A new class of small molecules that bind the HCVRNA IRES IIA subdomain with sub-micromolar affinity isreported. The benzimidazole ‘hit' 1 with a KD ∼100 μM to a29-mer RNA model of Domain IIA was identified from a180000-member library using mass spectrometry-based screening methods. Further MS-assisted SAR (structure−activityrelationships) studies afforded benzimidazole derivatives withsub-micromolar binding affinity for the IIA RNA construct. Theoptimized benzimidazoles demonstrated activity in a cellularreplicon assay at concentrations comparable to their KD forthe RNA target.
