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CC BY V4.0, Open Access
Journal article
A mechanistic paradigm for broad-spectrum antivirals that target virus-cell fusion
PLoS pathogens, Vol.9(4), pp.e1003297-e1003297
2013
Handle:
https://hdl.handle.net/2376/116363
PMCID: PMC3630091
PMID: 23637597
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 ((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<10 nM), (2) red-shifted absorption spectra (for better tissue penetration), (3) increased quantum yield (efficiency of (1)O2 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.
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Details
- Title
- A mechanistic paradigm for broad-spectrum antivirals that target virus-cell fusion
- Creators
- Frederic Vigant - Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of AmericaHector C AguilarJihye LeeAxel HollmannLukas B TannerZeynep Akyol AtamanTatyana YunGuanghou ShuiDong ZhangDavid MeriwetherGleyder Roman-SosaLindsey R RobinsonTerry L JuelichHubert BuczkowskiSunwen ChouMiguel A R B CastanhoMike C WolfJennifer K SmithAshley BanyardMargaret KielianSrinivasa ReddyMarkus R WenkMatthias SelkeNuno C SantosAlexander N FreibergMichael E JungBenhur Lee
- Publication Details
- PLoS pathogens, Vol.9(4), pp.e1003297-e1003297
- Academic Unit
- Paul G. Allen School for Global Animal Health
- Publisher
- Public Library Science; United States
- Number of pages
- 14
- Grant note
- U01 AI082100 / NIAID NIH HHS SC1 GM084776 / NIGMS NIH HHS AI075647 / NIAID NIH HHS U01 AI070495 / NIAID NIH HHS R01 AI069317 / NIAID NIH HHS NIH-NIGMS5SC1GM084776 / NCI NIH HHS R01 AI075647 / NIAID NIH HHS U54 AI065359 / NIAID NIH HHS
- Identifiers
- 99900547777201842
- Language
- English
- Resource Type
- Journal article