title: Inhibition of acute-, latent-, and chronic-phase human immunodeficiency virus type 1 (HIV-1) replication by a bistriazoloacridone analog that selectively inhibits HIV-1 transcription.
abstract: Nanomolar concentrations of temacrazine (1,4-bis[3-(6-oxo-6H-v-triazolo[4,5,1-de]acridin-5-yl)amino-propyl ]piperazine) were discovered to inhibit acute human immunodeficiency virus type 1 (HIV-1) infections and suppress the production of virus from chronically and latently infected cells containing integrated proviral DNA. This bistriazoloacridone derivative exerted its mechanism of antiviral action through selective inhibition of HIV-1 transcription during the postintegrative phase of virus replication. Mechanistic studies revealed that temacrazine blocked HIV-1 RNA formation without interference with the transcription of cellular genes or with events associated with the HIV-1 Tat and Rev regulatory proteins. Although temacrazine inhibited the in vitro 3' processing and strand transfer activities of HIV-1 integrase, with a 50% inhibitory concentration of approximately 50 nM, no evidence of an inhibitory effect on the intracellular integration of proviral DNA into the cellular genome during the early phase of infection could be detected. Furthermore, temacrazine did not interfere with virus attachment or fusion to host cells or the enzymatic activities of HIV-1 reverse transcriptase or protease, and the compound was not directly virucidal. Demonstration of in vivo anti-HIV-1 activity by temacrazine identifies bistriazoloacridones as a new class of pharmaceuticals that selectively blocks HIV-1 transcription.
authors.affiliation: Laboratory of Antiviral Drug Mechanisms, Developmental Therapeutics Program, SAIC Frederick, Maryland 21702-1201, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Turpin
authors.forename: R W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: D
authors.initials: D
authors.lastname: Derse
authors.forename: M
authors.initials: M
authors.lastname: Hollingshead
authors.forename: K
authors.initials: K
authors.lastname: Williamson
authors.forename: C
authors.initials: C
authors.lastname: Palamone
authors.forename: M C
authors.initials: MC
authors.lastname: Osterling
authors.forename: S A
authors.initials: SA
authors.lastname: Hill
authors.forename: L
authors.initials: L
authors.lastname: Graham
authors.forename: C A
authors.initials: CA
authors.lastname: Schaeffer
authors.forename: M
authors.initials: M
authors.lastname: Bu
authors.forename: M
authors.initials: M
authors.lastname: Huang
authors.forename: W M
authors.initials: WM
authors.lastname: Cholody
authors.forename: C J
authors.initials: CJ
authors.lastname: Michejda
authors.forename: W G
authors.initials: WG
authors.lastname: Rice
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000210:Acute-Phase Reaction; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D015694:Gene Products, rev / Q000187:drug effects / Q000378:metabolism; D015696:Gene Products, tat / Q000187:drug effects / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*; D054321:rev Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D000166:Acridines; D019380:Anti-HIV Agents; D015694:Gene Products, rev; D015696:Gene Products, tat; D010879:Piperazines; D054321:rev Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus; C111772:temacrazine