Isoquinolinesulphonamide Derivatives Inhibit Transcriptional Elongation of Human Immunodeficiency Virus Type 1 RNA in a Promyelocytic Model of Latency

• Published in: Antiviral chemistry & chemotherapy Vol. 10; no. 5; pp. 275 - 284
• Main Authors: Critchfield, JW, Ho, O, Roberts, BD, Van Lint, C, Verdin, E, Butera, ST
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.09.1999; International Medical Press; Sage Publications Ltd
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; AIDS/HIV; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Chromatin - genetics; Chromatin - physiology; Chromatin remodeling; Elongation; Enzyme inhibitors; Enzyme Inhibitors - pharmacology; HIV; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - growth & development; HIV-1 - physiology; HL-60 Cells - metabolism; HL-60 Cells - virology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Isoquinolines - pharmacology; Isoquinolinesulfonamides; Kinases; Latency; Long terminal repeat; Medical sciences; NF-kappa B - antagonists & inhibitors; NF-kappa B - physiology; Pharmacology. Drug treatments; Protein kinase C; Protein Kinase Inhibitors; Proteins; Ribonucleic acid; RNA; RNA viruses; RNA, Viral - drug effects; RNA, Viral - genetics; Structure-function relationships; Sulfonamides; Sulfonamides - pharmacology; Therapeutic applications; Transcription elongation; Transcription, Genetic - drug effects; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-α; Tumors; Virus Activation - drug effects; Virus Activation - genetics; Virus Latency - drug effects; Virus Latency - genetics; HIV-1 latency; cellular factors; transcriptional inhibitors; Isoquinoline derivatives; Sulfonamide; HIV-1 virus; Enzyme; Transferases; Retroviridae; Enzyme inhibitor; Lentivirus; Biological activity; Latency; Virus; Structure activity relation; Protein kinase; Antiviral; Replication; Human immunodeficiency virus; Elongation
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.1177/095632029901000506

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.