Publicação
A mechanistic paradigm for broad-spectrum antivirals that target virus-cell fusion
| dc.contributor.author | Vigant, Frederic | |
| dc.contributor.author | Lee, Jihye | |
| dc.contributor.author | Hollmann, Axel | |
| dc.contributor.author | Tanner, Lukas B. | |
| dc.contributor.author | Ataman, Zeynep Akyol | |
| dc.contributor.author | Yun, Tatyana | |
| dc.contributor.author | Shui, Guanghou | |
| dc.contributor.author | Aguilar, Hector C. | |
| dc.contributor.author | Zhang, Dong | |
| dc.contributor.author | Meriwether, David | |
| dc.contributor.author | Roman-Sosa, Gleyder | |
| dc.contributor.author | Robinson, Lindsey R. | |
| dc.contributor.author | Juelich, Terry L. | |
| dc.contributor.author | Buczkowski, Hubert | |
| dc.contributor.author | Chou, Sunwen | |
| dc.contributor.author | Castanho, Miguel A. R. B. | |
| dc.contributor.author | Wolf, Mike C. | |
| dc.contributor.author | Smith, Jennifer K. | |
| dc.contributor.author | Banyard, Ashley | |
| dc.contributor.author | Kielian, Margaret | |
| dc.contributor.author | Reddy, Srinivasa | |
| dc.contributor.author | Wenk, Markus R. | |
| dc.contributor.author | Selke, Matthias | |
| dc.contributor.author | Santos, Nuno C. | |
| dc.contributor.author | Freiberg, Alexander N. | |
| dc.contributor.author | Jung, Michael E. | |
| dc.contributor.author | Lee, Benhur | |
| dc.date.accessioned | 2014-03-10T12:35:32Z | |
| dc.date.available | 2014-03-10T12:35:32Z | |
| dc.date.issued | 2013 | |
| dc.description | © 2013 Vigant et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | eng |
| dc.description.abstract | LJ001 is a lipophilic thiazolidine derivative that inhibits the entry of numerous enveloped viruses at non-cytotoxic concentrations (IC50≤0.5 mM), 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 viruscell 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. | eng |
| dc.description.sponsorship | This work was supported by NIH grants U01 AI070495, U01 AI082100, R01 AI069317, U54 AI065359 (PSWRCE) (to BL), AI075647 (to MK), NIH-NIGMS 5SC1GM084776 (to DZ and MS), and by Fundação para a Ciência e a Tecnologia – Ministério da Educação e Ciêcia (Portugal) project PTDC/SAU-BEB/099142/2008 (to NCS) and fellowship SFRH/BPD/72037/2010 (to AH) and Veterans Affairs research funds (SC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | eng |
| dc.identifier.citation | PLOS Pathogens April 2013, Volume 9, Issue 4, e1003297 | eng |
| dc.identifier.issn | 1553-7366 | |
| dc.identifier.uri | http://dx.doi.org/10.1371/journal.ppat.1003297 | |
| dc.identifier.uri | http://hdl.handle.net/10451/10708 | |
| dc.language.iso | eng | por |
| dc.peerreviewed | yes | por |
| dc.publisher | PLOS | por |
| dc.title | A mechanistic paradigm for broad-spectrum antivirals that target virus-cell fusion | eng |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.citation.title | PLOS Pathogens | eng |
| rcaap.rights | openAccess | por |
| rcaap.type | article | por |