Abstract
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 (1O2) quenchers, qualifying LJ001 as a type II photosensitizer. Unsaturated phospholipids were the main target modified by LJ001-generated 1O2. Hydroxylated fatty acid species were detected in model and viral membranes treated with LJ001, but not its inactive molecular analog, LJ025. 1O2-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 1O2-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<10 nM), (2) red-shifted absorption spectra (for better tissue penetration), (3) increased quantum yield (efficiency of 1O2 generation), and (4) 10–100-fold improved bioavailability. Candidate compounds in our new series moderately but significantly (p≤0.01) delayed the time to death in a murine lethal challenge model of Rift Valley Fever Virus (RVFV). The viral membrane may be a viable target for broad-spectrum antivirals that target virus-cell fusion.
Highlights
Advances in antiviral therapeutics have allowed for effective management of specific viral infections, most notably human immunodeficiency virus (HIV) [1]
We generated a new class of membrane-targeted broad-spectrum antivirals with improved photochemical, photophysical, and pharmacokinetic properties leading to encouraging in vivo efficacy against a lethal emerging pathogen
This study provides a mechanistic paradigm for the development of membranetargeting broad-spectrum antivirals that target the biophysical process underlying virus-cell fusion and that exploit the difference between inert viral membranes and their biogenic cellular counterparts
Summary
Advances in antiviral therapeutics have allowed for effective management of specific viral infections, most notably human immunodeficiency virus (HIV) [1]. The one-bug-one-drug paradigm of drug discovery is insufficient to meet the looming threat of emerging and re-emerging viral pathogens that endangers global human and livestock health. This underscores the need for broad-spectrum antivirals that act on multiple viruses based on some commonality in their viral life cycle, rather than on specific viral proteins. A few broad-spectrum antivirals have been described that target enveloped virus entry [2,3,4,5,6] or RNA virus replication [7,8,9,10] The former targets the viral membrane, or more precisely, the biophysical constraints of the virus-cell membrane fusion process, while the latter targets nucleic acid metabolic pathways. We posited that the antiviral activity of LJ001 relies on exploiting the physiological difference between inert viral membranes and biogenic cellular membranes with reparative capabilities [4]
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