Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication.
West Nile virus (WNV) is a neurotropic flavivirus transmitted by the bite of mosquitoes that causes meningitis and encephalitis in humans, horses, and birds. Several studies have highlighted that flavivirus infection is highly dependent on cellular lipids for virus replication and infectious particle biogenesis. The first steps of lipid synthesis involve the carboxylation of acetyl coenzyme A (acetyl-CoA) to malonyl-CoA that is catalyzed by the acetyl-CoA carboxylase (ACC). This makes ACC a key enzyme of lipid synthesis that is currently being evaluated as a therapeutic target for different disorders, including cancers, obesity, diabetes, and viral infections. We have analyzed the effect of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) on infection by WNV. Lipidomic analysis of TOFA-treated cells confirmed that this drug reduced the cellular content of multiple lipids, including those directly implicated in the flavivirus life cycle (glycerophospholipids, sphingolipids, and cholesterol). Treatment with TOFA significantly inhibited the multiplication of WNV in a dose-dependent manner. Further analysis of the antiviral effect of this drug showed that the inhibitory effect was related to a reduction of viral replication. Furthermore, treatment with another ACC inhibitor, 3,3,14,14-tetramethylhexadecanedioic acid (MEDICA 16), also inhibited WNV infection. Interestingly, TOFA and MEDICA 16 also reduced the multiplication of Usutu virus (USUV), a WNV-related flavivirus. These results point to the ACC as a druggable cellular target suitable for antiviral development against WNV and other flaviviruses.
Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Madrid, Spain.
Teresa
T
Merino-Ramos
Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Madrid, Spain.
Ángela
Á
Vázquez-Calvo
Department of Biomedicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.
Josefina
J
Casas
Department of Virology and Microbiology, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.
Francisco
F
Sobrino
Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Madrid, Spain.
Juan-Carlos
JC
Saiz
Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Madrid, Spain Department of Virology and Microbiology, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain martin.mangel@inia.es.
Miguel A
http://orcid.org/0000-0001-6015-3613
MA
Martín-Acebes
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D015870:Gene Expression; D020404:Glycerophospholipids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D010169:Palmitic Acids / Q000494:pharmacology*; D013107:Sphingolipids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects; D014902:West Nile virus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D005663:Furans; D020404:Glycerophospholipids; D000960:Hypolipidemic Agents; D010169:Palmitic Acids; D013107:Sphingolipids; C014289:5-(tetradecyloxy)-2-furancarboxylic acid; C056166:MEDICA 16; D002784:Cholesterol; D000103:Acetyl-CoA Carboxylase