title: Multivalent binding oligomers inhibit HIV Tat-TAR interaction critical for viral replication.
abstract: We describe the development of a new type of scaffold to target RNA structures. Multivalent binding oligomers (MBOs) are molecules in which multiple sidechains extend from a polyamine backbone such that favorable RNA binding occurs. We have used this strategy to develop MBO-based inhibitors to prevent the association of a protein-RNA complex, Tat-TAR, that is essential for HIV replication. In vitro binding assays combined with model cell-based assays demonstrate that the optimal MBOs inhibit Tat-TAR binding at low micromolar concentrations. Antiviral studies are also consistent with the in vitro and cell-based assays. MBOs provide a framework for the development of future RNA-targeting molecules.
authors.affiliation: Laboratory of Bioorganic Chemistry, NIDDK, NIH, DHHS, Bethesda, MD 20892, USA. appellad@niddk.nih.gov
authors.forename: Deyun
authors.initials: D
authors.lastname: Wang
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Iera
authors.forename: Heather
authors.initials: H
authors.lastname: Baker
authors.forename: Priscilla
authors.initials: P
authors.lastname: Hogan
authors.forename: Roger
authors.initials: R
authors.lastname: Ptak
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.forename: Tracy
authors.initials: T
authors.lastname: Hartman
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: Alexandre
authors.initials: A
authors.lastname: Desjardins
authors.forename: Ao
authors.initials: A
authors.lastname: Yang
authors.forename: Pascale
authors.initials: P
authors.lastname: Legault
authors.forename: Venkat
authors.initials: V
authors.lastname: Yedavalli
authors.forename: Kuan-Teh
authors.initials: KT
authors.lastname: Jeang
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Appella
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000187:drug effects / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; D054322:tat Gene Products, Human Immunodeficiency Virus