Vinylogous Ureas as a Novel Class of Inhibitors of Reverse Transcriptase-Associated Ribonuclease H Activity

Michaela Wendeler, Hsiu-Fang Lee, Alun Bermingham, Jennifer T Miller, Oleg Chertov, Marion K Bona, Noel S Baichoo, Maryam Ehteshami, John Beutler, Barry R O'Keefe, Matthias Götte, Mamuka Kvaratskhelia, etc.

ACS Chem Biol. 2008 Oct 17;3(10):635-44.

PMID: 18831589

Abstract:

High-throughput screening of National Cancer Institute libraries of synthetic and natural compounds identified the vinylogous ureas 2-amino-5,6,7,8-tetrahydro-4 H-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 beta-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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP40106125	NSC727447		40106-12-5	Price