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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 12 January 2010, Vol.107(2), pp.521-8
    Description: A virally encoded superfamily-2 (SF2) helicase (NS3h) is essential for the replication of hepatitis C virus, a leading cause of liver disease worldwide. Efforts to elucidate the function of NS3h and to develop inhibitors against it, however, have been hampered by limited understanding of its molecular mechanism. Here we show x-ray crystal structures for a set of NS3h complexes, including ground-state and transition-state ternary complexes captured with ATP mimics (ADP.BeF(3) and ). These structures provide, for the first time, three conformational snapshots demonstrating the molecular basis of action for a SF2 helicase. Upon nucleotide binding, overall domain rotation along with structural transitions in motif V and the bound DNA leads to the release of one base from the substrate base-stacking row and the loss of several interactions between NS3h and the 3' DNA segment. As nucleotide hydrolysis proceeds into the transition state, stretching of a "spring" helix and another overall conformational change couples rearrangement of the (d)NTPase active site to additional hydrogen-bonding between NS3h and DNA. Together with biochemistry, these results demonstrate a "ratchet" mechanism involved in the unidirectional translocation and define the step size of NS3h as one base per nucleotide hydrolysis cycle. These findings suggest feasible strategies for developing specific inhibitors to block the action of this attractive, yet largely unexplored drug target.
    Keywords: DNA Helicases -- Chemistry ; Hepacivirus -- Enzymology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Nature, June 5, 2014, Vol.510(7503), p.43(2)
    Description: A stampede of recent clinical studies suggests that we are on the cusp of developing well-tolerated, orally delivered drugs that can effectively eradicate hepatitis C virus from most, if not all, infected individuals.
    Keywords: Liver Cirrhosis – Care and Treatment ; Hepatitis C Virus – Care and Treatment
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Nature, May 6, 2010, Vol.465(7294), p.42(3)
    Description: Chronic infection with this virus (HCV) can lead to liver disorders such as fibrosis, cirrhosis and hepatocellular carcinoma, and it is a major reason for liver transplantation. In a strategy designed to focus on new targets, the group selected candidates...
    Keywords: Hepatitis C -- Prevention ; Hepatitis C -- Care And Treatment ; Drug Targeting -- Research ; Protease Inhibitors -- Research ; Proteases -- Physiological Aspects
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 4
    Language: English
    In: Nature Medicine, May, 2011, Vol.17(5), p.542(3)
    Keywords: Disease Susceptibility -- Health Aspects ; Disease Susceptibility -- Research ; Hepatitis C Virus -- Research ; Hepatitis C Virus -- Health Aspects ; Hepatitis C Virus -- Genetic Aspects ; Liver Diseases -- Causes Of ; Liver Diseases -- Care And Treatment ; Liver Diseases -- Patient Outcomes ; Protein-tyrosine Kinase -- Health Aspects ; Protein-tyrosine Kinase -- Genetic Aspects ; Protein-tyrosine Kinase -- Research
    ISSN: 1078-8956
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  • 5
    Language: English
    In: The Journal of biological chemistry, 08 July 2016, Vol.291(28), pp.14499-509
    Description: Genomic DNA replication requires helicases to processively unwind duplexes. Although helicases encoded by positive-strand RNA viruses are necessary for RNA genome replication, their functions are not well understood. We determined structures of the hepatitis C virus helicase (NS3h) in complex with the transition state ATP mimic ADP·AlF4 (-) and compared them with the previous nucleic acid-associated ternary complexes. The results suggested that nucleic acid binding promotes a structural change of the spring helix at the transition state, optimizing the interaction network centered on the nucleophilic water. Analysis of ATP hydrolysis with and without conformational restraints on the spring helix further supported the importance of its action for both nucleic acid-stimulated and basal catalysis. We further found that an F238P substitution, predicted to destabilize the helix, diminished viral RNA replication without significantly affecting ATP-dependent duplex unwinding. The stability of the secondary structure, thus, seems critical for additional functions of NS3h. Taken together, the results suggest that the spring helix may be central to the coordination of multiple modes of NS3h action. Further characterization centered on this element may help understand the molecular details of how the viral helicase facilitates RNA replication. This new structural information may also aid efforts to develop specific inhibitors targeting this essential viral enzyme.
    Keywords: Atpase ; RNA Helicase ; RNA Virus ; Hepatitis C Virus (Hcv) ; Structure-Function ; Viral Replication ; Hepacivirus -- Metabolism ; Hepatitis C -- Virology ; Viral Nonstructural Proteins -- Metabolism
    E-ISSN: 1083-351X
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  • 6
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 2012, Vol.109(36), pp.14610-14615
    Description: Dengue virus (DENV) is a global disease threat for which there are no approved antivirals or vaccines. Establishing state-of-the-art screening systems that rely on fluorescent or luminescent reporters may accelerate the development of anti-DENV therapeutics. However, relatively few reporter DENV platforms exist. Here, we show that DENV can be genetically engineered to express a green fluorescent protein or firefly luciferase. Reporter viruses are infectious in vitro and in vivo and are sensitive to antiviral compounds, neutralizing antibodies, and interferons. Bioluminescence imaging was used to follow the dynamics of DENV infection in mice and revealed that the virus localized predominantly to lymphoid and gut-associated tissues. The high-throughput potential of reporter DENV was demonstrated by screening a library of more than 350 IFN-stimulated genes for antiviral activity. Several antiviral effectors were identified, and they targeted DENV at two distinct life cycle steps. These viruses provide a powerful platform for applications ranging from validation of vaccine candidates to antiviral discovery. ; p. 14610-14615.
    Keywords: Dengue Virus ; Therapeutics ; Neutralizing Antibodies ; Green Fluorescent Protein ; Vaccines ; Neutralization ; Interferons ; Antiviral Agents ; Genes ; Luciferase ; Mice ; Genetic Engineering ; Screening ; Antiviral Properties ; Fluorescence ; Viruses ; Dengue ; Bioluminescence ; Image Analysis ; Tissues
    ISSN: 0027-8424
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  • 7
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 23 February 2010, Vol.107(8), pp.3764-9
    Description: The hepatitis C virus (HCV) life cycle involves multiple steps, but most current drug candidates target only viral replication. The inability to systematically discover inhibitors targeting multiple steps of the HCV life cycle has hampered antiviral development. We present a simple screen for HCV antivirals based on the alleviation of HCV-mediated cytopathic effect in an engineered cell line-n4mBid. This approach obviates the need for a secondary screen to avoid cytotoxic false-positive hits. Application of our screen to 1280 compounds, many in clinical trials or approved for therapeutic use, yielded 〉200 hits. Of the 55 leading hits, 47 inhibited one or more aspects of the HCV life cycle by 〉40%. Six compounds blocked HCV entry to levels similar to an antibody (JS-81) targeting the HCV entry receptor CD81. Seven hits inhibited HCV replication and/or infectious virus production by 〉100-fold, with one (quinidine) inhibiting infectious virus production by 450-fold relative to HCV replication levels. This approach is simple and inexpensive and should enable the rapid discovery of new classes of HCV life cycle inhibitors.
    Keywords: Cytoprotection ; Antiviral Agents -- Isolation & Purification ; Hepacivirus -- Drug Effects ; Virus Replication -- Drug Effects
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 8
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 22 June 2010, Vol.107(25), pp.11153-4
    Description: Author contributions: M.A.S. and C.M.R. wrote the paper.
    Keywords: Virus Replication ; Orthomyxoviridae -- Metabolism ; RNA, Small Interfering -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 9
    In: Nature, 2011, Vol.472(7344), p.481
    Description: The type I interferon response protects cells against invading viral pathogens. The cellular factors that mediate this defence are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery more than 25 years ago, only a few have been characterized with respect to antiviral activity. For most ISG products, little is known about their antiviral potential, their target specificity and their mechanisms of action. Using an overexpression screening approach, here we show that different viruses are targeted by unique sets of ISGs. We find that each viral species is susceptible to multiple antiviral genes, which together encompass a range of inhibitory activities. To conduct the screen, more than 380 human ISGs were tested for their ability to inhibit the replication of several important human and animal viruses, including hepatitis C virus, yellow fever virus, West Nile virus, chikungunya virus, Venezuelan equine encephalitis virus and human immunodeficiency virus type-1. Broadly acting effectors included IRF1, C6orf150 (also known as MB21D1), HPSE, RIG-I (also known as DDX58), MDA5 (also known as IFIH1) and IFITM3, whereas more targeted antiviral specificity was observed with DDX60, IFI44L, IFI6, IFITM2, MAP3K14, MOV10, NAMPT (also known as PBEF1), OASL, RTP4, TREX1 and UNC84B (also known as SUN2). Combined expression of pairs of ISGs showed additive antiviral effects similar to those of moderate type I interferon doses. Mechanistic studies uncovered a common theme of translational inhibition for numerous effectors. Several ISGs, including ADAR, FAM46C, LY6E and MCOLN2, enhanced the replication of certain viruses, highlighting another layer of complexity in the highly pleiotropic type I interferon system.
    Keywords: Gene Expression Regulation -- Genetics ; Interferon Type I -- Immunology ; Viruses -- Immunology;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 10
    In: Nature, 2003, Vol.426(6963), p.129
    Keywords: Antiviral Agents–Administration & Dosage ; Carbamates–Pharmacology ; Clinical Trials As Topic–Therapeutic Use ; Drug Design–Administration & Dosage ; Hepacivirus–Chemistry ; Hepatitis C–Pharmacokinetics ; Humans–Pharmacology ; Macrocyclic Compounds–Drug Effects ; Quinolines–Enzymology ; Serine Proteinase Inhibitors–Physiology ; Thiazoles–Drug Therapy ; Viral Load–Administration & Dosage ; Viral Nonstructural Proteins–Pharmacology ; Viral Nonstructural Proteins–Therapeutic Use ; Viral Nonstructural Proteins–Administration & Dosage ; Viral Nonstructural Proteins–Chemistry ; Viral Nonstructural Proteins–Pharmacokinetics ; Viral Nonstructural Proteins–Pharmacology ; Viral Nonstructural Proteins–Antagonists & Inhibitors ; Viral Nonstructural Proteins–Metabolism ; Antiviral Agents ; Biln 2061 ; Carbamates ; Macrocyclic Compounds ; Ns3 Protein, Hepatitis C Virus ; Quinolines ; Serine Proteinase Inhibitors ; Thiazoles ; Viral Nonstructural Proteins;
    ISSN: 0028-0836
    E-ISSN: 14764687
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