title: Discovery of potent nucleotide-mimicking competitive inhibitors of hepatitis C virus NS3 helicase.
abstract: Among the enzymes involved in the life cycle of HCV, the non-structural protein NS3, with its double function of protease and NTPase/helicase, is essential for the virus replication. Exploiting our previous knowledge in the development of nucleotide-mimicking NS3 helicase (NS3h) inhibitors endowed with key structural and electronic features necessary for an optimal ligand-enzyme interaction, we developed the tetrahydroacridinyl derivative 3a as the most potent NS3h competitive inhibitor reported to date (HCV NS3h K(i)=20 nM).
authors.affiliation: European Research Centre for Drug Discovery and Development, Università di Siena, via Aldo Moro, 53100 Siena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.forename: Samantha
authors.initials: S
authors.lastname: Zanoli
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Romano
authors.forename: Pierangela
authors.initials: P
authors.lastname: Tripaldi
authors.forename: Luisa
authors.initials: L
authors.lastname: Savini
authors.forename: Isabella
authors.initials: I
authors.lastname: Fiorini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Borrelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D055808:Drug Discovery; D016174:Hepacivirus / Q000201:enzymology*; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D006834:Hydrazines; D011719:Pyrazines; D011804:Quinolines; 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