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Dengue fever is an important emerging public health concern, with several million viral infections occurring annually, for which no effective therapy currently exists. The NS3 protein from Dengue virus is a multifunctional protein of 69 kDa, endowed with protease, helicase, and nucleoside 5'-triphosphatase (NTPase) activities. Thus, NS3 plays an important(More)
Together with the NS5 polymerase, the NS3 helicase has a pivotal function in flavivirus RNA replication and constitutes an important drug target. We captured the dengue virus NS3 helicase at several stages along the catalytic pathway including bound to single-stranded (ss) RNA, to an ATP analogue, to a transition-state analogue and to ATP hydrolysis(More)
Dengue virus, a member of the family Flaviviridae of positive-strand RNA viruses, has seven non-structural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5. Except for enzymic activities contained within NS3 and NS5, the roles of the other proteins in virus replication and pathogenesis are not well defined. In this study, a physical interaction between(More)
A recombinant form of yellow fever virus (YFV) NS3 protease, linked via a nonapeptide to the minimal NS2B co-factor sequence (CF40-gly-NS3pro190), was expressed in Escherichia coli and shown to be catalytically active. It efficiently cleaved the fluorogenic tetrapeptide substrate Bz-norleucine-lysine-arginine-arginine-AMC, which was previously optimized for(More)
New treatments are urgently needed to combat the increasing number of dengue fever cases in endemic countries as well as amongst a large number of travellers from non-endemic countries. Of the 10 virus encoded proteins, NS3 (non-structural 3) and NS5 carry out all the enzymatic activities needed for polyprotein processing and genome replication, and are(More)
With the incidence of dengue fever increasing all over the world, there is an urgent need for therapies. While drug discovery for any disease is a long and difficult process with uncertain success, dengue fever poses an additional complication in that most of the target patient population is young and lives in developing countries with very limited health(More)
We performed a mutational analysis of the NS3 helicase of dengue virus to test insights gleaned from its crystal structure and identified four residues in the full-length protein that severely impaired either its RTPase and ATPase (Arg-457-458, Arg-460, Arg-463) or helicase (Ile-365, Arg-376) activity. Alanine substitution of Lys-396, which is located at(More)
Infectious diseases caused by flaviviruses are important emerging public health concerns and new vaccines and therapeutics are urgently needed. The NS3 protein from flavivirus is a multifunctional protein with protease, helicase and nucleoside 5' triphosphatase activities (NTPase). Thus, NS3 plays a crucial role in viral replication and represents an(More)
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