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

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Borowski P., Mueller O., Niebuhr A., Kalitzky M., Hwang L.-H., Schmitz H., Siwecka M. A., Kulikowski T.

2000

vol. 47

issue 1

173-180

To enhance the inhibitory potential of 1-β-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 μM) as compared to ribavirin (IC50 > 500 μM). 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.

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1 Acta Biochimica Polonica

1 2000

1 Borowski P.

1 Hwang L.-H.

1 Kalitzky M.

1 Kulikowski T.

1 Mueller O.

1 Niebuhr A.

1 Schmitz H.

1 Siwecka M. A.

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