Effect of compounds (9, 13, 20 and 21) on the HIV-1 transcription in TZM-bl cells infected with HIV-1NL4-3
We developed a cellular screening system capable of simultaneously evaluating the functional activities of Tat-induced LTR transcription and general cellular expression. Herein, we identified and optimized novel HIV-1 Tat inhibitory compounds that contain an oxadiazole core. To assess the inhibitory effect of our lead compounds on Tat-mediated HIV-1 transcription, we performed RNA-seq analyses of the HIV-1 transcripts in the compound-treated HIV-1-infected cells. The read counts of the transcripts mapped to the HIV-1 genome were substantially reduced in the compound 9- or 13-treated cells; however, the decrease of the read counts was not observed in the HIV-1 infected cells with the ineffective compounds (20 and 21). These data indicate that the viral transcription step is a target for our lead compounds. Overall design: Novel oxadiazole compounds that inhibit HIV-1 Tat-mediated viral transcription were identified. To elucidate the Molecular mechanism underlying the Tat inhibition of compounds, we performed the level of viral transcripts using an RNA-seq analysis gene expression of our lead compounds treated-HIV-1 infected cells. Comparative gene expression profiling analysis of RNA-seq data for DMSO and compounds (9, 13, 20 and 21) treated cells.