Genomic-based high throughput screening identifies small molecules that differentially inhibit the antiviral and immunomodulatory effects of IFN-alpha.
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.
Chen
Bo
B
Respiratory, Inflammation and Autoimmunity Department, MedImmune Inc., Gaithersburg, Maryland, USA.
Zong
Qin
Q
Cibotti
Ricardo
R
Morris
Chad
C
Castaneda
Juana
J
Naiman
Brian
B
Liu
Derong
D
Glodek
Anna
A
Sims
Gary P
GP
Herbst
Ronald
R
Horrigan
Stephen K
SK
Kiener
Peter A
PA
Soppet
Dan
D
Coyle
Anthony J
AJ
Audoly
Laurent
L
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*
D000998:Antiviral Agents; D007155:Immunologic Factors; D016898:Interferon-alpha; D054852:Small Molecule Libraries