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Celastrol Inhibits Tat-Mediated Human Immunodeficiency Virus (HIV) Transcription and Replication
Authors:Vivek Narayan  Chris Chiaro  Bharat B. Aggarwal  K. Sandeep Prabhu
Affiliation:
  • 1 Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
  • 2 Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
  • 3 Experimental Therapeutics Program, MD Anderson Cancer Center, Houston, TX 77030, USA
  • Abstract:Current drugs used for antiretroviral therapy against human immunodeficiency virus (HIV) have a narrow spectrum of activity and, more often, have associated toxicities and severe side effects in addition to developing resistance. Thus, there is a need to develop new therapeutic strategies against HIV/AIDS to complement the already existing ones. Surprisingly, transactivator of transcription (Tat), an early virus-encoded protein required for the efficient transcription of the HIV genome, has not been developed as a target for small molecular therapeutics. We have previously described the ability of an endogenous Michael acceptor electrophile (MAE), 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), to inhibit Tat-dependent transcription by targeting its cysteine (Cys)-rich domain. In an effort to identify other MAEs possessing inhibitory activity against HIV-1 Tat, we tested a collection of plant-derived compounds with electrophilic properties, including curcumin, rosmarinic acid, and gambogic acid, for their ability to inhibit Tat. Celastrol (Cel), a triterpenoid MAE isolated from Tripterygium wilfordii, exhibited the highest inhibitory activity against Tat. Using biochemical techniques, we demonstrate that Cel, by covalently modifying the cysteine thiols, inhibits Tat transactivation function. Using circular dichroism spectroscopy, we show that alkylation of Tat brought about a change in the secondary structure of Tat, which inhibited the transcription elongation of the HIV proviral genome by effecting mechanisms other than Tat-TAR (transactivation-responsive region) interaction. Our results demonstrate the underlying mechanism of antiretroviral activity of the plant-derived MAEs and suggest that Cel could serve as a lead compound to develop novel antiviral therapeutics.
    Keywords:FA, ferulic acid   Cur, curcumin   tCur, tetrahydro curcumin   GA, gambogic acid   DGA, dihydro gambogic acid   RA, rosmarinic acid   Cel, celastrol   bCel, celastrol biotinamide   MAE, Michael acceptor electrophile   CD, circular dichroism   Tat, transactivator of transcription   P-TEFb, positive transcription elongation factor b   RNAPII, RNA polymerase II   HIV, human immunodeficiency virus   TAR, transactivation-responsive region   LTR, long terminal repeat   rTat, recombinant Tat   HRP, horseradish peroxidase   GSH, reduced glutathione   qPCR, quantitative PCR   NIH, National Institutes of Health   DMSO, dimethyl sulfoxide   S.E.M., standard error of the mean
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