Publicação
Cell membrane composition drives selectivity and toxicity of designed cyclic helix−loop−helix peptides with cell penetrating and tumor suppressor properties
| dc.contributor.author | Philippe, Grégoire J.-B. | |
| dc.contributor.author | Gaspar, Diana | |
| dc.contributor.author | Sheng, Caibin | |
| dc.contributor.author | Huang, Yen-Hua | |
| dc.contributor.author | Benfield, Aurélie H. | |
| dc.contributor.author | Condon, Nicholas D. | |
| dc.contributor.author | Weidmann, Joachim | |
| dc.contributor.author | Lawrence, Nicole | |
| dc.contributor.author | Löwer, Alexander | |
| dc.contributor.author | Castanho, Miguel A. R. B. | |
| dc.contributor.author | Craik, David J. | |
| dc.contributor.author | Henriques, Sónia Troeira | |
| dc.date.accessioned | 2023-04-21T11:08:51Z | |
| dc.date.available | 2023-04-21T11:08:51Z | |
| dc.date.issued | 2019 | |
| dc.description | © 2019 American Chemical Society | pt_PT |
| dc.description.abstract | The tumor suppressor protein p53 is inactive in a large number of cancers, including some forms of sarcoma, breast cancer, and leukemia, due to overexpression of its intrinsic inhibitors MDM2 and MDMX. Reactivation of p53 tumor suppressor activity, via disruption of interactions between MDM2/X and p53 in the cytosol, is a promising strategy to treat cancer. Peptides able to bind MDM2 and/or MDMX were shown to prevent MDM2/X:p53 interactions, but most possess low cell penetrability, low stability, and/or high toxicity to healthy cells. Recently, the designed peptide cHLH-p53-R was reported to possess high affinity for MDM2, resistance toward proteases, cell-penetrating properties, and toxicity toward cancer cells. This peptide uses a stable cyclic helix−loop−helix (cHLH) scaffold, which includes two helices connected with a Gly loop and cyclized to improve stability. In the current study, we were interested in examining the cell selectivity of cHLH-p53-R, its cellular internalization, and ability to reactivate the p53 pathway. We designed analogues of cHLH-p53-R and employed biochemical and biophysical methodologies using in vitro model membranes and cell-based assays to compare their structure, activity, and mode-of-action. Our studies show that cHLH is an excellent scaffold to stabilize and constrain p53-mimetic peptides with helical conformation, and reveal that anticancer properties of cHLH-p53-R are mediated by its ability to selectively target, cross, and disrupt cancer cell membranes, and not by activation of the p53 pathway. These findings highlight the importance of examining the mode-of-action of designed peptides to fully exploit their potential to develop targeted therapies. | pt_PT |
| dc.description.sponsorship | The project was supported by a National Health Medical Research Council (NHMRC) project grant (APP1084965) by a Fundação para a Ciência e a Tecnologia (FCT I.P., Portugal) project grant (PTDC/BBB-BQB/1693/2014) and by a Marie Skłodowska-Curie Research and Innovation Staff Exchange grant (RISE; call: H2020-MSCA-RISE-2014, Grant agreement 644167). Live cell microscopy (Spinning disc confocal microscopy and SYTOX green experiment) was performed at the Australian Cancer Research Foundation (ACRF)/Institute for Molecular Bioscience Cancer Biology Imaging Facility, which was established with the support of the ACRF. S.T.H. is an Australian Research Council (ARC) Future Fellow (FT150100398), D.J.C. is an ARC Australian Laureate Fellow (FL150100146). G.J-B.P. has a UQ scholarship. The Translational Research Institute is supported by a grant from the Australian Government. | pt_PT |
| dc.description.version | info:eu-repo/semantics/publishedVersion | pt_PT |
| dc.identifier.citation | ACS Chem. Biol. 2019, 14, 9, 2071–2087 | pt_PT |
| dc.identifier.doi | 10.1021/acschembio.9b00593 | pt_PT |
| dc.identifier.eissn | 1554-8937 | |
| dc.identifier.issn | 1554-8929 | |
| dc.identifier.uri | http://hdl.handle.net/10451/57215 | |
| dc.language.iso | eng | pt_PT |
| dc.peerreviewed | yes | pt_PT |
| dc.publisher | American Chemical Society | pt_PT |
| dc.relation | 644167 | pt_PT |
| dc.relation | Cell-cell communication in metastatic breast cancer: a control point that can lead to breast cancer treatment | |
| dc.relation.publisherversion | https://pubs.acs.org/journal/acbcct | pt_PT |
| dc.title | Cell membrane composition drives selectivity and toxicity of designed cyclic helix−loop−helix peptides with cell penetrating and tumor suppressor properties | pt_PT |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.awardTitle | Cell-cell communication in metastatic breast cancer: a control point that can lead to breast cancer treatment | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBBB-BQB%2F1693%2F2014/PT | |
| oaire.citation.endPage | 2087 | pt_PT |
| oaire.citation.startPage | 2071 | pt_PT |
| oaire.citation.title | ACS Chemical Biology | pt_PT |
| oaire.citation.volume | 14 | pt_PT |
| oaire.fundingStream | 3599-PPCDT | |
| person.familyName | Gaspar | |
| person.familyName | Castanho | |
| person.givenName | Diana | |
| person.givenName | Miguel | |
| person.identifier | 103438 | |
| person.identifier.orcid | 0000-0002-9602-567X | |
| person.identifier.orcid | 0000-0001-7891-7562 | |
| person.identifier.rid | M-9562-2015 | |
| person.identifier.scopus-author-id | 55180303000 | |
| person.identifier.scopus-author-id | 56605575600 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| rcaap.rights | restrictedAccess | pt_PT |
| rcaap.type | article | pt_PT |
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