| Autor: |
Emert-Sedlak L; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA., Kodama T, Lerner EC, Dai W, Foster C, Day BW, Lazo JS, Smithgall TE |
| Jazyk: |
angličtina |
| Zdroj: |
ACS chemical biology [ACS Chem Biol] 2009 Nov 20; Vol. 4 (11), pp. 939-47. |
| DOI: |
10.1021/cb900195c |
| Abstrakt: |
Nef is an HIV-1 accessory protein essential for AIDS progression and an attractive target for drug discovery. Lack of a catalytic function makes Nef difficult to assay in chemical library screens. We developed a high-throughput screening assay for inhibitors of Nef function by coupling it to one of its host cell binding partners, the Src-family kinase Hck. Hck activation is dependent upon Nef in this assay, providing a direct readout of Nef activity in vitro. Using this screen, a unique diphenylfuropyrimidine was identified as a strong inhibitor of Nef-dependent Hck activation. This compound also exhibited remarkable antiretroviral effects, blocking Nef-dependent HIV replication in cell culture. Structurally related analogs were synthesized and shown to exhibit similar Nef-dependent antiviral activity, identifying the diphenylfuropyrimidine substructure as a new lead for antiretroviral drug development. This study demonstrates that coupling noncatalytic HIV accessory factors with host cell target proteins addressable by high-throughput assays may afford new avenues for the discovery of anti-HIV agents. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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