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Isoquinolinesulphonamide derivatives inhibit transcriptional elongation of human immunodeficiency virus type 1 RNA in a promyelocytic model of latency
- Source :
- Scopus-Elsevier
-
Abstract
- 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-α-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 κB 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 isoquinoline-sulphonamide analogues are most likely inhibiting a kinase target essential for HIV-1 transcriptional elongation whose identity may provide new therapeutic targets for intervention.
- Subjects :
- 0301 basic medicine
Transcription, Genetic
Anti-HIV Agents
030106 microbiology
HIV Infections
HL-60 Cells
01 natural sciences
MAP2K7
03 medical and health sciences
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
Humans
ASK1
Enzyme Inhibitors
Protein kinase A
Protein Kinase Inhibitors
Protein kinase C
Sulfonamides
biology
Cyclin-dependent kinase 4
Tumor Necrosis Factor-alpha
Cyclin-dependent kinase 2
NF-kappa B
General Medicine
Isoquinolines
Protein kinase R
Chromatin
0104 chemical sciences
Cell biology
Virus Latency
010404 medicinal & biomolecular chemistry
Biochemistry
biology.protein
HIV-1
RNA, Viral
Cyclin-dependent kinase 9
Virus Activation
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Scopus-Elsevier
- Accession number :
- edsair.doi.dedup.....4e0016ba646b308f2750c291ab10fb53