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.

NUCKS1, a novel Tat coactivator, plays a crucial role in HIV-1 replication by increasing Tat-mediated viral transcription on the HIV-1 LTR promoter

“…We used an mRNA microarray assay to examine HIV-1-latent cell lines (Figure 6). Positively Tat-regulating factors such as CCNT1, protein phospatase 1(PP1), and p300/CBP did not have lower expression levels in latent cells compared with normal cells, suggesting that the basal expression of these factors may not be associated with latent infection [47,48]. Negatively Tat-regulating factors including BanF1, BRD7, and thioredoxin reductase-1 (TXNRD1) did not show consistent differences in their expression patterns between latent and normal cells [49][50][51].…”

Ethnomedicinal Wisdom

“…In fact its name comes from a French term for the tonka bean coumarou. Coumarins have been proven to be potent against many viruses like HIV (Lin et al, 2011b), HSV (Ghannadi et al, 2014), Dengue and Chikungunya (Gomez-Calderon et al, 2017). • Flavones, flavonoids, and flavonols…”

Therapeutic potential of coumarins as antiviral agents

“…Thus, 4-phenyl-coumarins which are acting through a novel mechanism could be a potential lead for the development of potent therapeutic agent in the management of AIDS and drug-resistant HIV strains [67]. Later scientist from the same laboratory reported two more compounds (86,87) of same class, 4-PC as potent HIV transcription inhibitors acting mainly through interference of NF-kB and Tat functions (Fig. 16) [68].…”

“…The compound acts by targeting viral RNPs that are responsible for viral RNA synthesis [85]. This same molecule (BPR2-D2) was later established as an effective anti-HIV agent (BPRHIV001) which inhibits Tat-Mediated Transcription through Akt pathway (EC 50 ¼ 1.3 nM) [86]. Thus this molecule has the potential to become a promising lead compound for the development of a novel therapeutic agent effective against both HIV-1 and influenza infections ( Fig.…”