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  Ketoamide Resistance and Hepatitis C Virus Fitness in Val55 Variants of the NS3 Serine Protease

Welsch, C., Schweizer, S., Shimakami, T., Domingues, F. S., Kim, S., Lemon, S. M., et al. (2012). Ketoamide Resistance and Hepatitis C Virus Fitness in Val55 Variants of the NS3 Serine Protease. Antimicrobial Agents and Chemotherapy, 56(4), 1907-1915. doi:10.1128/AAC.05184-11.

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Genre: Zeitschriftenartikel
Latex : Ketoamide Resistance and Hepatitis {C} Virus Fitness in {Val55} Variants of the {NS3} Serine Protease

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318394/ (beliebiger Volltext)
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 Urheber:
Welsch, Christoph1, Autor           
Schweizer, Sabine2, Autor
Shimakami, Testsuro2, Autor
Domingues, Francisco S.2, Autor           
Kim, Seungtaek2, Autor
Lemon, Stanley M.2, Autor
Antes, Iris2, Autor           
Affiliations:
1Computational Biology and Applied Algorithmics, MPI for Informatics, Max Planck Society, ou_40046              
2External Organizations, ou_persistent22              

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Schlagwörter: Antiviral Agents/*pharmacology Cell Line Cells, Cultured Computer Simulation *Drug Resistance, Viral Genotype Hepacivirus/*drug effects/enzymology/*genetics Humans Models, Molecular Plasmids/genetics Proline/analogs & derivatives/pharmacology Protein Conformation RNA, Viral/biosynthesis/genetics Serine Proteinase Inhibitors/*pharmacology Transfection Viral Nonstructural Proteins/*antagonists & inhibitors/*genetics Virus Replication/drug effects
 Zusammenfassung: Drug-resistant viral variants are a major issue in the use of direct-acting antiviral agents in chronic hepatitis C. Ketoamides are potent inhibitors of the NS3 protease, with V55A identified as mutation associated with resistance to boceprevir. Underlying molecular mechanisms are only partially understood. We applied a comprehensive sequence analysis to characterize the natural variability at Val55 within dominant worldwide patient strains. A residue-interaction network and molecular dynamics simulation were applied to identify mechanisms for ketoamide resistance and viral fitness in Val55 variants. An infectious H77S.3 cell culture system was used for variant phenotype characterization. We measured antiviral 50% effective concentration (EC(5)(0)) and fold changes, as well as RNA replication and infectious virus yields from viral RNAs containing variants. Val55 was found highly conserved throughout all hepatitis C virus (HCV) genotypes. The conservative V55A and V55I variants were identified from HCV genotype 1a strains with no variants in genotype 1b. Topology measures from a residue-interaction network of the protease structure suggest a potential Val55 key role for modulation of molecular changes in the protease ligand-binding site. Molecular dynamics showed variants with constricted binding pockets and a loss of H-bonded interactions upon boceprevir binding to the variant proteases. These effects might explain low-level boceprevir resistance in the V55A variant, as well as the Val55 variant, reduced RNA replication capacity. Higher structural flexibility was found in the wild-type protease, whereas variants showed lower flexibility. Reduced structural flexibility could impact the Val55 variant's ability to adapt for NS3 domain-domain interaction and might explain the virus yield drop observed in variant strains.

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Sprache(n): eng - English
 Datum: 2011-12-222012-01-172012
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: PMID: 22252823
PMC: PMC3318394
DOI: 10.1128/AAC.05184-11
URI: http://www.ncbi.nlm.nih.gov/pubmed/22252823
BibTex Citekey: Welsch2012z
Anderer: Local-ID: A76C4F979CD85F52C1257B120044B815-Welsch2012z
 Art des Abschluß: -

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Quelle 1

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Titel: Antimicrobial Agents and Chemotherapy
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: American Society for Microbiology (ASM)
Seiten: - Band / Heft: 56 (4) Artikelnummer: - Start- / Endseite: 1907 - 1915 Identifikator: ISSN: 0066-4804
CoNE: https://pure.mpg.de/cone/journals/resource/954925458050