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dc.contributor.authorMutter, Natalie L
dc.contributor.authorSoskine, Misha
dc.contributor.authorHuang, Gang
dc.contributor.authorAlbuquerque, Inês S
dc.contributor.authorBernardes, Gonçalo JL
dc.contributor.authorMaglia, Giovanni
dc.date.accessioned2018-12-05T00:30:38Z
dc.date.available2018-12-05T00:30:38Z
dc.date.issued2018-11-16
dc.identifier.issn1554-8929
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286307
dc.description.abstractImmunotoxins are proteins containing a cell-targeting element linked to a toxin that are under investigation for next-generation cancer treatment. However, these agents are difficult to synthesize, chemically heterogeneous, expensive, and show toxicity toward healthy cells. In this work, we describe the synthesis and characterization of a new type of immunotoxin that showed exquisite selectivity toward targeted cells. In our construct, targeting molecules were covalently attached or genetically fused to oligomeric pore-forming toxins. The activity of the immunotoxin was then caged by fusing a soluble protein to the transmembrane domain and activated via cleavage with furin, which is a protease that is overexpressed in many cancer cells. During the several coupling steps, directed evolution allowed the efficient synthesis of the molecules in E. coli cells, as well as selection for further specificity toward targeted cells. The final construct showed no off-target activity, while acquiring an additional degree of specificity toward the targeted cells upon activation. The pore-forming toxins described here do not require internalization to operate, while the many protomeric subunits can be individually modified to refine target specificity.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherAmerican Chemical Society (ACS)
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCell Line, Tumor
dc.subjectCell Membrane
dc.subjectAnimals
dc.subjectHumans
dc.subjectSea Anemones
dc.subjectEscherichia coli
dc.subjectSalmonella typhi
dc.subjectFolic Acid
dc.subjectFurin
dc.subjectTetrahydrofolate Dehydrogenase
dc.subjectRecombinant Fusion Proteins
dc.subjectCnidarian Venoms
dc.subjectImmunotoxins
dc.subjectDirected Molecular Evolution
dc.subjectMutagenesis
dc.subjectDrug Design
dc.subjectPore Forming Cytotoxic Proteins
dc.subjectProteolysis
dc.titleModular Pore-Forming Immunotoxins with Caged Cytotoxicity Tailored by Directed Evolution.
dc.typeArticle
prism.endingPage3160
prism.issueIdentifier11
prism.publicationDate2018
prism.publicationNameACS Chem Biol
prism.startingPage3153
prism.volume13
dc.identifier.doi10.17863/CAM.33617
dcterms.dateAccepted2018-10-02
rioxxterms.versionofrecord10.1021/acschembio.8b00720
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-11
dc.contributor.orcidMutter, Natalie L [0000-0002-9144-7443]
dc.contributor.orcidBernardes, Gonçalo JL [0000-0001-6594-8917]
dc.contributor.orcidMaglia, Giovanni [0000-0003-2784-0811]
dc.identifier.eissn1554-8937
rioxxterms.typeJournal Article/Review
pubs.funder-project-idThe Royal Society (uf110046)
pubs.funder-project-idEuropean Research Council (676832)
cam.issuedOnline2018-10-16


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International