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

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.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Narayan V,Ravindra KC,Chiaro C,Cary D,Aggarwal BB,Henderson AJ,Prabhu KS

doi

10.1016/j.jmb.2011.04.013

subject

Has Abstract

pub_date

2011-07-29 00:00:00

pages

972-83

issue

5

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(11)00428-1

journal_volume

410

pub_type

杂志文章

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