Myristic acid analogs are inhibitors of Junin virus replication.
The effects of two myristic acid analogs on Junin virus (JV) replication were investigated. The compounds chosen for the study were DL-2-hydroxymyristic acid (2OHM), an inhibitor of N-myristoyltransferase (NMT), which binds the enzyme and blocks protein myristoylation, and 13-oxamyristic acid (13OM), a competitive inhibitor of NMT which incorporates into the protein instead of myristic acid. Both types of analogs achieved dose-dependent inhibition of viral multiplication at concentrations not affecting cell viability. The 50% inhibitory concentration values determined by a virus-yield inhibition assay for different strains of JV, including a human pathogenic strain, and for the related arenavirus, Tacaribe, were in the range 1.6 to 20.1 microM, with 13OM as the most active compound. From time of addition and removal experiments, it can be concluded that both analogs inhibit a late stage in the JV replicative cycle, and their effect was partially reversible. The cytoplasmic and surface expression of JV glycoproteins was not affected in the presence of the compounds, as revealed by immunofluorescence staining, suggesting that JV glycoprotein myristoylation would not be essential for the intracellular transport of the envelope proteins, but it may have an important role in their interaction with the plasma membrane during virus budding.
Cordo
S M
SM
Laboratorio de Virología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Piso 4, 1428 Buenos Aires, Argentina.
Candurra
N A
NA
Damonte
E B
EB
D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000956:Antigens, Viral / Q000096:biosynthesis; D000998:Antiviral Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D018051:Junin virus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D007848:Laurates / Q000494:pharmacology; D009226:Myristates / Q000378:metabolism / Q000494:pharmacology*; D009227:Myristic Acids / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013997:Time Factors; D014709:Vero Cells; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects*
D000956:Antigens, Viral; D000998:Antiviral Agents; D007848:Laurates; D009226:Myristates; D009227:Myristic Acids; D014764:Viral Proteins; C017418:alpha-hydroxymyristic acid; C067939:12-methoxydodecanoate; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase