title: ATP-binding domain of NTPase/helicase as a target for hepatitis C antiviral therapy.
abstract: 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.
authors.affiliation: Bernhard-Nocht-Institute for Tropical Medicine, Department of Virology, Hamburg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Borowski
authors.forename: O
authors.initials: O
authors.lastname: Mueller
authors.forename: A
authors.initials: A
authors.lastname: Niebuhr
authors.forename: M
authors.initials: M
authors.lastname: Kalitzky
authors.forename: L H
authors.initials: LH
authors.lastname: Hwang
authors.forename: H
authors.initials: H
authors.lastname: Schmitz
authors.forename: M A
authors.initials: MA
authors.lastname: Siwecka
authors.forename: T
authors.initials: T
authors.lastname: Kulikowsk
mesh_terms: 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
chemical_list: D000998:Antiviral Agents; D000255:Adenosine Triphosphate; D017766:Acid Anhydride Hydrolases; D043583:Nucleoside-Triphosphatase; D004265:DNA Helicases