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Identification of diverse microbial metabolites as potent inhibitors of HIV-1 Tat transactivation.
- Source :
-
Chemistry & biodiversity [Chem Biodivers] 2005 Jan; Vol. 2 (1), pp. 112-22. - Publication Year :
- 2005
-
Abstract
- 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 (M(R) 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 microM. 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 microM) but was not toxic at 100 microM in an equivalent cytotoxicity assay. The compound exhibited antiviral activity with an IC50 value of 6.2 microM 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.
- Subjects :
- Bacteria chemistry
Cell Line
Fungi chemistry
Gene Products, tat genetics
Gene Products, tat metabolism
Humans
Molecular Structure
Anti-HIV Agents metabolism
Anti-HIV Agents pharmacology
Bacteria metabolism
Fungi metabolism
Gene Expression Regulation, Viral drug effects
Gene Products, tat antagonists & inhibitors
Transcriptional Activation drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1612-1880
- Volume :
- 2
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Chemistry & biodiversity
- Publication Type :
- Academic Journal
- Accession number :
- 17191924
- Full Text :
- https://doi.org/10.1002/cbdv.200490162