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Cell Rep ; 36(5): 109479, 2021 08 03.
Article in English | MEDLINE | ID: covidwho-1328702


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.

Antiviral Agents/pharmacology , COVID-19/virology , Class III Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Lipid Metabolism/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Virus Replication/drug effects , Aminopyridines/pharmacology , Animals , Caco-2 Cells , Cell Line , Chlorocebus aethiops , Class III Phosphatidylinositol 3-Kinases/metabolism , Fatty Acid Synthases/drug effects , Fatty Acid Synthases/genetics , Gene Knockout Techniques , Humans , Lipoylation/drug effects , Pyrimidines/pharmacology , RNA, Viral/metabolism , Triglycerides/metabolism , Vero Cells
Cell Calcium ; 94: 102360, 2021 03.
Article in English | MEDLINE | ID: covidwho-1064903


Ion channels are necessary for correct lysosomal function including degradation of cargoes originating from endocytosis. Almost all enveloped viruses, including coronaviruses (CoVs), enter host cells via endocytosis, and do not escape endosomal compartments into the cytoplasm (via fusion with the endolysosomal membrane) unless the virus-encoded envelope proteins are cleaved by lysosomal proteases. With the ongoing outbreak of severe acute respiratory syndrome (SARS)-CoV-2, endolysosomal two-pore channels represent an exciting and emerging target for antiviral therapies. This review focuses on the latest knowledge of the effects of lysosomal ion channels on the cellular entry and uncoating of enveloped viruses, which may aid in development of novel therapies against emerging infectious diseases such as SARS-CoV-2.

Antiviral Agents/therapeutic use , COVID-19/virology , Ion Channels/physiology , Lysosomes/virology , SARS-CoV-2/physiology , Viral Envelope/physiology , Virus Internalization , Virus Uncoating , Aminopyridines/pharmacology , Aminopyridines/therapeutic use , Antiviral Agents/pharmacology , Drug Design , Endocytosis , Endosomes/metabolism , Endosomes/virology , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Hydrazones/pharmacology , Hydrazones/therapeutic use , Ion Channels/classification , Lysosomes/enzymology , Lysosomes/metabolism , Models, Biological , Morpholines/pharmacology , Morpholines/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Vacuolar Proton-Translocating ATPases/physiology , Virus Internalization/drug effects , Virus Uncoating/drug effects
Sci Rep ; 10(1): 13866, 2020 08 17.
Article in English | MEDLINE | ID: covidwho-720849


The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein - ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.

Betacoronavirus/drug effects , Computational Biology/methods , Coronavirus Infections/metabolism , Drug Discovery/methods , Drug Repositioning/methods , Pneumonia, Viral/metabolism , Aminopyridines/pharmacology , Angiotensin-Converting Enzyme 2 , Benzodioxoles/pharmacology , Betacoronavirus/chemistry , Binding Sites , COVID-19 , Coronavirus Infections/virology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Protein Binding/drug effects , Protein Conformation , Protein Domains/drug effects , Protein Interaction Maps/drug effects , SARS-CoV-2 , Simeprevir/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism