Fatty Acid Analogs as Inhibitor of Arenavirus Replication

DAMONTE ELSA, CORDO SANDRA , CANDURRA NÉLIDA

San Diego, EE. UU

Congreso; 11th International Conference on Antiviral Research; 1998

Intenational Society for Antiviral Research (ISAR)

Two major types of fatty acylation of viral proteins, the incorporation of palmitic acid (C16:0) or myristic acid (C14:0), has been shown to be essential for diverse processes during infection with retroviruses and other clinically important viruses. Consequently, protein palmitoylation and myristoylation became a novel and promising target for antiviral agents. In the present study, fatty acid analogs have been evaluated in vitro as potential inhibitors of Junin virus (JV), agent of Argentine hemorrhagic fever, and the antigenically related arenavirus Tacaribe (TV). The tested compounds were 2-hydroxytetradecanoic acid (2-hydroxymyristic acid 2HM), 12-methoxydodecanoic acid (13-oxamyristic acid 13OM) and 2-hydroxyhexadecanoic acid (2-hydroxypalmitic acid 2HP). The three analogs inhibited the multiplication of JV, strains Iv4454 and XJ, and TV in a dose dependent manner, as determined by a virus yield inhibition assay in Vero cells. The IC50 values ranged from 8 to 40 mM, with 2HM and 13OM as the most active inhibitors. Both extracellular and intracellular virus yields were similarly reduced. Neither compound was toxic to Vero cells in an MTT-based assay at concentrations up to 100 mM. A limited pulse og only 4 h with 2HM or 2HP after several cycles of infection was enough to inhibit virus production, probably due to their effect on a late event in JV infective cycle. By immunofluorescence staining and by radiolabeling with 35S methionine followed of immunoprecipitation it was shown that the fatty acid analogs did not inhibit viral protein synthesis but markedly blocked the presence of the envelope glycoprotein GP38 at the cell surface, preventing the production of infectious virions.