SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target.
Antiviral Agents
/ pharmacology
Benzoates
/ chemistry
Biosynthetic Pathways
/ drug effects
Influenza A virus
/ drug effects
Lipid Metabolism
/ drug effects
Lipids
/ biosynthesis
Middle East Respiratory Syndrome Coronavirus
/ drug effects
Protein Binding
Retinoids
/ chemistry
Sterol Regulatory Element Binding Proteins
/ metabolism
Tetrahydronaphthalenes
/ chemistry
Virus Diseases
/ prevention & control
Virus Replication
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 01 2019
10 01 2019
Historique:
received:
25
06
2018
accepted:
07
12
2018
entrez:
12
1
2019
pubmed:
12
1
2019
medline:
21
3
2019
Statut:
epublish
Résumé
Viruses are obligate intracellular microbes that exploit the host metabolic machineries to meet their biosynthetic demands, making these host pathways potential therapeutic targets. Here, by exploring a lipid library, we show that AM580, a retinoid derivative and RAR-α agonist, is highly potent in interrupting the life cycle of diverse viruses including Middle East respiratory syndrome coronavirus and influenza A virus. Using click chemistry, the overexpressed sterol regulatory element binding protein (SREBP) is shown to interact with AM580, which accounts for its broad-spectrum antiviral activity. Mechanistic studies pinpoint multiple SREBP proteolytic processes and SREBP-regulated lipid biosynthesis pathways, including the downstream viral protein palmitoylation and double-membrane vesicles formation, that are indispensable for virus replication. Collectively, our study identifies a basic lipogenic transactivation event with broad relevance to human viral infections and represents SREBP as a potential target for the development of broad-spectrum antiviral strategies.
Identifiants
pubmed: 30631056
doi: 10.1038/s41467-018-08015-x
pii: 10.1038/s41467-018-08015-x
pmc: PMC6328544
doi:
Substances chimiques
Antiviral Agents
0
Benzoates
0
Lipids
0
Retinoids
0
Sterol Regulatory Element Binding Proteins
0
Tetrahydronaphthalenes
0
Am 580
102121-60-8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
120Subventions
Organisme : NIAID NIH HHS
ID : P01 AI060699
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI129269
Pays : United States
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