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Pan-serotype dengue virus inhibitor JNJ-A07 targets NS4A-2K-NS4B interaction with NS2B/NS3 and blocks replication organelle formation

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...

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Main Authors: Kiemel, Dominik (Author) , Kröll, Ann-Sophie (Author) , Denolly, Solène (Author) , Haselmann, Uta (Author) , Bonfanti, Jean-François (Author) , Andres, Jose Ignacio (Author) , Ghosh, Brahma (Author) , Geluykens, Peggy (Author) , Kaptein, Suzanne J. F. (Author) , Wilken, Lucas (Author) , Scaturro, Pietro (Author) , Neyts, Johan (Author) , Van Loock, Marnix (Author) , Goethals, Olivia (Author) , Bartenschlager, Ralf (Author)
Format: Article (Journal)
Language:English
Published: 19 July 2024
In: Nature Communications
Year: 2024, Volume: 15, Pages: 1-20
ISSN:2041-1723
DOI:10.1038/s41467-024-50437-3
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-024-50437-3
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-024-50437-3
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Author Notes: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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Summary: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.
Item Description:Gesehen am 23.10.2024
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-024-50437-3

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