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| Verfasst von: | Kiemel, Dominik [VerfasserIn]  |
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| | Kröll, Ann-Sophie [VerfasserIn] |
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| | Denolly, Solène [VerfasserIn] |
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| | Haselmann, Uta [VerfasserIn] |
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| | Bonfanti, Jean-François [VerfasserIn] |
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| | Andres, Jose Ignacio [VerfasserIn] |
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| | Ghosh, Brahma [VerfasserIn] |
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| | Geluykens, Peggy [VerfasserIn] |
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| | Kaptein, Suzanne J. F. [VerfasserIn] |
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| | Wilken, Lucas [VerfasserIn] |
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| | Scaturro, Pietro [VerfasserIn] |
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| | Neyts, Johan [VerfasserIn] |
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| | Van Loock, Marnix [VerfasserIn] |
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| | Goethals, Olivia [VerfasserIn] |
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| | Bartenschlager, Ralf [VerfasserIn] |
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| Titel: | Pan-serotype dengue virus inhibitor JNJ-A07 targets NS4A-2K-NS4B interaction with NS2B/NS3 and blocks replication organelle formation |
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| Verf.angabe: | Dominik Kiemel, Ann-Sophie Helene Kroell, Solène Denolly, Uta Haselmann, Jean-François Bonfanti, Jose Ignacio Andres, Brahma Ghosh, Peggy Geluykens, Suzanne J. F. Kaptein, Lucas Wilken, Pietro Scaturro, Johan Neyts, Marnix Van Loock, Olivia Goethals & Ralf Bartenschlager |
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| E-Jahr: | 2024 |
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| Jahr: | 19 July 2024 |
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| Umfang: | 20 S. |
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| Illustrationen: | Illustrationen |
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| Fussnoten: | Gesehen am 23.10.2024 |
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| Titel Quelle: | Enthalten in: Nature Communications |
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| Ort Quelle: | [London] : Springer Nature, 2010 |
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| Jahr Quelle: | 2024 |
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| Band/Heft Quelle: | 15(2024), Artikel-ID 6080, Seite 1-20 |
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| ISSN Quelle: | 2041-1723 |
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| Abstract: | Dengue fever represents a significant medical and socio-economic burden in (sub)tropical regions, yet antivirals for treatment or prophylaxis are lacking. JNJ-A07 was described as highly active against the different genotypes within each serotype of the disease-causing dengue virus (DENV). Based on clustering of resistance mutations it has been assumed to target DENV non-structural protein 4B (NS4B). Using a photoaffinity labeling compound with high structural similarity to JNJ-A07, here we demonstrate binding to NS4B and its precursor NS4A-2K-NS4B. Consistently, we report recruitment of the compound to intracellular sites enriched for these proteins. We further specify the mechanism-of-action of JNJ-A07, which has virtually no effect on viral polyprotein cleavage, but targets the interaction between the NS2B/NS3 protease/helicase complex and the NS4A-2K-NS4B cleavage intermediate. This interaction is functionally linked to de novo formation of vesicle packets (VPs), the sites of DENV RNA replication. JNJ-A07 blocks VPs biogenesis with little effect on established ones. A similar mechanism-of-action was found for another NS4B inhibitor, NITD-688. In summary, we unravel the antiviral mechanism of these NS4B-targeting molecules and show how DENV employs a short-lived cleavage intermediate to carry out an early step of the viral life cycle. |
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| DOI: | doi:10.1038/s41467-024-50437-3 |
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| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
kostenfrei: Volltext: https://doi.org/10.1038/s41467-024-50437-3 |
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| | kostenfrei: Volltext: https://www.nature.com/articles/s41467-024-50437-3 |
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| | DOI: https://doi.org/10.1038/s41467-024-50437-3 |
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| Datenträger: | Online-Ressource |
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| Sprache: | eng |
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| Sach-SW: | Dengue virus |
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| | Molecular medicine |
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| | Preventive medicine |
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| | Target identification |
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| | Viral infection |
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| K10plus-PPN: | 1906643962 |
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| Verknüpfungen: | → Zeitschrift |
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Pan-serotype dengue virus inhibitor JNJ-A07 targets NS4A-2K-NS4B interaction with NS2B/NS3 and blocks replication organelle formation / Kiemel, Dominik [VerfasserIn]; 19 July 2024 (Online-Ressource)
