Novel indolocarbazole protein kinase C inhibitors prevent reactivation of HIV-1 in latently infected cells.
Suppression of human immunodeficiency virus-1 (HIV-1) reactivation in latently infected cells by protein kinase C (PKC) inhibitors has been described. Based on an initial finding with the indolocarbazole inhibitor Gö 6976 we have examined several members of this new class of potent and specific PKC inhibitors with respect to their ability to prevent the PKC-mediated induction of HIV-1 replication in the latently infected U1 cell line. Two of these compounds strongly inhibited not only PMA-induced release of p24-antigen and infectious virus particles into the supernatant (50% inhibition at 0.04-0.35 microM) but also TNF-alpha-mediated HIV-1 reactivation in the same concentration range. Significant lower toxicities compared to Gö 6976 were observed for the new compounds, with 50% cytotoxic concentrations at 5.2 microM for Gö 7775 and 3.4 microM for Gö 7716. This resulted in selectivity indices which were 10-20-times higher compared to the reference compound Gö 6976 and were comparable to those of registered anti-AIDS drugs. No anti-HIV-1 activity was observed for a closely related indolocarbazole analogue with no inhibitory activity in the PKC in vitro enzyme assay. This study demonstrates the important role of PKC in reactivation of HIV-1 in latently infected cells and points to the potential of indolocarbazoles to preserve the latent state of HIV-1 infection.
Pätzold
S
S
Abteilung Biochemische Pharmakologie, Gödecke AG, Freiburg, Germany.
Schneider
J
J
Rudolph
C
C
Marmé
D
D
Schächtele
C
C
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000633:toxicity; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects
D000970:Antineoplastic Agents; D002227:Carbazoles; D007211:Indoles; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate