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Dissertation zugänglich unter
URN: urn:nbn:de:gbv:18-40654
URL: http://ediss.sub.uni-hamburg.de/volltexte/2009/4065/


Halogenierte Benzimidazole und Benzotriazole als Hemmstoffe der NTPase/Helikase von Hepatitis C und verwandten Viren

Halogenated banzimidazoles and benzotriazoles as inhibitors of the NTPase/helicase activities of hepatitis C and related viruses

Buchenau, Johanna

Originalveröffentlichung: (2008) Eur. J. Biochem. 270,1645–1653 (2003)
pdf-Format:
 Dokument 1.pdf (1.855 KB) 


SWD-Schlagwörter: Flaviviren , Nucleosidanaloga , Helicase , Benzimidazol , Hepatitis C
Basisklassifikation: 44.43
Institut: Medizin
DDC-Sachgruppe: Medizin, Gesundheit
Dokumentart: Dissertation
Hauptberichter: Schmitz, Herbert (Prof. Dr.)
Sprache: Deutsch
Tag der mündlichen Prüfung: 17.02.2009
Erstellungsjahr: 2008
Publikationsdatum: 27.03.2009
Kurzfassung auf Englisch: A search has been initiated for lead inhibitors of the non-structural protein 3 (NS3)-associated NTPase/helicase
activities of hepatitis C virus, the related West Nile virus, Japanese encephalitis virus and the human mitochondrial Suv3 enzyme. Random screening of a broad range of unrelated low-molecular mass compounds, employing both RNA and DNA substrates, revealed that 4,5,6,7-tetrabromobenzotriazole (TBBT) hitherto known as a potent
highly selective inhibitor of protein kinase 2, is a good inhibitor of the helicase, but not NTPase, activity of hepatitis C virus NTPase/helicase. The IC50 is approximately 20 µM with a DNA substrate,but only 60 µM with an RNA substrate. Several related analogues of TBBT were enzyme and/or substrate-specific inhibitors. For example, 5,6-dichloro-1-(â-D-ribofuranosyl)benzotriazole (DRBT) was a good, and selective, inhibitor of the West Nile virus enzyme with an RNA substrate (IC50 ~ 0.3 µM),but much weaker with a DNA substrate (IC50 ~ 3 µM). Preincubation of the enzymes, but not substrates, with DRBT enhanced inhibitory potency, e.g. the IC50 vs the hepatitis C virus helicase activity was reduced from 1.5 to 0.1 µM. No effect of preincubation was noted with TBBT, suggesting a different mode of interaction with the enzyme. The tetrachloro congener of TBBT, 4,5,6,7,-tetrachlorobenzotriazole (TCBT; a much weaker inhibitor of casein kinase 2) is also a much weaker inhibitor than TBBT of all four helicases. Kinetic studies, supplemented by comparison of ATP-binding sites, indicated that, unlike the case with casein kinase 2, the mode of action of the inhibitors vs the helicases is not by interaction with the catalytic ATP-binding site, but rather by occupation of an allosteric nucleoside/nucleotide binding site. The halogeno benzimidazoles and benzotriazoles included in this study are excellent lead compounds for the development of more potent inhibitors of hepatitis C virus and other viral NTPase/helicases.

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