title: Identification of diverse microbial metabolites as potent inhibitors of HIV-1 Tat transactivation.
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.
authors.affiliation: Merck Research Laboratories, P. O. Box 2000, Rahway, NJ 07065, USA.
authors.forename: Hiranthi
authors.initials: H
authors.lastname: Jayasuriya
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Zink
authors.forename: Jon D
authors.initials: JD
authors.lastname: Polishook
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Bills
authors.forename: Anne W
authors.initials: AW
authors.lastname: Dombrowski
authors.forename: Olga
authors.initials: O
authors.lastname: Genilloud
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Pelaez
authors.forename: Lucia
authors.initials: L
authors.lastname: Herranz
authors.forename: Donette
authors.initials: D
authors.lastname: Quamina
authors.forename: Russell B
authors.initials: RB
authors.lastname: Lingham
authors.forename: Renee
authors.initials: R
authors.lastname: Danzeizen
authors.forename: Pia L
authors.initials: PL
authors.lastname: Graham
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Tomassini
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: 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*
chemical_list: D019380:Anti-HIV Agents; D015696:Gene Products, tat