A Mechanistic Paradigm for Broad-Spectrum Antivirals that Target Virus-Cell Fusion

Frederic Vigant, Jihye Lee, Axel Hollmann, Lukas B. Tanner, Zeynep Akyol Ataman, Tatyana Yun, Guanghou Shui, Hector C. Aguilar, Dong Zhang, David Meriwether, Gleyder Roman-Sosa, Lindsey R. Robinson, Terry L. Juelich, Hubert Buczkowski, Sunwen Chou, Miguel A R B Castanho, Mike C. Wolf, Jennifer K. Smith, Ashley Banyard, Margaret KielianSrinivasa Reddy, Markus R. Wenk, Matthias Selke, Nuno C. Santos, Alexander N. Freiberg, Michael E. Jung, Benhur Lee

Research output: Contribution to journalArticle

42 Citations (Scopus)

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 (IC501O2 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.

Original languageEnglish (US)
Article numbere1003297
JournalPLoS Pathogens
Volume9
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

Cell Fusion
Antiviral Agents
Viruses
Membranes
Phospholipids
Photosensitizing Agents
Rift Valley fever virus
Thiazolidines
Virus Internalization
Singlet Oxygen
Membrane Fluidity
Cytoprotection
Lipid Bilayers
Structure-Activity Relationship
Hydroxylation
Hydroxyl Radical
Hydrogen Peroxide
Biological Availability
Fatty Acids
Cell Membrane

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Vigant, F., Lee, J., Hollmann, A., Tanner, L. B., Akyol Ataman, Z., Yun, T., ... Lee, B. (2013). A Mechanistic Paradigm for Broad-Spectrum Antivirals that Target Virus-Cell Fusion. PLoS Pathogens, 9(4), [e1003297]. https://doi.org/10.1371/journal.ppat.1003297

A Mechanistic Paradigm for Broad-Spectrum Antivirals that Target Virus-Cell Fusion. / Vigant, Frederic; Lee, Jihye; Hollmann, Axel; Tanner, Lukas B.; Akyol Ataman, Zeynep; Yun, Tatyana; Shui, Guanghou; Aguilar, Hector C.; Zhang, Dong; Meriwether, David; Roman-Sosa, Gleyder; Robinson, Lindsey R.; Juelich, Terry L.; Buczkowski, Hubert; Chou, Sunwen; Castanho, Miguel A R B; Wolf, Mike C.; Smith, Jennifer K.; Banyard, Ashley; Kielian, Margaret; Reddy, Srinivasa; Wenk, Markus R.; Selke, Matthias; Santos, Nuno C.; Freiberg, Alexander N.; Jung, Michael E.; Lee, Benhur.

In: PLoS Pathogens, Vol. 9, No. 4, e1003297, 04.2013.

Research output: Contribution to journalArticle

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, MARB, Wolf, MC, Smith, JK, Banyard, A, Kielian, M, Reddy, S, Wenk, MR, Selke, M, Santos, NC, Freiberg, AN, Jung, ME & Lee, B 2013, 'A Mechanistic Paradigm for Broad-Spectrum Antivirals that Target Virus-Cell Fusion', PLoS Pathogens, vol. 9, no. 4, e1003297. https://doi.org/10.1371/journal.ppat.1003297
Vigant F, Lee J, Hollmann A, Tanner LB, Akyol Ataman Z, Yun T et al. A Mechanistic Paradigm for Broad-Spectrum Antivirals that Target Virus-Cell Fusion. PLoS Pathogens. 2013 Apr;9(4). e1003297. https://doi.org/10.1371/journal.ppat.1003297
Vigant, Frederic ; Lee, Jihye ; Hollmann, Axel ; Tanner, Lukas B. ; Akyol Ataman, Zeynep ; Yun, Tatyana ; Shui, Guanghou ; Aguilar, Hector C. ; Zhang, Dong ; Meriwether, David ; Roman-Sosa, Gleyder ; Robinson, Lindsey R. ; Juelich, Terry L. ; Buczkowski, Hubert ; Chou, Sunwen ; Castanho, Miguel A R B ; Wolf, Mike C. ; Smith, Jennifer K. ; Banyard, Ashley ; Kielian, Margaret ; Reddy, Srinivasa ; Wenk, Markus R. ; Selke, Matthias ; Santos, Nuno C. ; Freiberg, Alexander N. ; Jung, Michael E. ; Lee, Benhur. / A Mechanistic Paradigm for Broad-Spectrum Antivirals that Target Virus-Cell Fusion. In: PLoS Pathogens. 2013 ; Vol. 9, No. 4.
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AU - Lee, Jihye

AU - Hollmann, Axel

AU - Tanner, Lukas B.

AU - Akyol Ataman, Zeynep

AU - Yun, Tatyana

AU - Shui, Guanghou

AU - Aguilar, Hector C.

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AU - Meriwether, David

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AU - Smith, Jennifer K.

AU - Banyard, Ashley

AU - Kielian, Margaret

AU - Reddy, Srinivasa

AU - Wenk, Markus R.

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