Discovery and characterization of an HIV-1 Tat antagonist.
Ro 5-3335, 7-chloro-5-(2-pyrryl)-3H-1,4-benzo-diazepin-2-(H)-one, has been shown to inhibit gene expression controlled by the human immunodeficiency virus-1 (HIV-1) LTR promoter. The inhibition was specific for the viral transcriptional transactivator Tat. The compound did not inhibit the basal activity of the HIV-1 LTR or the activity of promoters not responsive to Tat. Consistent with its mode of action, Ro 5-3335 inhibited HIV-1 replication (IC50 = 0.1-1 microM) by reducing viral RNA synthesis in acutely, as well as chronically, infected cells in vitro. The compound was active against HIV-1 and HIV-2, and AZT-resistant clinical isolates.
Hsu
M C
MC
Department of Virology, Hoffmann-La Roche Inc., Nutley, NJ 07110.
Schutt
A D
AD
Holly
M
M
Slice
L W
LW
Sherman
M I
MI
Richman
D D
DD
Potash
M J
MJ
Volsky
D J
DJ
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D017353:Gene Deletion; D015870:Gene Expression / Q000187:drug effects; D015696:Gene Products, tat / Q000037:antagonists & inhibitors*; D015756:Genes, tat / Q000187:drug effects*; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D007700:Kinetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology; D054322:tat Gene Products, Human Immunodeficiency Virus
D000998:Antiviral Agents; D001570:Benzodiazepinones; D015696:Gene Products, tat; D011758:Pyrroles; D054322:tat Gene Products, Human Immunodeficiency Virus; C072173:Ro 5-3335; D015215:Zidovudine