SAR by MS: discovery of a new class of RNA-binding small molecules for the hepatitis C virus: internal ribosome entry site IIA subdomain

J Med Chem. 2005 Nov 17;48(23):7099-102. doi: 10.1021/jm050815o.

Abstract

A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole 'hit' 1 with a KD approximately 100 microM to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry-based screening methods. Further MS-assisted SAR (structure-activity relationships) studies afforded benzimidazole derivatives with sub-micromolar binding affinity for the IIA RNA construct. The optimized benzimidazoles demonstrated activity in a cellular replicon assay at concentrations comparable to their KD for the RNA target.

MeSH terms

  • Base Sequence
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology
  • Benzimidazoles / toxicity
  • Binding Sites
  • Cell Line
  • Databases, Factual
  • Hepacivirus / genetics*
  • Hepacivirus / physiology
  • Humans
  • Mass Spectrometry
  • Models, Molecular*
  • Molecular Sequence Data
  • Nucleic Acid Conformation
  • Quantitative Structure-Activity Relationship*
  • RNA, Viral / chemistry*
  • RNA, Viral / metabolism
  • Ribosomes / chemistry
  • Ribosomes / drug effects*
  • Ribosomes / metabolism
  • Virus Replication

Substances

  • Benzimidazoles
  • RNA, Viral