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 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.
Jayasuriya
Hiranthi
H
Merck Research Laboratories, P. O. Box 2000, Rahway, NJ 07065, USA.
Zink
Deborah L
DL
Polishook
Jon D
JD
Bills
Gerald F
GF
Dombrowski
Anne W
AW
Genilloud
Olga
O
Pelaez
Fernando F
FF
Herranz
Lucia
L
Quamina
Donette
D
Lingham
Russell B
RB
Danzeizen
Renee
R
Graham
Pia L
PL
Tomassini
Joanne E
JE
Singh
Sheo B
SB
D019380:Anti-HIV Agents / Q000378:metabolism* / Q000494:pharmacology*; D001419:Bacteria / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D005658:Fungi / Q000737:chemistry / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D015533:Transcriptional Activation / Q000187:drug effects*
D019380:Anti-HIV Agents; D015696:Gene Products, tat