title: A small-molecule probe induces a conformation in HIV TAR RNA capable of binding drug-like fragments.
abstract: The HIV-1 transactivation response (TAR) element-Tat interaction is a potentially valuable target for treating HIV infection, but efforts to develop TAR-binding antiviral drugs have not yet yielded a successful candidate for clinical development. In this work, we describe a novel approach toward screening fragments against RNA that uses a chemical probe to target the Tat-binding region of TAR. This probe fulfills two critical roles in the screen: by locking the RNA into a conformation capable of binding other fragments, it simultaneously allows the identification of proximal binding fragments by ligand-based NMR. Using this approach, we have discovered six novel TAR-binding fragments, three of which were docked relative to the probe-RNA structure using experimental NMR restraints. The consistent orientations of functional groups in our data-driven docked structures and common electrostatic properties across all fragment leads reveal a surprising level of selectivity by our fragment-sized screening hits. These models further suggest linking strategies for the development of higher-affinity lead compounds for the inhibition of the TAR-Tat interaction.
authors.affiliation: Department of Chemistry, University of Washington, Box 351700, Seattle, WA 98195, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Davidson
authors.forename: Darren W
authors.initials: DW
authors.lastname: Begley
authors.forename: Carmen
authors.initials: C
authors.lastname: Lau
authors.forename: Gabriele
authors.initials: G
authors.lastname: Varani
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015335:Molecular Probes / Q000494:pharmacology*; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D012367:RNA, Viral / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D015335:Molecular Probes; D012367:RNA, Viral; D054852:Small Molecule Libraries