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;48(23):7099-102

Ibis Therapeutics, A Division of Isis Pharmaceuticals Inc., 1891 Rutherford Road, Carlsbad, California 92008, USA.

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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Source
http://pubs.acs.org/doi/abs/10.1021/jm050815o
Publisher Site
http://dx.doi.org/10.1021/jm050815oDOI Listing
November 2005
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