title: High-affinity recognition of HIV-1 frameshift-stimulating RNA alters frameshifting in vitro and interferes with HIV-1 infectivity.
abstract: The life cycle of the human immunodeficiency virus type 1 (HIV-1) has an absolute requirement for ribosomal frameshifting during protein translation in order to produce the polyprotein precursor of the viral enzymes. While an RNA stem-loop structure (the "HIV-1 Frameshift Stimulating Signal", or HIV-1 FSS) controls the frameshift efficiency and has been hypothesized as an attractive therapeutic target, developing compounds that selectively bind this RNA and interfere with HIV-1 replication has proven challenging. Building on our prior discovery of a "hit" molecule able to bind this stem-loop, we now report the development of compounds displaying high affinity for the HIV-1 FSS. These compounds are able to enhance frameshifting more than 50% in a dual-luciferase assay in human embryonic kidney cells, and they strongly inhibit the infectivity of pseudotyped HIV-1 virions.
authors.affiliation: Departments of Chemistry, ‡Biochemistry and Biophysics, and §Dermatology, University of Rochester , Rochester, New York 14642, United States.
authors.forename: Leslie O
authors.initials: LO
authors.lastname: Ofori
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hilimire
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Bennett
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Brown
authors.forename: Harold C
authors.initials: HC
authors.lastname: Smith
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Miller
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018965:Frameshifting, Ribosomal; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D049409:Luciferases, Firefly / Q000235:genetics / Q000378:metabolism; D049410:Luciferases, Renilla / Q000235:genetics / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics*; D013237:Stereoisomerism; D014771:Virion / Q000187:drug effects / Q000472:pathogenicity; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D004220:Disulfides; D011804:Quinolines; D012367:RNA, Viral; D049410:Luciferases, Renilla; D049409:Luciferases, Firefly