CONICET | Buscador de Institutos y Recursos Humanos

Targeting membranes of enveloped viruses represents an exciting new paradigm to explore regarding the development of broad-spectrum antivirals. It was recently reported that a new aryl methyldiene rhodanine derivative, named LJ001, and oxazolidine-2,4-dithione [1], named LJ1003 [2], act on the viral membrane, avoiding its fusion with the target cell membrane. The aim of the present work was to study the interactions of both active compounds (LJ001 and JL103) and LJ025 (an inactive analog used as negative control)with biological membrane models, in order to clarify the mechanism of action of these new enveloped virus entry inhibitors. Fluorescence spectroscopy was used to quantify the partition and determine the location of the molecules on membranes, concluding that the three molecules are able to interact with lipid membranes. However, JL103 has a much more interfacial location. The ability of the compounds to produce reactive oxygen molecules in the membrane was tested by using DMA, which reacts selectively with singlet oxygen to form the non-fluorescent 9,10-endoperoxide. The changes that these molecules are able to promote on the lipid packing and fluidity of lipid membranes were assessed by surface pressure, DPH and TMA-DPH fluorescence anisotropy and Laurdan generalized polarization measurements. Finally the ability to impair membrane fusion was evaluated by Förster resonance energy transfer (FRET). Our results indicate that the production of singlet oxygen by LJ001 and JL103 are able to induce several changes on membrane properties, specially related with a decrease on its fluidity, concomitant with an increase on the order on the polar head groups region, promoting a synergistic effect between membrane curvature (or its inability to change) and fluidity, resulting in a inhibition of the formation of the fusion pore necessary for cell infection.

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