SAR by MS:  Discovery of a New Class of RNA-Binding Small Molecules for the Hepatitis C Virus:  Internal Ribosome Entry Site IIA Subdomain

A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole ‘hit' <BO>1</BO> with a K<INF>D</INF> ~100 μM 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 K<INF>D</INF> for the RNA target.