title: Direct Inhibition of Cellular Fatty Acid Synthase Impairs Replication of Respiratory Syncytial Virus and Other Respiratory Viruses.
abstract: Fatty acid synthase (FASN) catalyzes the de novo synthesis of palmitate, a fatty acid utilized for synthesis of more complex fatty acids, plasma membrane structure, and post-translational palmitoylation of host and viral proteins. We have developed a potent inhibitor of FASN (TVB-3166) that reduces the production of respiratory syncytial virus (RSV) progeny in vitro from infected human lung epithelial cells (A549) and in vivo from mice challenged intranasally with RSV. Addition of TVB-3166 to the culture medium of RSV-infected A549 cells reduces viral spread without inducing cytopathic effects. The antiviral effect of the FASN inhibitor is a direct consequence of reducing de novo palmitate synthesis; similar doses are required for both antiviral activity and inhibition of palmitate production, and the addition of exogenous palmitate to TVB-3166-treated cells restores RSV production. TVB-3166 has minimal effect on RSV entry but significantly reduces viral RNA replication, protein levels, viral particle formation and infectivity of released viral particles. TVB-3166 substantially impacts viral replication, reducing production of infectious progeny 250-fold. In vivo, oral administration of TVB-3166 to RSV-A (Long)-infected BALB/c mice on normal chow, starting either on the day of infection or one day post-infection, reduces RSV lung titers 21-fold and 9-fold respectively. Further, TVB-3166 also inhibits the production of RSV B, human parainfluenza 3 (PIV3), and human rhinovirus 16 (HRV16) progeny from A549, HEp2 and HeLa cells respectively. Thus, inhibition of FASN and palmitate synthesis by TVB-3166 significantly reduces RSV progeny both in vitro and in vivo and has broad-spectrum activity against other respiratory viruses. FASN inhibition may alter the composition of regions of the host cell membrane where RSV assembly or replication occurs, or change the membrane composition of RSV progeny particles, decreasing their infectivity.
authors.affiliation: 3-V Biosciences, Menlo Park, California, United States of America.
authors.forename: Yamini M
authors.initials: YM
authors.lastname: Ohol
authors.affiliation: 3-V Biosciences, Menlo Park, California, United States of America.
authors.forename: Zhaoti
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 3-V Biosciences, Menlo Park, California, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Kemble
authors.affiliation: 3-V Biosciences, Menlo Park, California, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Duke
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006367:HeLa Cells; D056945:Hep G2 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D054878:Lipoylation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D019308:Palmitic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D010224:Parainfluenza Virus 3, Human / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D012229:Rhinovirus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D019308:Palmitic Acid; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I