title: Isolation and characterization of the fungal metabolite 3-O-methylviridicatin as an inhibitor of tumour necrosis factor alpha-induced human immunodeficiency virus replication.
abstract: The cytokine tumour necrosis factor alpha (TNF-alpha) has been shown to play a role in human immunodeficiency virus (HIV) replication by activating transcription of the provirus in both T cells and macrophages. Therefore, agents that block TNF-alpha-induced HIV expression could have therapeutic value in the treatment of AIDS. We have sought to identify antiviral agents that block TNF-alpha induction of HIV LTR-directed transcription, using a cell-based, virus-free assay system in automated high-throughput screening. HeLa cells were transfected with an HIV LTR-luciferase reporter plasmid and a stable line was isolated in which TNF-alpha increased luciferase production by two- to threefold. This cell line was used to screen approximately 15,000 fungal extracts. An inhibitory activity specific for TNF-alpha-induced HIV LTR transcription was observed in culture OS-F67406. The active component was isolated and identified as a known metabolite, 3-O-methylviridicatin, by NMR and mass spectrometry. No biological activity has been associated with this compound previously. This compound blocks TNF-alpha activation of the HIV LTR in the HeLa-based system, with an IC50 of 5 microM, and inhibited virus production in the OM-10.1 cell line, a model of chronic infection responsive to induction by TNF-alpha, with an IC50 of 2.5 microM.
authors.affiliation: OSI Pharmaceuticals, Uniondale, NY 11553, USA.
authors.forename: A
authors.initials: A
authors.lastname: Heguy
authors.forename: P
authors.initials: P
authors.lastname: Cai
authors.forename: P
authors.initials: P
authors.lastname: Meyn
authors.forename: D
authors.initials: D
authors.lastname: Houck
authors.forename: S
authors.initials: S
authors.lastname: Russo
authors.forename: R
authors.initials: R
authors.lastname: Michitsch
authors.forename: C
authors.initials: C
authors.lastname: Pearce
authors.forename: B
authors.initials: B
authors.lastname: Katz
authors.forename: G
authors.initials: G
authors.lastname: Bringmann
authors.forename: D
authors.initials: D
authors.lastname: Feineis
authors.forename: D L
authors.initials: DL
authors.lastname: Taylor
authors.forename: A S
authors.initials: AS
authors.lastname: Tyms
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D005658:Fungi / Q000737:chemistry*; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D016325:HIV Long Terminal Repeat; D006367:HeLa Cells; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015363:Quinolones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C116810:3-O-methylviridicatin; D019380:Anti-HIV Agents; D006912:Hydroxyquinolines; D015363:Quinolones; D014409:Tumor Necrosis Factor-alpha