Inhibitors of the NTPase/helicases of hepatitis C and related Flaviviridae viruses.
Abstract: In the search for inhibitors of the non-structural protein 3 (NS3)-associated NTPase/helicase activities of the hepatitis C virus (HCV), and of the related West Nile Virus (WNV), and Japanese Encephalitis Virus (JEV), random screening of a broad range of unrelated low-molecular weight compounds revealed that 4,5,6,7-tetrabromo-1H-benzotriazole (TBBT) is a good inhibitor of the helicase activity of HCV and WNV NTPase/helicases (IC50 >> 20 mM and 1.7 mM with a DNA substrate), but a very weak inhibitor of the JEV enzyme (IC50 >> 200 mM). The synthesis of new TBBT derivatives was undertaken and their inhibitory activities against HCV, WNV, and JEV NTPase/helicases and cytotoxicities were examined. The N-alkyl derivatives showed good activity and lower cytotoxicity than TBBT.
Bretner
Maria
M
Laboratory of Antimetabolites, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 5A Pawińskiego Str., 02-106 Warszawa, Poland. majka@ibb.waw.pl
Najda
Andzelika
A
Podwińska
Romualda
R
Baier
Andrea
A
Paruch
Katarzyna
K
Lipniacki
Andrzej
A
Piasek
Andrzej
A
Borowski
Peter
P
Kulikowski
Tadeusz
T
D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D004279:DNA, Viral / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D018067:Flaviviridae / Q000187:drug effects / Q000201:enzymology*; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D043583:Nucleoside-Triphosphatase / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D043583:Nucleoside-Triphosphatase; D004265:DNA Helicases