ATP-binding domain of NTPase/helicase as a target for hepatitis C antiviral therapy.

P Borowski; O Mueller; A Niebuhr; M Kalitzky; L H Hwang; H Schmitz; M A Siwecka; T Kulikowsk

doi:10.18388/abp.2000_4075

ATP-binding domain of NTPase/helicase as a target for hepatitis C antiviral therapy.

P Borowski Bernhard-Nocht-Institute for Tropical Medicine, Department of Virology, Hamburg, Germany.;
O Mueller
A Niebuhr
M Kalitzky
L H Hwang
H Schmitz
M A Siwecka
T Kulikowsk

DOI: https://doi.org/10.18388/abp.2000_4075

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.

Published

2000-03-31

Issue

Vol. 47 No. 1 (2000)

Section

Articles

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