dc.contributor.author | Amu, Sylvie | |
dc.contributor.author | Fallon, Padraic | |
dc.date.accessioned | 2020-03-19T22:36:23Z | |
dc.date.available | 2020-03-19T22:36:23Z | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020 | en |
dc.identifier.citation | Alí Alejo, Carolina Sánchez, Sylvie Amu, Padraic G. Fallon and Antonio Alcamí 2, 'Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor', 2020, Journal of Clinical Medicine;, 9;, 1; https://doi.org/10.3390/jcm9010025 | en |
dc.identifier.other | Y | |
dc.identifier.uri | http://hdl.handle.net/2262/91833 | |
dc.description | PUBLISHED | en |
dc.description.abstract | The inhibition of tumor necrosis factor (TNF) through the use of either antibodies or soluble receptors is a highly effective strategy for the clinical control of chronic inflammatory conditions such as rheumatoid arthritis. Different viruses have similarly exploited this concept by expressing a set of specifically tailored secreted TNF decoy receptors to block host inflammatory responses. Poxviruses have been shown to encode at least two distinct molecules, termed Cytokine response modifier D (CrmD) and CrmB, in which a TNF inhibitor is combined with a chemokine inhibitor on the same molecule. The ectromelia virus CrmD protein was found to be a critical determinant of virulence in vivo, being able to control local inflammation to allow further viral spread and the establishment of a lethal infection. Strikingly, both the TNF and the chemokine inhibitory domains are required for the full activity of CrmD, suggesting a model in which inhibition of TNF is supported by the concomitant blockade of a reduced set of chemokines. Inspired by this model, we reasoned that a similar strategy could be applied to modify the clinically used human TNF receptor (etanercept), producing a generation of novel, more effective therapeutic agents. Here we show the analysis of a set of fusion proteins derived from etanercept by addition of a viral chemokine-binding protein. A bifunctional inhibitor capable of binding to and blocking the activity of TNF as well as a set of chemokines is generated that is active in the prevention of arthritis in a murine disease model. | en |
dc.description.sponsorship | This work was funded by the Spanish Ministry of Science and Innovation (grants TRA2009-0038 and SAF2012-38957), and by the Spanish Ministry of Science, Innovation and Universities and European Union (European Regional Development’s Funds, FEDER) (grant RTI2018-097581-B-I00). P.G.F. was supported by Science Foundation Ireland. | en |
dc.format.extent | 1-25 | en |
dc.language.iso | en | en |
dc.relation.ispartofseries | Journal of Clinical Medicine; | |
dc.relation.ispartofseries | 9; | |
dc.relation.ispartofseries | 1; | |
dc.rights | Y | en |
dc.subject | tumor necrosis factor | en |
dc.subject | chemokine | en |
dc.subject | receptor | en |
dc.subject | inflammation | en |
dc.subject | immune evasion | en |
dc.subject | virus | en |
dc.title | Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor | en |
dc.type | Journal Article | en |
dc.type.supercollection | scholarly_publications | en |
dc.type.supercollection | refereed_publications | en |
dc.identifier.peoplefinderurl | http://people.tcd.ie/pfallon | |
dc.identifier.rssinternalid | 215008 | |
dc.identifier.doi | https://doi.org/10.3390/jcm9010025 | |
dc.rights.ecaccessrights | openAccess | |
dc.subject.TCDTheme | Cancer | en |
dc.subject.TCDTheme | Immunology, Inflammation & Infection | en |
dc.subject.TCDTag | CHEMOKINES | en |
dc.subject.TCDTag | Immune evasion | en |
dc.subject.TCDTag | Inflammation | en |
dc.subject.TCDTag | Receptors | en |
dc.subject.TCDTag | TUMOR NECROSIS FACTOR | en |
dc.subject.TCDTag | VIRUS | en |
dc.identifier.orcid_id | 0000-0002-8401-7293 | |
dc.status.accessible | N | en |
dc.contributor.sponsor | European Union (EU) | en |
dc.contributor.sponsorGrantNumber | RTI2018-097581-B-I00 | en |
dc.contributor.sponsor | Spanish Ministry of Science and Innovation | en |
dc.contributor.sponsorGrantNumber | TRA2009-0038 | en |
dc.contributor.sponsor | Spanish Ministry of Science and Innovation | en |
dc.contributor.sponsorGrantNumber | SAF2012-38957 | en |
dc.contributor.sponsor | Science Foundation Ireland | en |