Isoquinolinesulphonamide derivatives inhibit transcriptional elongation of human immunodeficiency virus type 1 RNA in a promyelocytic model of latency.
Using the OM-10.1 promyelocytic model of inducible human immunodeficiency virus type 1 (HIV-1) infection, we tested a panel of known protein kinase inhibitors for an ability to block tumour necrosis factor-alpha-induced HIV-1 expression. Among the compounds tested, the broad-spectrum protein kinase inhibitor H-7 uniquely blocked HIV-1 expression at the level of viral transcription, but did not inhibit nuclear factor kappaB activation or function. In structure-activity analysis this inhibitory activity of H-7 on HIV-1 expression corresponded with the known structural requirements for the interaction of H-7 with the ATP-binding region of protein kinase C, suggesting that it was indeed related to the kinase inhibitory properties of H-7. The mechanism of H-7 transcriptional inhibition did not involve chromatin remodelling at the HIV-1 long terminal repeat promoter, as shown by nuc-1 disruption, and appeared to involve HIV-1 RNA elongation but not initiation. Therefore, H-7 and related isoquinolinesulphonamide analogues are most likely inhibiting a kinase target essential for HIV-1 transcriptional elongation whose identity may provide new therapeutic targets for intervention.
Critchfield
J W
JW
HIV and Retrovirology Branch, Division of AIDS, STD and TB Laboratory Research, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
Ho
O
O
Roberts
B D
BD
Van Lint
C
C
Verdin
E
E
Butera
S T
ST
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002843:Chromatin / Q000235:genetics / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000502:physiology; D018922:HL-60 Cells / Q000378:metabolism / Q000821:virology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D047428:Protein Kinase Inhibitors; D012367:RNA, Viral / Q000187:drug effects* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014775:Virus Activation / Q000187:drug effects / Q000235:genetics; D017735:Virus Latency / Q000187:drug effects / Q000235:genetics*
D019380:Anti-HIV Agents; D002843:Chromatin; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D012367:RNA, Viral; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine