Vinylogous ureas as a novel class of inhibitors of reverse transcriptase-associated ribonuclease H activity.

来自 NCBI

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作者：

M Wendeler，HF Lee，A Bermingham，JT Miller，O Chertov，MK Bona，NS Baichoo，M Ehteshami，J Beutler，BR O’Keefe

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摘要：

High-throughput screening of National Cancer Institute libraries of synthetic and natural compounds identified the vinylogous ureas 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (NSC727447) and N-[3-(aminocarbonyl)-4,5-dimethyl-2-thienyl]-2-furancarboxamide (NSC727448) as inhibitors of the ribonuclease H (RNase H) activity of HIV-1 and HIV-2 reverse transcriptase (RT). A Yonetani?Theorell analysis demonstrated that NSC727447, and the active-site hydroxytropolone RNase H inhibitor β-thujaplicinol were mutually exclusive in their interaction with the RNase H domain. Mass spectrometric protein footprinting of the NSC727447 binding site indicated that residues Cys280 and Lys281 in helix I of the thumb subdomain of p51 were affected by ligand binding. Although DNA polymerase and pyrophosphorolysis activities of HIV-1 RT were less sensitive to inhibition by NSC727447, protein footprinting indicated that NSC727447 occupied the equivalent region of the p66 thumb. Site-directed mutagenesis using reconstituted p66/p51 heterodimers substituted with natural or non-natural amino acids indicates that altering the p66 RNase H primer grip significantly affects inhibitor sensitivity. NSC727447 thus represents a novel class of RNase H antagonists with a mechanism of action differing from active site, divalent metal-chelating inhibitors that have been reported.

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关键词：

Runx adhesion survival microarray transcription

DOI：

10.1016/j.jnoncrysol.2005.09.027

被引量：

107

年份：

2008