Tropolone and its Derivatives as Inhibitors of the Helicase Activity of Hepatitis C Virus Nucleotide Triphosphatase/helicase

Borowski, Peter; Lang, M; Haag, Annemarie; Baier, Andrea

doi:10.1177/095632020701800206

Cited by 12 publications

(9 citation statements)

References 29 publications

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“…Several compounds have been identified as RNA helicase of inhibitors of flavi- and other RNA viruses (Borowski et al, 2007; Carta et al, 2006; Frick, 2007; Johansson et al, 2003; Maga et al, 2005; Wu et al, 2006; Xi, 2007). Borowski et al, (2002) reported a WNV helicase inhibitor which also was active in cellular assays (IC 50 = 25–30 μM).…”

Section: Targeting Critical Functions Of Individual Flaviviral Prmentioning

confidence: 99%

Molecular targets for flavivirus drug discovery

2009

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Flaviviruses are a major cause of infectious disease in humans. Dengue virus causes an estimated 50 million cases of febrile illness each year, including an increasing number of cases of hemorrhagic fever. West Nile virus, which recently spread from the Mediterranean basin to the Western Hemisphere, now causes thousands of sporadic cases of encephalitis annually. Despite the existence of licensed vaccines, yellow fever, Japanese encephalitis and tick-borne encephalitis also claim many thousands of victims each year across their vast endemic areas. Antiviral therapy could potentially reduce morbidity and mortality from flavivirus infections, but no effective drugs are currently available. This article introduces a collection of papers in Antiviral Research on molecular targets for flavivirus antiviral drug design and murine models of dengue virus disease that aims to encourage drug development efforts. After reviewing the flavivirus replication cycle, we discuss the envelope glycoprotein, NS3 protease, NS3 helicase, NS5 methyltransferase and NS5 RNA-dependent RNA polymerase as potential drug targets, with special attention being given to the viral protease. The other viral proteins are the subject of individual articles in the journal. Together, these papers highlight current status of drug discovery efforts for flavivirus diseases and suggest promising areas for further research.

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Section: Targeting Critical Functions Of Individual Flaviviral Prmentioning

confidence: 99%

Molecular targets for flavivirus drug discovery

2009

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“…One of the non-structural proteins is a multifunctional enzyme possessing an N-terminal protease domain and a C-terminal ATPase/helicase domain. The helicase portion of non-structural protein 3 (NS3) is needed for HCV RNA replication (16, 17), but while many potent small molecule inhibitors for this helicase target have been discovered (18-21), none have entered the clinic. Many assays specific for HCV helicase activity have been developed such as those based on ELISA (22), scintillation proximity assays (23), flashplate methods (24), and FRET (25, 26) but they all suffer from the same drawbacks as the aforementioned general helicase assays.…”

Section: Introductionmentioning

confidence: 99%

Monitoring Helicase Activity with Molecular Beacons

Belon

Frick

2008

BioTechniques

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A high-throughput, fluorescence-based helicase assay using molecular beacons is described. The assay is tested using the NS3 helicase encoded by the hepatitis C virus (HCV) and shown to accurately monitor helicase action on both DNA and RNA. In the assay, a single stranded DNA oligonucleotide molecular beacon featuring a fluorescent moiety attached to one end and a quencher attached to the other is annealed to a second longer DNA or RNA oligonucleotide. Upon strand separation by a helicase and ATP, the beacon strand forms an intramolecular hairpin that brings the tethered fluorescent and quencher molecules into juxtaposition, quenching fluorescence. Unlike currently available “real-time” helicase assays, the molecular-beacon based helicase assay is irreversible and as such does not require the addition of extra DNA strands to prevent products from re-annealing. Several variants of the new assay are described and experimentally verified using both Cy3 and Cy5 beacons, including one based on a sequence from the HCV genome. The HCV genome based molecular beacon helicase assay is used to demonstrate how such an assay can be used in high-throughput screens and to analyze HCV helicase inhibitors.

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“…Approximately 2% of open reading frames in eukaryotes code for helicases or helicaselike proteins. Besides eukaryotes, many viruses also code for helicases [32] that have conserved motifs, and helicases are good targets for developing antiviral compounds [33][34][35][36][37]. Helicases are molecular motor proteins that translocate along nucleic acids and separate double-stranded nucleic acids using the energy generated by nucleoside 5 0 -triphosphate (NTP) hydrolysis.…”

Section: Helicase-dependent Dna Amplificationmentioning

confidence: 99%

Isothermal DNA amplification in vitro: the helicase-dependent amplification system

Jeong

Park

Kim

2009

Cell. Mol. Life Sci.

121

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Since the development of polymerase chain reaction, amplification of nucleic acids has emerged as an elemental tool for molecular biology, genomics, and biotechnology. Amplification methods often use temperature cycling to exponentially amplify nucleic acids; however, isothermal amplification methods have also been developed, which do not require heating the double-stranded nucleic acid to dissociate the synthesized products from templates. Among the several methods used for isothermal DNA amplification, the helicase-dependent amplification (HDA) is discussed in this review with an emphasis on the reconstituted DNA replication system. Since DNA helicase can unwind the double-stranded DNA without the need for heating, the HDA system provides a very useful tool to amplify DNA in vitro under isothermal conditions with a simplified reaction scheme. This review describes components and detailed aspects of current HDA systems using Escherichia coli UvrD helicase and T7 bacteriophage gp4 helicase with consideration of the processivity and efficiency of DNA amplification.

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Tropolone and its Derivatives as Inhibitors of the Helicase Activity of Hepatitis C Virus Nucleotide Triphosphatase/helicase

Cited by 12 publications

References 29 publications

Molecular targets for flavivirus drug discovery

Molecular targets for flavivirus drug discovery

Monitoring Helicase Activity with Molecular Beacons

Isothermal DNA amplification in vitro: the helicase-dependent amplification system

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