ATP-binding domain of NTPase/helicase as a target for hepatitis C antiviral therapy.
To enhance the inhibitory potential of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin) vs hepatitis C virus (HCV) NTPase/helicase, ribavirin-5'-triphosphate (ribavirin-TP) was synthesized and investigated. Ribavirin-TP was prepared with the use of modified Yoshikawa-Ludwig-Mishra-Broom procedure (cf. Mishra & Broom, 1991, J. Chem. Soc., Chem. Commun, 1276-1277) involving phosphorylation of unprotected nucleoside. Kinetic analysis revealed enhanced inhibitory potential of ribavirin-TP (IC50=40 microM) as compared to ribavirin (IC50 > 500 microM). Analysis of the inhibition type by means of graphical methods showed a competitive type of inhibition with respect to ATP. In view of the relatively low specificity towards nucleoside-5'-triphosphates (NTP) of the viral NTPase/helicases, it could not be ruled out that the investigated enzyme hydrolyzed the ribavirin-TP to less potent products. Investigations on non- hydrolysable analogs of ribavirin-TP or ribavirin-5'-diphosphate (ribavirin-DP) are currently under way.
Borowski
P
P
Bernhard-Nocht-Institute for Tropical Medicine, Department of Virology, Hamburg, Germany.
Mueller
O
O
Niebuhr
A
A
Kalitzky
M
M
Hwang
L H
LH
Schmitz
H
H
Siwecka
M A
MA
Kulikowsk
T
T
D017766:Acid Anhydride Hydrolases / Q000187:drug effects / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D004265:DNA Helicases / Q000187:drug effects / Q000378:metabolism*; D016174:Hepacivirus / Q000201:enzymology*; D006526:Hepatitis C / Q000188:drug therapy*; D043583:Nucleoside-Triphosphatase
D000998:Antiviral Agents; D000255:Adenosine Triphosphate; D017766:Acid Anhydride Hydrolases; D043583:Nucleoside-Triphosphatase; D004265:DNA Helicases