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Identification of Diverse Microbial Metabolites as Potent Inhibitors of HIV‐1 Tat Transactivation
Author(s) -
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.
Publication year - 2005
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200490162
Subject(s) - transactivation , chemistry , human immunodeficiency virus (hiv) , identification (biology) , computational biology , biochemistry , virology , transcription factor , gene , biology , botany
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 IC 50 values ranging from 0.0002 to 100 μ M . The most active compound was the quinoxiline bicyclic octadepsipeptides, UK‐63598, which inhibited Tat‐dependent transactivation with an IC 50 value of 0.2 n M and exhibited a 100‐fold therapeutic window with respect to toxicity. In a single‐cycle antiviral assay, UK‐6358 inhibited viral replication with an IC 50 value of 0.5 n M ; however, it appeared to be equally toxic at that concentration. Monocillin IV was significantly less active (Tat transactivation inhibitory IC 50 of 5 μ M ) but was not toxic at 100 μ M in an equivalent cytotoxicity assay. The compound exhibited antiviral activity with an IC 50 value of 6.2 μ M 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.