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15–Deoxy‐Δ 12 ’ 14 ‐prostaglandin J 2 inhibits HIV‐1 transactivating protein, Tat, through covalent modification
Author(s) -
Kalantari Parisa,
Narayan Vivek,
Henderson Andrew J.,
Prabhu K. Sandeep
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-124982
Subject(s) - transactivation , cyclopentenone , covalent bond , chemistry , ketone , viral replication , transcription factor , biology , biochemistry , stereochemistry , virology , virus , gene , organic chemistry
Controlling the HIV/AIDS epidemic remains a major challenge, with approximately 5 million new HIV infections annually. Cyclopentenone prostaglandins (CyPG), such as 15‐deoxy‐△ 1214 ‐PGJ 2 (15d‐PGJ 2 ), are arachidonic acid‐derived endogenous electrophiles that possess anti‐HIV activity by an unknown mechanism. Given that the reactive α,β‐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 2α , or PGD 2 that lack the reactive α,β‐unsaturated ketone were ineffective. The inhibition of Tat activity by 15d‐PGJ 2 was dose‐dependent, with an IC 50 of 1.2 βM and independent of NF‐κB 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.— Kalantari, P.,Narayan, V., Henderson, A. J., Prabhu, K. S. 15‐Deoxy‐A12,14‐prostaglandin J2 inhibits HIV‐1 transactivating protein, Tat, through covalent modification. FASEBJ. 23, 2366–2373 (2009)