RO 90-7501 enhances TLR3 and RLR agonist induced antiviral response

PLoS One. 2012;7(10):e42583. doi: 10.1371/journal.pone.0042583. Epub 2012 Oct 3.

Abstract

Recognition of virus infection by innate pattern recognition receptors (PRRs), including membrane-associated toll-like receptors (TLR) and cytoplasmic RIG-I-like receptors (RLR), activates cascades of signal transduction pathways leading to production of type I interferons (IFN) and proinflammatory cytokines that orchestrate the elimination of the viruses. Although it has been demonstrated that PRR-mediated innate immunity plays an essential role in defending virus from infection, it also occasionally results in overwhelming production of proinflammatory cytokines that cause severe inflammation, blood vessel leakage and tissue damage. In our efforts to identify small molecules that selectively enhance PRR-mediated antiviral, but not the detrimental inflammatory response, we discovered a compound, RO 90-7501 ('2'-(4-Aminophenyl)-[2,5'-bi-1H-benzimidazol]-5-amine), that significantly promoted both TLR3 and RLR ligand-induced IFN-β gene expression and antiviral response, most likely via selective activation of p38 mitogen-activated protein kinase (MAPK) pathway. Our results thus imply that pharmacological modulation of PRR signal transduction pathways in favor of the induction of a beneficial antiviral response can be a novel therapeutic strategy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemistry
  • Amines / pharmacology*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Blotting, Western
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / antagonists & inhibitors*
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Gene Expression / drug effects
  • HEK293 Cells
  • Host-Pathogen Interactions / drug effects
  • Humans
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Luciferases / genetics
  • Luciferases / metabolism
  • Molecular Structure
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Poly I-C / pharmacology*
  • Promoter Regions, Genetic / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 3 / antagonists & inhibitors*
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / metabolism
  • Vesicular stomatitis Indiana virus / drug effects*
  • Vesicular stomatitis Indiana virus / physiology
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • (2'-(4-aminophenyl)-(2,5'-bi-1H-benzimidazol)-5-amine)
  • Amines
  • Antiviral Agents
  • Benzimidazoles
  • NF-kappa B
  • Toll-Like Receptor 3
  • Interferon-beta
  • Luciferases
  • p38 Mitogen-Activated Protein Kinases
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Poly I-C