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

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

Punit P Seth  1 , Alycia Miyaji, Elizabeth A Jefferson, Kristin A Sannes-Lowery, Stephen A Osgood, Stephanie S Propp, Ray Ranken, Christian Massire, Rangarajan Sampath, David J Ecker, Eric E Swayze, Richard H Griffey
Affiliations

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

Punit P Seth et al. J Med Chem. .

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.

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