A mechanistic paradigm for broad-spectrum antivirals that target virus-cell fusion.

VIGANT F ; LEE J; HOLLMANN A; TANNER LB; AKYOL ATAMAN Z; YUN T; SHUI G; AGUILAR HC; ZHANG D; MERIWETHER D; ROMAN-SOSA G; ROBINSON LR; JUELICH TL; BUCZKOWSKI H; CHOU S; CASTANHO MA; WOLF MC; SMITH JK; BANYARD A; KIELIAN M; REDDY S; WENK MR; SELKE M; SANTOS NC; FREIBERG AN; JUNG ME; LEE B

PLOS PATHOGENS

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2013 p. 1 - 14

1553-7366

LJ001 is a lipophilic thiazolidine derivative that inhibits the entry of numerous enveloped viruses at non-cytotoxic concentrations (IC50 ≤ 0.5 µM), and was posited to exploit the physiological difference between static viral membranes and biogenic cellular membranes. We now report on the molecular mechanism that results in LJ001´s specific inhibition of virus-cell fusion. The antiviral activity of LJ001 was light-dependent, required the presence of molecular oxygen, and was reversed by singlet oxygen ((1)O2) quenchers, qualifying LJ001 as a type II photosensitizer. Unsaturated phospholipids were the main target modified by LJ001-generated (1)O2. Hydroxylated fatty acid species were detected in model and viral membranes treated with LJ001, but not its inactive molecular analog, LJ025. (1)O2-mediated allylic hydroxylation of unsaturated phospholipids leads to a trans-isomerization of the double bond and concurrent formation of a hydroxyl group in the middle of the hydrophobic lipid bilayer. LJ001-induced (1)O2-mediated lipid oxidation negatively impacts on the biophysical properties of viral membranes (membrane curvature and fluidity) critical for productive virus-cell membrane fusion. LJ001 did not mediate any apparent damage on biogenic cellular membranes, likely due to multiple endogenous cytoprotection mechanisms against phospholipid hydroperoxides. Based on our understanding of LJ001´s mechanism of action, we designed a new class of membrane-intercalating photosensitizers to overcome LJ001´s limitations for use as an in vivo antiviral agent. Structure activity relationship (SAR) studies led to a novel class of compounds (oxazolidine-2,4-dithiones) with (1) 100-fold improved in vitro potency (IC50