SAR by MS: discovery of a new class of RNA-binding small molecules for the hepatitis C virus: internal ribosome entry site IIA subdomain.
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.
Seth
Punit P
PP
Ibis Therapeutics, A Division of Isis Pharmaceuticals Inc., 1891 Rutherford Road, Carlsbad, California 92008, USA.
Miyaji
Alycia
A
Jefferson
Elizabeth A
EA
Sannes-Lowery
Kristin A
KA
Osgood
Stephen A
SA
Propp
Stephanie S
SS
Ranken
Ray
R
Massire
Christian
C
Sampath
Rangarajan
R
Ecker
David J
DJ
Swayze
Eric E
EE
Griffey
Richard H
RH
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
D001562:Benzimidazoles; D012367:RNA, Viral