Isoquinolinesulphonamide derivatives inhibit transcriptional elongation ofhuman immunodeficiency virus type 1 RNA in a promyelocytic model of latency

Using the OM-10.1 promyelocytic model of inducible human immunodeficiency v irus type 1 (HIV-1) infection, we tested a panel of known protein kinase in hibitors 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 trans cription, but did not inhibit nuclear factor kappa B activation or function . In structure-activity analysis this inhibitory activity of H-7 on HIV-1 e xpression corresponded with the known structural requirements for the inter action of H-7 with the ATP-binding region of protein kinase C, suggesting t hat it was indeed related to the kinase inhibitory properties of H-7. The m echanism of H-7 transcriptional inhibition did not involve chromatin remode lling at the HIV-1 long terminal repeat promoter, as shown by nuc-1 disrupt ion, and appeared to involve HIV-1 RNA elongation but not initiation. There fore, H-7 and related isoquinoline-sulphonamide analogues are most likely i nhibiting a kinase target essential for HIV-1 transcriptional elongation wh ose identity may provide new therapeutic targets for intervention.