Pan-serotype dengue virus inhibitor JNJ-A07 targets NS4A-2K-NS4B interaction with NS2B/NS3 and blocks replication organelle formation.
Dengue Virus
/ drug effects
Viral Nonstructural Proteins
/ metabolism
Virus Replication
/ drug effects
Antiviral Agents
/ pharmacology
Humans
Dengue
/ virology
Serogroup
RNA Helicases
/ metabolism
Serine Endopeptidases
/ metabolism
Protein Binding
Animals
Organelles
/ metabolism
Viral Proteases
Aminophenols
Membrane Proteins
Indoles
DEAD-box RNA Helicases
Nucleoside-Triphosphatase
Butyrates
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 Jul 2024
19 Jul 2024
Historique:
received:
26
06
2023
accepted:
05
07
2024
medline:
20
7
2024
pubmed:
20
7
2024
entrez:
19
7
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39030239
doi: 10.1038/s41467-024-50437-3
pii: 10.1038/s41467-024-50437-3
doi:
Substances chimiques
Viral Nonstructural Proteins
0
Antiviral Agents
0
RNA Helicases
EC 3.6.4.13
Serine Endopeptidases
EC 3.4.21.-
NS4B protein, Dengue virus
0
NS4A protein, Dengue virus
0
NS2B protein, flavivirus
0
NS3 protein, flavivirus
0
NS3 protease, dengue virus
EC 3.4.21.-
nonstructural protein 2B, Dengue virus
0
(+)-4-(3-((1-(4-chlorophenyl)-2-oxo2-(6-(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid
0
Viral Proteases
EC 3.4.-
Aminophenols
0
Membrane Proteins
0
Indoles
0
DEAD-box RNA Helicases
EC 3.6.4.13
Nucleoside-Triphosphatase
EC 3.6.1.15
Butyrates
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6080Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB 1129 project number 240245660
Organisme : Wellcome Trust (Wellcome)
ID : 106327/Z/14
Organisme : Wellcome Trust (Wellcome)
ID : 089328/Z/09
Organisme : Agentschap Innoveren en Ondernemen (Flanders Innovation & Entrepreneurship)
ID : IWT 150863
Organisme : Agentschap Innoveren en Ondernemen (Flanders Innovation & Entrepreneurship)
ID : IWT 150863
Organisme : Wellcome Trust (Wellcome)
ID : 106327/Z/14
Organisme : Wellcome Trust (Wellcome)
ID : 089328/Z/09
Informations de copyright
© 2024. The Author(s).
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