Identification of Diverse Microbial Metabolites as Potent Inhibitors of HIV-1 Tat Transactivation

HIV‐1 Tat is one of six regulatory proteins that are required for viral replication and is an attractive target for the development of new anti‐HIV agents. Screening of microbial extracts using a whole cell Tat‐dependent transactivation assay, which guided the separation of the active broths, led to...

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Published in:	Chemistry & biodiversity Vol. 2; no. 1; pp. 112 - 122
Main Authors:	Jayasuriya, Hiranthi, Zink, Deborah L., Polishook, Jon D., Bills, Gerald F., Dombrowski, Anne W., Genilloud, Olga, Pelaez, Fernando F., Herranz, Lucia, Quamina, Donette, Lingham, Russell B., Danzeizen, Renee, Graham, Pia L., Tomassini, Joanne E., Singh, Sheo B.
Format:	Journal Article
Language:	English
Published:	Zürich WILEY-VCH Verlag 01-01-2005 WILEY‐VCH Verlag
Subjects:	Anti-HIV Agents - metabolism Anti-HIV Agents - pharmacology Bacteria - chemistry Bacteria - metabolism Cell Line Fungi - chemistry Fungi - metabolism Gene Expression Regulation, Viral - drug effects Gene Products, tat - antagonists & inhibitors Gene Products, tat - genetics Gene Products, tat - metabolism Human immunodeficiency virus 1 Humans Molecular Structure Transcriptional Activation - drug effects
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Summary:	HIV‐1 Tat is one of six regulatory proteins that are required for viral replication and is an attractive target for the development of new anti‐HIV agents. Screening of microbial extracts using a whole cell Tat‐dependent transactivation assay, which guided the separation of the active broths, led to the identification of five structurally diverse classes (MR range 232–1126) of natural products. These include i) three sesquiterpenoids, namely, sporogen‐AO1, petasol, and 6‐dehydropetasol, ii) two resorcylic 14‐membered lactones, namely monorden and monocillin IV, iii) a ten‐membered lactone, iv) a quinoline and quinoxiline bicyclic octadepsipeptides, namely echinomycin and UK‐63598, and v) a cyclic heptapeptide, ternatin. These compounds displayed varying degrees of potencies with IC50 values ranging from 0.0002 to 100 μM. The most active compound was the quinoxiline bicyclic octadepsipeptides, UK‐63598, which inhibited Tat‐dependent transactivation with an IC50 value of 0.2 nM and exhibited a 100‐fold therapeutic window with respect to toxicity. In a single‐cycle antiviral assay, UK‐6358 inhibited viral replication with an IC50 value of 0.5 nM; however, it appeared to be equally toxic at that concentration. Monocillin IV was significantly less active (Tat transactivation inhibitory IC50 of 5 μM) but was not toxic at 100 μM in an equivalent cytotoxicity assay. The compound exhibited antiviral activity with an IC50 value of 6.2 μM in the single‐cycle antiviral assay and a sixfold therapeutic window. Details of the isolation, fermentation, and biological activities of these structurally diverse natural products are described.
Bibliography:	ArticleID:CBDV200490162 istex:7DED2320DDDEC2E11B25913F7A92566336B75976 ark:/67375/WNG-5NWRWPRD-6 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	1612-1872 1612-1880
DOI:	10.1002/cbdv.200490162