Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2005-11, Vol.48 (23), p.7099-7102

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2005

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 ∼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 D for the RNA target.