Inhibitors of VPS34 and fatty-acid metabolism suppress SARS-CoV-2 replication

Coronaviruses rely on host membranes for entry, establishment of replication centers, and egress. Compounds targeting cellular membrane biology and lipid biosynthetic pathways have previously shown promise as antivirals and are actively being pursued as treatments for other conditions. Here, we test...

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Veröffentlicht in:Cell reports (Cambridge) Jg. 36; H. 5; S. 109479
Hauptverfasser: Williams, Caroline G., Jureka, Alexander S., Silvas, Jesus A., Nicolini, Anthony M., Chvatal, Stacie A., Carlson-Stevermer, Jared, Oki, Jennifer, Holden, Kevin, Basler, Christopher F.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 03.08.2021
The Authors
Schlagworte:
Aminopyridines - pharmacology
Animals
antiviral
Antiviral Agents - pharmacology
autophagy
Caco-2 Cells
Cell Line
Chlorocebus aethiops
Class III Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Class III Phosphatidylinositol 3-Kinases - metabolism
coronavirus
COVID-19
COVID-19 - virology
fatty acid
Fatty Acid Synthases - drug effects
Fatty Acid Synthases - genetics
Gene Knockout Techniques
Humans
Lipid Metabolism - drug effects
Lipoylation - drug effects
membranes
phosphoinositol 3 kinase
Pyrimidines - pharmacology
RNA, Viral - metabolism
SARS coronavirus 2
SARS-CoV-2 - drug effects
SARS-CoV-2 - physiology
Triglycerides - metabolism
Vero Cells
Virus Replication - drug effects
COVID-19
membranes
autophagy
phosphoinositol 3 kinase
antiviral
fatty acid
coronavirus
SARS coronavirus 2
ISSN:2211-1247, 2211-1247
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Zusammenfassung:Coronaviruses rely on host membranes for entry, establishment of replication centers, and egress. Compounds targeting cellular membrane biology and lipid biosynthetic pathways have previously shown promise as antivirals and are actively being pursued as treatments for other conditions. Here, we test small molecule inhibitors that target the PI3 kinase VPS34 or fatty acid metabolism for anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity. Our studies determine that compounds targeting VPS34 are potent SARS-CoV-2 inhibitors. Mechanistic studies with compounds targeting multiple steps up- and downstream of fatty acid synthase (FASN) identify the importance of triacylglycerol production and protein palmitoylation as requirements for efficient viral RNA synthesis and infectious virus production. Further, FASN knockout results in significantly impaired SARS-CoV-2 replication that can be rescued with fatty acid supplementation. Together, these studies clarify roles for VPS34 and fatty acid metabolism in SARS-CoV-2 replication and identify promising avenues for the development of countermeasures against SARS-CoV-2. [Display omitted] •VPS34 and fatty acid metabolism inhibitors impair SARS-CoV-2 growth•Post-entry steps in the SARS-CoV-2 replication cycle are impaired•The inhibitors alter SARS-CoV2 replication center morphology•Knockout of fatty acid synthase also impairs SARS-CoV-2 growth Williams et al. employ pharmacological inhibitor and genetic knockout approaches to demonstrate critical roles for the class III phosphatidylinositol 3-kinase VPS34 and fatty acid metabolism in SARS-CoV-2 growth. The data further implicate triacylglycerol production and protein palmitoylation as critical functions related to fatty acid metabolism that are needed by SARS-CoV-2.
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Present address: Texas Biomedical Research Institute, San Antonio, TX 78227, USA
These authors contributed equally
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2021.109479