title: Identification of small molecules with type I interferon inducing properties by high-throughput screening.
abstract: The continuous emergence of virus that are resistant to current anti-viral drugs, combined with the introduction of new viral pathogens for which no therapeutics are available, creates an urgent need for the development of novel broad spectrum antivirals. Type I interferon (IFN) can, by modulating the cellular expression profile, stimulate a non-specific antiviral state. The antiviral and adjuvant properties of IFN have been extensively demonstrated; however, its clinical application has been so far limited. We have developed a human cell-based assay that monitors IFN-β production for use in a high throughput screen. Using this assay we screened 94,398 small molecules and identified 18 compounds with IFN-inducing properties. Among these, 3 small molecules (C3, E51 and L56) showed activity not only in human but also in murine and canine derived cells. We further characterized C3 and showed that this molecule is capable of stimulating an anti-viral state in human-derived lung epithelial cells. Furthermore, the IFN-induction by C3 is not diminished by the presence of influenza A virus NS1 protein or hepatitis C virus NS3/4A protease, which make this molecule an interesting candidate for the development of a new type of broad-spectrum antiviral. In addition, the IFN-inducing properties of C3 also suggest its potential use as vaccine adjuvant.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Gil
authors.forename: Juan
authors.initials: J
authors.lastname: Ayllon
authors.forename: Mila Brum
authors.initials: MB
authors.lastname: Ortigoza
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Megan L
authors.initials: ML
authors.lastname: Shaw
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D007370:Interferon Type I; D054852:Small Molecule Libraries; D017361:Viral Nonstructural Proteins; C085820:INS1 protein, influenza virus; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases