title: 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.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, No. 1 Chang-Te Street, Taipei, Taiwan.
authors.forename: Pi-Han
authors.initials: PH
authors.lastname: Lin
authors.forename: Yi-Yu
authors.initials: YY
authors.lastname: Ke
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Su
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Shiao
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
authors.forename: Yu-Kai
authors.initials: YK
authors.lastname: Chao
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Lee
authors.forename: Chuan-Liang
authors.initials: CL
authors.lastname: Kao
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Sui-Yuan
authors.initials: SY
authors.lastname: Chang
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D003374:Coumarins / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation; D014158:Transcription, Genetic / Q000187:drug effects*; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors*; D000099224:p300-CBP-Associated Factor
chemical_list: D019380:Anti-HIV Agents; D003374:Coumarins; D051058:Oncogene Protein v-akt; D050880:p300-CBP Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D000099224:p300-CBP-Associated Factor; C030123:coumarin