunomodulatory effects of IFN-alpha.
abstract: Multiple lines of evidence suggest that inhibition of Type I Interferons, including IFN-alpha, may provide a therapeutic benefit for autoimmune diseases. Using a chemical genomics approach integrated with cellular and in vivo assays, we screened a small compound library to identify modulators of IFN-alpha biological effects. A genomic fingerprint was developed from both ex vivo patient genomic information and in vitro gene modulation from IFN-alpha cell-based stimulation. A high throughput genomic-based screen then was applied to prioritize 268 small molecule inhibitors targeting 41 different intracellular signaling pathways. Active compounds were profiled further for their ability to inhibit the activation and differentiation of human monocytes using disease-related stimuli. Inhibitors targeting NF-kappaB or Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling emerged as "dissociated inhibitors" because they did not modulate IFN-alpha anti-viral effects against HSV-1 but potently inhibited other immune-related functions. This work describes a novel strategy to identify small molecule inhibitors for the treatment of autoimmune disorders.
authors.affiliation: Respiratory, Inflammation and Autoimmunity Department, MedImmune Inc., Gaithersburg, Maryland, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.forename: Qin
authors.initials: Q
authors.lastname: Zong
authors.forename: Ricardo
authors.initials: R
authors.lastname: Cibotti
authors.forename: Chad
authors.initials: C
authors.lastname: Morris
authors.forename: Juana
authors.initials: J
authors.lastname: Castaneda
authors.forename: Brian
authors.initials: B
authors.lastname: Naiman
authors.forename: Derong
authors.initials: D
authors.lastname: Liu
authors.forename: Anna
authors.initials: A
authors.lastname: Glodek
authors.forename: Gary P
authors.initials: GP
authors.lastname: Sims
authors.forename: Ronald
authors.initials: R
authors.lastname: Herbst
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Horrigan
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kiener
authors.forename: Dan
authors.initials: D
authors.lastname: Soppet
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: Laurent
authors.initials: L
authors.lastname: Audoly
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015894:Genome, Human; D023281:Genomics / Q000295:instrumentation / Q000379:methods; D006801:Humans; D007155:Immunologic Factors / Q000037:antagonists & inhibitors; D016898:Interferon-alpha / Q000037:antagonists & inhibitors*; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D054852:Small Molecule Libraries / Q000032:analysis* / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D007155:Immunologic Factors; D016898:Interferon-alpha; D054852:Small Molecule Libraries