Inhibition of HIV-1 Tat-mediated transcription by a coumarin derivative, BPRHIV001, through the Akt pathway.

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.

• Authors: Pi-Han Lin, Yi-Yu Ke, Chun-Ting Su, Hui-Yi Shiao, Hsing-Pang Hsieh, Yu-Kai Chao, Chun-Nan Lee, Chuan-Liang Kao, Yu-Sheng Chao, Sui-Yuan Chang
• Journal: Journal of virology (J Virol) Vol. 85 Issue 17 Pg. 9114-26 (Sep 2011) ISSN: 1098-5514 [Electronic] United States
• PMID: 21697490 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Coumarins
• tat Gene Products, Human Immunodeficiency Virus
• coumarin
• p300-CBP Transcription Factors
• p300-CBP-associated factor
• Oncogene Protein v-akt

Topics

• Anti-HIV Agents (pharmacology)
• Cell Line
• Coumarins (pharmacology)
• HIV-1 (drug effects, physiology)
• Humans
• Microbial Sensitivity Tests
• Oncogene Protein v-akt (metabolism)
• Phosphorylation
• Transcription, Genetic (drug effects)
• p300-CBP Transcription Factors (metabolism)
• tat Gene Products, Human Immunodeficiency Virus (antagonists & inhibitors)