title: SAR by MS: discovery of a new class of RNA-binding small molecules for the hepatitis C virus: internal ribosome entry site IIA subdomain.
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.
authors.affiliation: Ibis Therapeutics, A Division of Isis Pharmaceuticals Inc., 1891 Rutherford Road, Carlsbad, California 92008, USA.
authors.forename: Punit P
authors.initials: PP
authors.lastname: Seth
authors.forename: Alycia
authors.initials: A
authors.lastname: Miyaji
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Jefferson
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Sannes-Lowery
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Osgood
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Propp
authors.forename: Ray
authors.initials: R
authors.lastname: Ranken
authors.forename: Christian
authors.initials: C
authors.lastname: Massire
authors.forename: Rangarajan
authors.initials: R
authors.lastname: Sampath
authors.forename: David J
authors.initials: DJ
authors.lastname: Ecker
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
authors.forename: Richard H
authors.initials: RH
authors.lastname: Griffey
mesh_terms: D001483:Base Sequence; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D001665:Binding Sites; D002460:Cell Line; D016208:Databases, Factual; D016174:Hepacivirus / Q000235:genetics* / Q000502:physiology; D006801:Humans; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D021281:Quantitative Structure-Activity Relationship; D012367:RNA, Viral / Q000737:chemistry* / Q000378:metabolism; D012270:Ribosomes / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D014779:Virus Replication
chemical_list: D001562:Benzimidazoles; D012367:RNA, Viral