Specific targeting of hepatitis C virus NS3 RNA helicase. Discovery of the potent and selective competitive nucleotide-mimicking inhibitor QU663.
Hepatitis C virus (HCV) infection is an emerging global epidemic, and no effective cure is yet available. Interferon-alpha (INFalpha) and pegylated INFs, in combination or otherwise with ribavirin, have proven to be effective in no more than 50% of chronically infected patients. New and better therapeutic strategies are therefore needed. HCV nonstructural protein 3 (NS3) RNA helicase (h) is a promising target for developing new therapeutics. QU663 was discovered as a potent new selective inhibitor of the helicase reaction of HCV NS3 (K(i) = 0.75 microM), competing with the nucleic acid substrate without affecting ATPase function, even at high concentrations. QU663 is one of a new generation of small-molecule nucleotide-mimicking inhibitors which are potential anti-HCV agents. A thorough molecular modeling study was carried out to explain the molecular basis of NS3h inhibition by QU663. The resulting three-dimensional interaction model is discussed.
Maga
Giovanni
G
Istituto di Genetica Molecolare, CNR-Pavia, via Abbiategrasso 207, 27100 Pavia, Italy.
Gemma
Sandra
S
Fattorusso
Caterina
C
Locatelli
Giada A
GA
Butini
Stefania
S
Persico
Marco
M
Kukreja
Gagan
G
Romano
Maria Pia
MP
Chiasserini
Luisa
L
Savini
Luisa
L
Novellino
Ettore
E
Nacci
Vito
V
Spadari
Silvio
S
Campiani
Giuseppe
G
D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D004279:DNA, Viral / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology; D006868:Hydrolysis; D018716:Molecular Mimicry; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D020365:RNA Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000255:Adenosine Triphosphate; D000998:Antiviral Agents; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D006834:Hydrazines; D011719:Pyrazines; D011804:Quinolines; D011810:Quinoxalines; D020365:RNA Helicases; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C504331:QU663 compound