Celastrol inhibits tat-mediated human immunodeficiency virus (HIV) transcription and replication

Vivek Narayan, Kodihalli C. Ravindra, Chris Chiaro, Daniele Cary, Bharat B. Aggarwal, Andrew J. Henderson, Kumble Sandeep Prabhu

Research output: Contribution to journalArticle

24 Citations (Scopus)

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-Δ 12,14-prostaglandin J 2 (15d-PGJ 2), 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.

Original languageEnglish (US)
Pages (from-to)972-983
Number of pages12
JournalJournal of Molecular Biology
Volume410
Issue number5
DOIs
StatePublished - Jul 29 2011

Fingerprint

Trans-Activators
Virus Replication
HIV
Transcriptional Activation
Cysteine
Tripterygium
Genome
tripterine
Curcumin
Alkylation
Phytochemicals
Therapeutics
Circular Dichroism
Sulfhydryl Compounds
Prostaglandins
Antiviral Agents
HIV-1
Spectrum Analysis
Acquired Immunodeficiency Syndrome
Viruses

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Cite this

Narayan, Vivek ; Ravindra, Kodihalli C. ; Chiaro, Chris ; Cary, Daniele ; Aggarwal, Bharat B. ; Henderson, Andrew J. ; Prabhu, Kumble Sandeep. / Celastrol inhibits tat-mediated human immunodeficiency virus (HIV) transcription and replication. In: Journal of Molecular Biology. 2011 ; Vol. 410, No. 5. pp. 972-983.
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Celastrol inhibits tat-mediated human immunodeficiency virus (HIV) transcription and replication. / Narayan, Vivek; Ravindra, Kodihalli C.; Chiaro, Chris; Cary, Daniele; Aggarwal, Bharat B.; Henderson, Andrew J.; Prabhu, Kumble Sandeep.

In: Journal of Molecular Biology, Vol. 410, No. 5, 29.07.2011, p. 972-983.

Research output: Contribution to journalArticle

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