ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2009
15-Deoxy-Delta12,14-prostaglandin J2 inhibits HIV-1 transactivating protein, Tat, through covalent modification.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 33 citations in OpenAlex.
- Review
- Cyclopentenone Prostaglandins: Biologically Active Lipid Mediators Targeting Inflammation.Frontiers in physiology · 2021Review
- Selenium and selenoproteins in prostanoid metabolism and immunity.Critical reviews in biochemistry and molecular biology · 2019Review
- Current Strategies for Elimination of HIV-1 Latent Reservoirs Using Chemical Compounds Targeting Host and Viral Factors.AIDS research and human retroviruses · 2019Review
- 15d-Prostaglandin J2 induced reactive oxygen species-mediated apoptosis during experimental visceral leishmaniasis.Journal of molecular medicine (Berlin, Germany) · 2016Article
- Didehydro-Cortistatin A: a new player in HIV-therapy?Expert review of anti-infective therapy · 2016Article
- 15-Deoxy-ΔFrontiers in immunology · 2016Article
- Targeting HIV transcription: the quest for a functional cure.Current topics in microbiology and immunology · 2015Review
- Article
- Leukotrienes inhibit early stages of HIV-1 infection in monocyte-derived microglia-like cells.Journal of neuroinflammation · 2012Article
- Targeting of histone acetyltransferase p300 by cyclopentenone prostaglandin Δ(12)-PGJ(2) through covalent binding to Cys(1438).Chemical research in toxicology · 2012Article
- Interactions between prostaglandins, leukotrienes and HIV-1: possible implications for the central nervous system.Retrovirology · 2012Review
- Nuclear receptor signaling inhibits HIV-1 replication in macrophages through multiple trans-repression mechanisms.Journal of virology · 2011Article
- Celastrol inhibits Tat-mediated human immunodeficiency virus (HIV) transcription and replication.Journal of molecular biology · 2011Article
- Article
- Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia.PloS one · 2009Article
- Prostaglandin ABrazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Controlling the HIV/AIDS epidemic remains a major challenge, with approximately 5 million new HIV infections annually. Cyclopentenone prostaglandins (CyPG), such as 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), are arachidonic acid-derived endogenous electrophiles that possess anti-HIV activity by an unknown mechanism. Given that the reactive alpha,beta-unsaturated ketone in the cyclopentenone ring of 15d-PGJ(2) covalently modifies key Cys thiols in select proteins, we hypothesized that 15d-PGJ(2) inhibits HIV transcription and replication by targeting Cys thiols in HIV-1 Tat. Tat is a potent transactivator of viral gene expression required for HIV transcriptional elongation and replication. Our studies indicate that 15d-PGJ(2) treatment of cells inhibits Tat-dependent transcription and replication of HIV-1, while 9,10-dihydro-15d-PGJ(2), PGE(2), PGF(2alpha), or PGD(2) that lack the reactive alpha,beta-unsaturated ketone were ineffective. The inhibition of Tat activity by 15d-PGJ(2) was dose-dependent, with an IC(50) of 1.2 microM and independent of NF-kappaB pathway. Furthermore, using a biotinylated derivative of 15d-PGJ(2), we demonstrate that 15d-PGJ(2) modifies free Cys-thiols in Tat to form covalent Michael adducts and that the interaction was further increased on reduction of Tat. 15d-PGJ(2)-modified Tat was unable to transactivate the HIV long terminal repeat in U937 human macrophages. These data demonstrate that Tat acts as a molecular target of CyPG leading to the inhibition of transcription and also suggest a novel therapeutic approach to complement current antiretroviral strategies for HIV/AIDS.
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