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dc.contributor.advisorSchmitz, Herbert (Prof. Dr.)
dc.contributor.authorBuchenau, Johanna
dc.date.accessioned2020-10-19T12:23:51Z-
dc.date.available2020-10-19T12:23:51Z-
dc.date.issued2008
dc.identifier.urihttps://ediss.sub.uni-hamburg.de/handle/ediss/2502-
dc.description.abstractA 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.en
dc.language.isodede
dc.publisherStaats- und Universitätsbibliothek Hamburg Carl von Ossietzky
dc.relation.isbasedonEur. J. Biochem. 270,1645–1653 (2003)
dc.rightshttp://purl.org/coar/access_right/c_abf2
dc.subject.ddc610 Medizin, Gesundheit
dc.titleHalogenierte Benzimidazole und Benzotriazole als Hemmstoffe der NTPase/Helikase von Hepatitis C und verwandten Virende
dc.title.alternativeHalogenated banzimidazoles and benzotriazoles as inhibitors of the NTPase/helicase activities of hepatitis C and related virusesen
dc.typedoctoralThesis
dcterms.dateAccepted2009-02-17
dc.rights.ccNo license
dc.rights.rshttp://rightsstatements.org/vocab/InC/1.0/
dc.subject.bcl44.43 Medizinische Mikrobiologie
dc.subject.gndFlaviviren
dc.subject.gndNucleosidanaloga
dc.subject.gndHelicase
dc.subject.gndBenzimidazol
dc.subject.gndHepatitis C
dc.type.casraiDissertation-
dc.type.dinidoctoralThesis-
dc.type.driverdoctoralThesis-
dc.type.statusinfo:eu-repo/semantics/publishedVersion
dc.type.thesisdoctoralThesis
tuhh.opus.id4065
tuhh.opus.datecreation2009-03-27
tuhh.type.opusDissertation-
thesis.grantor.departmentMedizin
thesis.grantor.placeHamburg
thesis.grantor.universityOrInstitutionUniversität Hamburg
dcterms.DCMITypeText-
tuhh.gvk.ppn603734324
dc.identifier.urnurn:nbn:de:gbv:18-40654
item.creatorOrcidBuchenau, Johanna-
item.fulltextWith Fulltext-
item.languageiso639-1other-
item.advisorGNDSchmitz, Herbert (Prof. Dr.)-
item.grantfulltextopen-
item.creatorGNDBuchenau, Johanna-
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