The Rigid Amphipathic Fusion Inhibitor dUY11 Acts through Photosensitization of Viruses

Vigant, Frédéric; Hollmann, Axel; Lee, Jihye; Santos, Nuno C.; Jung, Michael E.; Lee, Benhur

doi:10.1128/jvi.02907-13

Cited by 63 publications

(65 citation statements)

References 27 publications

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“…Influenza A virus encoding Gaussia luciferase (IFV Luc ) was provided by the lab of Dr. Peter Palese [33]. Vesicular stomatitis virus (VSV)-GFP, herpes simplex 1 (HSV1)-GFP, Newcastle disease virus (NDV)-GFP, Sendai virus (SeV)-GFP and the broad-spectrum antiviral JL122 were used as previously described [34,35,36]. Podofilox, nocodazole and colchicine were purchased from Sigma-Aldrich (St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

The Microtubule Inhibitor Podofilox Inhibits an Early Entry Step of Human Cytomegalovirus

Cohen

Schwarz

Vigant

et al. 2016

Viruses

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Human cytomegalovirus is a ubiquitous β-herpesvirus that infects many different cell types through an initial binding to cell surface receptors followed by a fusion event at the cell membrane or endocytic vesicle. A recent high-throughput screen to identify compounds that block a step prior to viral gene expression identified podofilox as a potent and nontoxic inhibitor. Time-of-addition studies in combination with quantitative-PCR analysis demonstrated that podofilox limits an early step of virus entry at the cell surface. Podofilox was also able to drastically reduce infection by herpes simplex 1, an α-herpesvirus with a very similar entry process to CMV. Podofilox caused a reduced maximal plateau inhibition of infection by viruses with single step binding processes prior to fusion-like Newcastle disease virus, Sendai virus, and influenza A virus or viruses that enter via endocytosis like vesicular stomatitis virus and a clinical-like strain of CMV. These results indicate that microtubules appear to be participating in the post-binding step of virus entry including the pre- and post-penetration events. Modulation of the plasma membrane is required to promote virus entry for herpesviruses, and that podofilox, unlike colchicine or nocodazole, is able to preferentially target microtubule networks at the plasma membrane.

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Section: Methodsmentioning

confidence: 99%

The Microtubule Inhibitor Podofilox Inhibits an Early Entry Step of Human Cytomegalovirus

Cohen

Schwarz

Vigant

et al. 2016

Viruses

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“…In this context, a binary mixture of phospholipid with a double bond at C9 in the oleoyl chain (POPC) and a completely saturated phospholipid (DPPC) (Figure 1b) is a simple model to evaluate the effect of the 1 O 2 produced by JL103 on membrane nanoarchitecture. As we previously demonstrated, photosensitization of viral membranes requires the presence of unsaturated acyl chains 2, 4, 5, 12 (as the case of POPC). In contrast with DPPC a saturated lipid, where there are no carbon-carbon double bonds available for 1 O 2 attack.…”

Section: Resultsmentioning

confidence: 83%

“…The presence of these oxidized phospholipids results in several membrane properties changes, which negatively impact on its ability to undergo the extreme membrane curvature transitions necessary for virus-cell fusion. These compounds only affect the viral membrane, showing no significant cytotoxicity and not affecting cell–cell fusion 1, 2, 4 . This is related to the differences between the biogenic properties of cell plasma membranes and those of static viral membranes.…”

Section: Introductionmentioning

confidence: 99%

“…These compounds act deleteriously on the virus envelope, but not at the cell membrane level. Later, we showed that LJ001 1, 3 and its oxazolidine counterpart (JL103) 2, 4 , all belonging to this new class, act as membrane-targeted photosensitizers. They generate singlet oxygen ( 1 O 2 ) in the membrane, changing its biophysical properties and leading to the inhibition of the viral-cell membrane fusion necessary for target cell infection 4, 5 .…”

Section: Introductionmentioning

confidence: 99%

“…Later, we showed that LJ001 1, 3 and its oxazolidine counterpart (JL103) 2, 4 , all belonging to this new class, act as membrane-targeted photosensitizers. They generate singlet oxygen ( 1 O 2 ) in the membrane, changing its biophysical properties and leading to the inhibition of the viral-cell membrane fusion necessary for target cell infection 4, 5 . 1 O 2 -mediated lipid oxidation targets the C=C double bonds of unsaturated phospholipid acyl chains, introducing polar hydroperoxide groups in the hydrophobic region of the lipid bilayer 6 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of singlet oxygen generated by a broad-spectrum viral fusion inhibitor on membrane nanoarchitecture

Hollmann

Gonçalves

Augusto

et al. 2015

Nanomedicine: Nanotechnology, Biology and Medicine

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Targeting membranes of enveloped viruses represents an exciting new paradigm to explore on the development of broad-spectrum antivirals. Recently, broad-spectrum small-molecule antiviral drug were described, preventing enveloped virus entry at an intermediate step, after virus binding but before virus–cell fusion. Those compounds, including an oxazolidine-2,4-dithione named JL103 that presented the most promissing results, act deleteriously on the virus envelope but not at the cell membrane level. In this work, by using atomic force microscopy (AFM), we aimed at unraveling the effects that JL103 is able to induce in the lipid membrane architecture at the nanoscale. Our results indicate that singlet oxygen produced by JL103 decreases membrane thickness, with and expansion of the area per phospholipid, by attacking the double bonds of unsaturated phospholipids. This membrane reorganization prevents the fusion between enveloped virus and target cell membranes, resulting in viral entry inhibition.

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Translation of Mycobacterium Survival Strategy to Develop a Lipo‐peptide based Fusion Inhibitor**

et al. 2021

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The entry of enveloped virus requires the fusion of viral and host cell membranes. An effective fusion inhibitor aiming at impeding such membrane fusion may emerge as a broad‐spectrum antiviral agent against a wide range of viral infections. Mycobacterium survives inside the phagosome by inhibiting phagosome–lysosome fusion with the help of a coat protein coronin 1. Structural analysis of coronin 1 and other WD40‐repeat protein suggest that the trp‐asp (WD) sequence is placed at distorted β‐meander motif (more exposed) in coronin 1. The unique structural feature of coronin 1 was explored to identify a simple lipo‐peptide sequence (myr‐WD), which effectively inhibits membrane fusion by modulating the interfacial order, water penetration, and surface potential. The mycobacterium inspired lipo‐dipeptide was successfully tested to combat type 1 influenza virus (H1N1) and murine coronavirus infections as a potential broad‐spectrum antiviral agent.

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The Rigid Amphipathic Fusion Inhibitor dUY11 Acts through Photosensitization of Viruses

Cited by 63 publications

References 27 publications

The Microtubule Inhibitor Podofilox Inhibits an Early Entry Step of Human Cytomegalovirus

The Microtubule Inhibitor Podofilox Inhibits an Early Entry Step of Human Cytomegalovirus

Effects of singlet oxygen generated by a broad-spectrum viral fusion inhibitor on membrane nanoarchitecture

Translation of Mycobacterium Survival Strategy to Develop a Lipo‐peptide based Fusion Inhibitor**

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