title: Discovery of selective, small-molecule inhibitors of RNA complexes--I. The Tat protein/TAR RNA complexes required for HIV-1 transcription.
abstract: We have developed a therapeutic program focusing on the inhibition of a human immunodeficiency virus-1 specific protein-RNA interaction. This program begins with a search for small organic molecules that would interfere with the binding of Tat protein to TAR RNA. The methodologies chosen to study the HIV-1 Tat-TAR interaction and inhibition include gel mobility shift assays, scintillation proximity assays, filtration assays, and mass spectrometry. These methods helped establish in vitro high-throughput screening assays which rapidly identified Tat-TAR inhibitors from our corporate compound library. Tat-activated reporter gene assays were then used to investigate the cellular activities of the Tat-TAR inhibitors. The cellular activity, selectivity, and toxicity data for select Tat-TAR inhibitors were determined. Evaluation of both the cellular data and the Tat-TAR inhibition results led to further testing in anti-HIV-1 infection assays.
authors.affiliation: BioOrganic Chemistry Section, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48106, USA.
authors.forename: H Y
authors.initials: HY
authors.lastname: Mei
authors.forename: D P
authors.initials: DP
authors.lastname: Mack
authors.forename: A A
authors.initials: AA
authors.lastname: Galan
authors.forename: N S
authors.initials: NS
authors.lastname: Halim
authors.forename: A
authors.initials: A
authors.lastname: Heldsinger
authors.forename: J A
authors.initials: JA
authors.lastname: Loo
authors.forename: D W
authors.initials: DW
authors.lastname: Moreland
authors.forename: K A
authors.initials: KA
authors.lastname: Sannes-Lowery
authors.forename: L
authors.initials: L
authors.lastname: Sharmeen
authors.forename: H N
authors.initials: HN
authors.lastname: Truong
authors.forename: A W
authors.initials: AW
authors.lastname: Czarnik
mesh_terms: D000595:Amino Acid Sequence; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001483:Base Sequence; D001570:Benzodiazepinones / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D015696:Gene Products, tat / Q000187:drug effects* / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D011758:Pyrroles / Q000494:pharmacology; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D000972:Antineoplastic Agents, Phytogenic; D001570:Benzodiazepinones; D015696:Gene Products, tat; D011758:Pyrroles; D012367:RNA, Viral; D054322:tat Gene Products, Human Immunodeficiency Virus; C072173:Ro 5-3335; D002166:Camptothecin