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Specific Targeting of Hepatitis C Virus NS3 RNA Helicase. Discovery of the Potent and Selective Competitive Nucleotide-Mimicking Inhibitor QU663

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journal contribution
posted on 19.07.2005, 00:00 by Giovanni Maga, Sandra Gemma, Caterina Fattorusso, Giada A. Locatelli, Stefania Butini, Marco Persico, Gagan Kukreja, Maria Pia Romano, Luisa Chiasserini, Luisa Savini, Ettore Novellino, Vito Nacci, Silvio Spadari, Giuseppe Campiani
Hepatitis C virus (HCV) infection is an emerging global epidemic, and no effective cure is yet available. Interferon-α (INFα) 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 (Ki = 0.75 μM), 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.