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Inhibition of the helicase activity of HCV NTPase-helicase by 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide-5'-triphosphate [ribavirin-TP]

100%

Borowski P., Lang M., Niebuhr A., Haag A., Schmitz H., Schulze zur Wiesch J., Choe J., Siwecka M. A., Kulikowski T.

Acta Biochimica Polonica

2001

tom 48

nr 3

In the presented study the ribavirin-TP — an established inhibitor of the NTPase activity of the superfamily NTPase/helicases II — was investigated as an inhibitor of the unwinding activity of the hepatitis C virus (HCV) NTPase/helicase. The kinetics of the reaction revealed that ribavirin-TP reduces the turnover number of the helicase reaction by a mechanism that does not correspond to that of the inhibition of the NTPase activity. Our results suggest that derivatives of ribavirin-TP with enhanced stability towards hydrolytic attack may be effective inhibitors of the enzyme.

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

100%

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

Acta Biochimica Polonica

2000

tom 47

nr 1

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 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.

Ograniczanie wyników

2 Acta Biochimica Polonica

2 Borowski P.

2 Kulikowski T.

2 Niebuhr A.

2 Schmitz H.

2 Siwecka M. A.

1 Choe J.

1 Haag A.

1 Hwang L. H.

1 Kalitzky M.

1 Lang M.

1 Mueller O.

1 Schulze zur Wiesch J.

1 2001

1 2000

Wyniki wyszukiwania

Inhibition of the helicase activity of HCV NTPase-helicase by 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide-5'-triphosphate [ribavirin-TP]

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