title: Development of Small Molecules with a Noncanonical Binding Mode to HIV-1 Trans Activation Response (TAR) RNA.
abstract: Small molecules that bind to RNA potently and specifically are relatively rare. The study of molecules that bind to the HIV-1 transactivation response (TAR) hairpin, a cis-acting HIV genomic element, has long been an important model system for the chemistry of targeting RNA. Here we report the synthesis, biochemical, and structural evaluation of a series of molecules that bind to HIV-1 TAR RNA. A promising analogue, 15, retained the TAR binding affinity of the initial hit and displaced a Tat-derived peptide with an IC50of 40 μM. NMR characterization of a soluble analogue, 2, revealed a noncanonical binding mode for this class of compounds. Finally, evaluation of 2 and 15 by selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) indicates specificity in binding to TAR within the context of an in vitro-synthesized 365-nt HIV-1 5'-untranslated region (UTR). Thus, these compounds exhibit a novel and specific mode of interaction with TAR, providing important suggestions for RNA ligand design.
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute , 376 Boyles Street, Room 225C, Frederick, Maryland 21702, United States.|Basic Research Laboratories, National Cancer Institute , Frederick, Maryland 21702, United States.
authors.forename: Fardokht A
authors.initials: FA
authors.lastname: Abulwerdi
authors.affiliation: Department of Chemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Shortridge
authors.affiliation: Basic Research Laboratories, National Cancer Institute , Frederick, Maryland 21702, United States.
authors.forename: Joanna
authors.initials: J
authors.lastname: Sztuba-Solinska
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute , 376 Boyles Street, Room 225C, Frederick, Maryland 21702, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Wilson
authors.affiliation: Basic Research Laboratories, National Cancer Institute , Frederick, Maryland 21702, United States.
authors.forename: Stuart F J
authors.initials: SF
authors.lastname: Le Grice
authors.affiliation: Department of Chemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Varani
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute , 376 Boyles Street, Room 225C, Frederick, Maryland 21702, United States.
authors.forename: John S
authors.identifier: 0000-0001-7459-783X
authors.initials: JS
authors.lastname: Schneekloth
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016325:HIV Long Terminal Repeat / Q000187:drug effects* / Q000235:genetics; D015394:Molecular Structure; D012367:RNA, Viral / Q000187:drug effects* / Q000235:genetics; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: D012367:RNA, Viral; D054852:Small Molecule Libraries