Identification of diverse microbial metabolites as potent inhibitors of HIV-1 Tat transactivation
| Autor: | Olga Genilloud, Pia L. Graham, Anne W. Dombrowski, Lucia Herranz, Sheo B. Singh, Gerald F. Bills, Hiranthi Jayasuriya, Russell B. Lingham, Deborah L. Zink, Donette S. Quamina, Joanne E. Tomassini, Fernando Pelaez, Renee Danzeizen, Jon D. Polishook |
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| Rok vydání: | 2006 |
| Předmět: |
Gene Expression Regulation
Viral Transcriptional Activation Stereochemistry Anti-HIV Agents Bioengineering Echinomycin Biochemistry Cell Line Transactivation chemistry.chemical_compound Humans Cytotoxicity Molecular Biology IC50 chemistry.chemical_classification Bicyclic molecule Bacteria Molecular Structure Chemistry Fungi General Chemistry General Medicine Viral replication Gene Products tat Molecular Medicine Lactone Ternatin |
| Zdroj: | Chemistrybiodiversity. 2(1) |
| ISSN: | 1612-1880 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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