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

摘要

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 K_D approx 100 muM 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_D for the RNA target.