Isolation and Characterization of the Fungal Metabolite 3-O-Methylviridicatin as an Inhibitor of Tumour Necrosis Factor α-Induced Human Immunodeficiency Virus Replication

Author:

Heguy A1,Cai P1,Meyn P1,Houck D1,Russo S1,Michitsch R1,Pearce C1,Katz B1,Bringmann G2,Feineis D2,Taylor DL3,Tyms AS3

Affiliation:

1. OSI Pharmaceuticals, 106 Charles Lindbergh Boulevard, Uniondale, NY 11553, USA

2. Institute of Organic Chemistry, Am Hubland, D-97074, Würzburg, Germany

3. MRC Collaborative Centre, 1–3 Burtonhole Lane, Mill Hill, London, NW7 1AD, UK

Abstract

The cytokine tumour necrosis factor α (TNF-α) 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-α-induced HIV expression could have therapeutic value in the treatment of AIDS. We have sought to identify antiviral agents that block TNF-α 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-α 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-α-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-α activation of the HIV LTR in the HeLa-based system, with an IC50 of 5 μM, and inhibited virus production in the OM-10.1 cell line, a model of chronic infection responsive to induction by TNF-α, with an IC50 of 2.5 μM.

Publisher

SAGE Publications

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