Publication
Enveloped viruses : a peptide inhibition strategy
| datacite.subject.fos | Ciências Naturais::Ciências Biológicas | pt_PT |
| dc.contributor.advisor | Santos, Nuno Fernando Duarte Cordeiro Correia dos | |
| dc.contributor.advisor | Hollmann, Axel | |
| dc.contributor.author | Augusto, Marcelo T. | |
| dc.date.accessioned | 2019-05-22T11:14:41Z | |
| dc.date.available | 2019-05-22T11:14:41Z | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2019 | |
| dc.description.abstract | The infection by enveloped viruses causes several diseases worldwide, which in some cases can develop to a chronic stage or lead to death. Overall, the lack of a cure or the emergence of strains resistant to commercial drugs is the driving force for the research and development of new alternative drugs. Peptides can be used to inhibit the fusion between enveloped viruses and host cells. The involvement of both membranes in the fusion process, aiming to deliver to the cell the viral genetic material, highlights the important role of the membrane. Based on these findings, several membrane fusion inhibitor peptides were developed to fight HIV-1, influenza and a few paramyxoviruses, such parainfluenza and Nipah virus, were conjugated to lipid anchors. The resulting lipid anchored-peptides were found to interact much more with biomembrane model systems (liposomes) and human blood cells (erythrocytes and peripheral blood mononuclear cells) in comparison to the unconjugated peptides. Furthermore, we found a correlation between membrane binding and antiviral activity. Polyethylenoglycol (PEG) is known for increasing the water solubility of molecules. Here, in order to improve the activity of the peptides, PEG was used as a linker between the peptide and the lipid anchor, and its effect on peptide-membrane interaction was also tested. We found that the length of the PEG influences the antiviral peptide potency, despite increasing peptide sensibility to proteases, which can be avoided with N-terminal lipid conjugation. Influenza fusion occurs inside the endosomes after pH acidification. We developed peptides aiming to be internalized in endosomes together with the virus. Despite the use of lipid anchors to promote membrane attachment, we added a cell penetrating peptide (CPP) sequence to increase membrane crossing. We found that the CPP by itself was not enough to promote membrane permeation. However, the combination of lipid tagging and a CPP was enough to promote peptide membrane anchoring and intracellular localization, especially when tocopherol was used as anchor. All the results obtained in the present Thesis support membranothropic behavior as a key factor in the final activity of the peptides against enveloped viruses. Furthermore, this Thesis provides important guidelines in terms of peptide design, based on the finding of a balance between peptide sequences, lipid anchor, linker length and peptide orientation. | pt_PT |
| dc.identifier.tid | 101454007 | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10451/38353 | |
| dc.language.iso | eng | pt_PT |
| dc.relation | BROAD-SPECTRUM FUSION INHIBITORS AGAINST ENVELOPED VIRUSES | |
| dc.subject | Inhibitor peptides | pt_PT |
| dc.subject | Lipid membrane | pt_PT |
| dc.subject | Membrane fusion inhibition | pt_PT |
| dc.subject | Enveloped viruses | pt_PT |
| dc.subject | Lipid anchors | pt_PT |
| dc.subject | Teses de doutoramento - 2018 | pt_PT |
| dc.title | Enveloped viruses : a peptide inhibition strategy | pt_PT |
| dc.type | doctoral thesis | |
| dspace.entity.type | Publication | |
| oaire.awardTitle | BROAD-SPECTRUM FUSION INHIBITORS AGAINST ENVELOPED VIRUSES | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F95624%2F2013/PT | |
| oaire.fundingStream | OE | |
| person.familyName | Augusto | |
| person.givenName | Marcelo | |
| person.identifier.orcid | 0000-0002-6536-3924 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| rcaap.rights | closedAccess | pt_PT |
| rcaap.type | doctoralThesis | pt_PT |
| relation.isAuthorOfPublication | 88403021-43c4-4a1f-bd75-0f488074f6b8 | |
| relation.isAuthorOfPublication.latestForDiscovery | 88403021-43c4-4a1f-bd75-0f488074f6b8 | |
| relation.isProjectOfPublication | c2f9d622-939c-43d2-9002-f5680cd56f6f | |
| relation.isProjectOfPublication.latestForDiscovery | c2f9d622-939c-43d2-9002-f5680cd56f6f | |
| thesis.degree.name | Tese doutoramento em Ciências Biomédicas (Bioquímica Médica) Universidade de Lisboa, Faculdade de Medicina, 2018 | pt_PT |