Identification of thieno[3,2-b]pyrrole derivatives as novel small molecule inhibitors of neurotropic alphaviruses

J Infect Dis. 2009 Apr 1;199(7):950-7. doi: 10.1086/597275.

Abstract

Neurotropic alphaviruses such as western, eastern, and Venezuelan equine encephalitis viruses cause serious and potentially fatal central nervous system infections in humans and are high-priority potential bioterrorism agents. There are currently no widely available vaccines or licensed therapies for these virulent pathogens. To identify potential novel antiviral drugs, we developed a cell-based assay with a western equine encephalitis virus replicon that expresses a luciferase reporter gene and screened a small molecule diversity library of 51,028 compounds. We identified and validated a thieno[3,2-b]pyrrole compound with a half maximal inhibitory concentration of <10 micromol/L, a selectivity index>20, and potent activity against live virus in cultured neuronal cells. Furthermore, a structure-activity relationship analysis with 20 related compounds identified several with enhanced activity profiles, including 6 with submicromolar half maximal inhibitory concentrations. In conclusion, we have identified a novel class of promising inhibitors with potent activity against virulent neurotropic alphaviruses.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alphavirus / drug effects*
  • Alphavirus / physiology
  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Biological Assay
  • Cell Line
  • Chlorocebus aethiops
  • Cricetinae
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship
  • Viral Regulatory and Accessory Proteins / metabolism
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Pyrroles
  • Viral Regulatory and Accessory Proteins