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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| Hauptverfasser: | , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
19 July 2024
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| In: |
Nature Communications
Year: 2024, Jahrgang: 15, Pages: 1-20 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-024-50437-3 |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a Pan-serotype dengue virus inhibitor JNJ-A07 targets NS4A-2K-NS4B interaction with NS2B/NS3 and blocks replication organelle formation |c 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 |
| 246 | 3 | 3 | |a Pan-serotype dengue virus inhibitor JNJ-A zero seven targets NSfourA-twoK-NSfourB interaction with NStwoB/NSthree and blocks replication organelle formation |
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| 520 | |a 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. | ||
| 650 | 4 | |a Dengue virus | |
| 650 | 4 | |a Molecular medicine | |
| 650 | 4 | |a Preventive medicine | |
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| 650 | 4 | |a Viral infection | |
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