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    Conjugation of folate via gelonin carbohydrate residues retains ribosomal-inactivating properties of the toxin and permits targeting to folate receptor positive cells.

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    Authors
    Atkinson, Sarah F
    Bettinger, Thierry
    Seymour, Leonard W
    Behr, Jean-Paul
    Ward, Christopher M
    Affiliation
    CRC Institute for Cancer Studies, University of Birmingham, Birmingham, B15 2TA United Kingdom.
    Issue Date
    2001-07-27
    
    Metadata
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    Abstract
    Conjugation of folate to proteins permits receptor-mediated endocytosis via the folate receptor (FR) and delivery of the conjugate into the cytoplasm of cells. Since many cancers up-regulate the FR it has enabled the targeting of toxins to tumor cells resulting in specific cell death. However, current conjugation methods rely on chemistries that can affect certain catalytic subunits, such as the A-chain of the plant toxin gelonin. As a result many folate-targeted toxins are a compromise between receptor/ligand interaction and toxin activity. We describe the first example of folate conjugated to a protein via carbohydrate residues, using a novel SH-folate intermediate. The folate-gelonin conjugate retains over 99% of toxin activity in a cell-free translational assay compared with unmodified gelonin and is able to bind the FR at the same affinity as free folic acid (10(-10) m). Additionally, the conjugate exhibits prolonged inhibition of protein synthesis in FR positive cell lines in vitro. Folate linked to gelonin via amino conjugation exhibits the same affinity for FR as free folic acid but the toxin is 225-fold less active in a cell-free translational assay. The effect of different conjugation methods on toxin activity and the implications for folate targeting of other glycoproteins are discussed.
    Citation
    Conjugation of folate via gelonin carbohydrate residues retains ribosomal-inactivating properties of the toxin and permits targeting to folate receptor positive cells. 2001, 276 (30):27930-5 J. Biol. Chem.
    Journal
    The Journal of Biological Chemistry
    URI
    http://hdl.handle.net/10541/85566
    DOI
    10.1074/jbc.M102825200
    PubMed ID
    11359781
    Type
    Article
    Language
    en
    ISSN
    0021-9258
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.M102825200
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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