Discovery of potent nucleotide-mimicking competitive inhibitors of hepatitis C virus NS3 helicase.
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).
Gemma
Sandra
S
European Research Centre for Drug Discovery and Development, Università di Siena, via Aldo Moro, 53100 Siena, Italy.
Butini
Stefania
S
Campiani
Giuseppe
G
Brindisi
Margherita
M
Zanoli
Samantha
S
Romano
Maria Pia
MP
Tripaldi
Pierangela
P
Savini
Luisa
L
Fiorini
Isabella
I
Borrelli
Giuseppe
G
Novellino
Ettore
E
Maga
Giovanni
G
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
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