Inhibition of HIV-1 Tat-mediated transcription by a coumarin derivative, BPRHIV001, through the Akt pathway
Journal
Journal of Virology
Journal Volume
85
Journal Issue
17
Pages
9114-9126
Date Issued
2011
Author(s)
Lin P.-H.
Ke Y.-Y.
Su C.-T.
Shiao H.-Y.
Hsieh H.-P.
Chao Y.-K.
Lee C.-N.
Chao Y.-S.
Abstract
The human immunodeficiency virus type 1 (HIV-1)-encoded RNA-binding protein Tat is known to play an essential role in viral gene expression. In the search for novel compounds to inhibit Tat transactivity, one coumarin derivative, BPRHIV001, was identified, with a 50% effective concentration (EC 50) against HIV-1 at 1.3 nM. BPRHIV001 is likely to exert its effects at the stage after initiation of RNAPII elongation since Tat protein expression and the assembly of the Tat/P-TEFb complex remained unchanged. Next, a reduction of the p300 protein level, known to modulate Tat function through acetylation, was observed upon BPRHIV001 treatment, while the p300 mRNA level was unaffected. A concordant reduction of phosphorylated Akt, which was shown to be closely related to p300 stability, was observed in the presence of BPRHIV001 and was accompanied by a decrease of phosphorylated PDPK1, a well-known Akt activator. Furthermore, the docking analysis revealed that the reduced PDPK1 phosphorylation likely resulted from the allosteric effect of interaction between BPRHIV001 and PDPK1. With strong synergistic effects with current reverse transcriptase inhibitors, BPRHIV001 has the potential to become a promising lead compound for the development of a novel therapeutic agent against HIV-1 infection. ? 2011, American Society for Microbiology.
SDGs
Other Subjects
bprhiv 001; coumarin derivative; messenger RNA; phosphoinositide dependent protein kinase 1; positive transcription elongation factor b; protein kinase B; protein p300; RNA binding protein; RNA binding protein Tat; RNA polymerase II; transactivator protein; unclassified drug; acetylation; allosterism; article; concentration response; controlled study; drug protein binding; enzyme phosphorylation; human; human cell; Human immunodeficiency virus 1; human tissue; molecular docking; priority journal; protein assembly; protein expression; protein function; protein stability; RNA translation; transactivation; virus inhibition; virus replication; Anti-HIV Agents; Cell Line; Coumarins; HIV-1; Humans; Microbial Sensitivity Tests; Oncogene Protein v-akt; p300-CBP Transcription Factors; Phosphorylation; tat Gene Products, Human Immunodeficiency Virus; Transcription, Genetic; Human immunodeficiency virus 1
Type
journal article