title: Structure-based drug design targeting an inactive RNA conformation: exploiting the flexibility of HIV-1 TAR RNA.
abstract: The targeting of RNA for the design of novel anti-viral compounds represents an area of vast potential. We have used NMR and computational methods to model the interaction of a series of synthetic inhibitors of the in vitro RNA binding activities of a peptide derived from the transcriptional activator protein, Tat, from human immunodeficiency virus type 1. Inhibition has been measured through the monitering of fluorescence resonance energy transfer between fluorescently labeled peptide and RNA components. A series of compounds containing a bi-aryl heterocycle as one of the three substituents on a benzylic scaffold, induce a novel, inactive TAR conformation by stacking between base-pairs at the site of a three-base bulge within TAR. The development of this series resulted in an enhancement in potency (with Ki < 100 nM in an in vitro assay) and the removal of problematic guanidinium moieties. Ligands from this series can act as inhibitors of Tat-induced transcription in a cell-free system. This study validates the drug design strategy of using a ligand to target the RNA receptor in a non-functional conformation.
authors.affiliation: RiboTargets, Ltd, Granta Park, Abington, Cambridge CB1 6GB, UK.
authors.forename: Alastair I H
authors.initials: AI
authors.lastname: Murchie
authors.forename: Ben
authors.initials: B
authors.lastname: Davis
authors.forename: Catherine
authors.initials: C
authors.lastname: Isel
authors.forename: Mohammad
authors.initials: M
authors.lastname: Afshar
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Drysdale
authors.forename: Justin
authors.initials: J
authors.lastname: Bower
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Potter
authors.forename: Ian D
authors.initials: ID
authors.lastname: Starkey
authors.forename: Terry M
authors.initials: TM
authors.lastname: Swarbrick
authors.forename: Shabana
authors.initials: S
authors.lastname: Mirza
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Prescott
authors.forename: Philippe
authors.initials: P
authors.lastname: Vaglio
authors.forename: Fareed
authors.initials: F
authors.lastname: Aboul-ela
authors.forename: Jonathan
authors.initials: J
authors.lastname: Karn
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism; D001483:Base Sequence; D015195:Drug Design; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism; D006146:Guanidines / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins; D009690:Nucleic Acid Conformation; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D012313:RNA / Q000737:chemistry*; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics*; D013329:Structure-Activity Relationship; D054322:tat Gene Products, Human Immunodeficiency Virus; D000099253:Trans-Activation Responsive RNA-Binding Protein
chemical_list: D019380:Anti-HIV Agents; D015696:Gene Products, tat; D006146:Guanidines; D009687:Nuclear Proteins; D010455:Peptides; D012313:RNA; D016601:RNA-Binding Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; C071598:TARBP1 protein, human; D000099253:Trans-Activation Responsive RNA-Binding Protein