Genomic-based high throughput screening identifies small molecules that differentially inhibit the antiviral and immunomodulatory effects of IFN-alpha
| Autor: | Chad Morris, Ricardo Cibotti, Ronald Herbst, Bo Chen, Anna Glodek, Anthony J. Coyle, Laurent P. Audoly, Juana Castaneda, Gary P. Sims, Stephen Horrigan, Derong Liu, Peter A. Kiener, Dan Soppet, Qin Zong, Brian Naiman |
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| Rok vydání: | 2008 |
| Předmět: |
Therapeutic gene modulation
High-throughput screening Down-Regulation Mice Inbred Strains Bioinformatics Antiviral Agents Models Biological stat Small Molecule Libraries Mice In vivo Genetics Animals Humans Immunologic Factors Molecular Biology Genetics (clinical) Cells Cultured Research Articles Oligonucleotide Array Sequence Analysis Chemistry Genome Human Gene Expression Profiling Interferon-alpha Genomics Small molecule Cell biology STAT protein Molecular Medicine Female Janus kinase Ex vivo Signal Transduction |
| Zdroj: | Molecular medicine (Cambridge, Mass.). 14(7-8) |
| ISSN: | 1076-1551 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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