• Login
    View Item 
    •   UMB Digital Archive
    • UMB Open Access Articles
    • UMB Open Access Articles 2019
    • View Item
    •   UMB Digital Archive
    • UMB Open Access Articles
    • UMB Open Access Articles 2019
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Author
    Li, X.
    Tolbert, W.D.
    Hu, H.-G.
    Date
    2019
    Journal
    Chemical Science
    Publisher
    Royal Society of Chemistry
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://dx.doi.org/10.1039/c8sc03275k
    Abstract
    Two major pharmacological hurdles severely limit the widespread use of small peptides as therapeutics: poor proteolytic stability and membrane permeability. Importantly, low aqueous solubility also impedes the development of peptides for clinical use. Various elaborate side chain stapling chemistries have been developed for α-helical peptides to circumvent this problem, with considerable success in spite of inevitable limitations. Here we report a novel peptide stapling strategy based on the dithiocarbamate chemistry linking the side chains of residues Lys(i) and Cys(i + 4) of unprotected peptides and apply it to a series of dodecameric peptide antagonists of the p53-inhibitory oncogenic proteins MDM2 and MDMX. Crystallographic studies of peptide-MDM2/MDMX complexes structurally validated the chemoselectivity of the dithiocarbamate staple bridging Lys and Cys at (i, i + 4) positions. One dithiocarbamate-stapled PMI derivative, DTCPMI, showed a 50-fold stronger binding to MDM2 and MDMX than its linear counterpart. Importantly, in contrast to PMI and its linear derivatives, the DTCPMI peptide actively traversed the cell membrane and killed HCT116 tumor cells in vitro by activating the tumor suppressor protein p53. Compared with other known stapling techniques, our solution-based DTC stapling chemistry is simple, cost-effective, regio-specific and environmentally friendly, promising an important new tool for the development of peptide therapeutics with improved pharmacological properties including aqueous solubility, proteolytic stability and membrane permeability. Copyright 2019 The Royal Society of Chemistry.
    Sponsors
    We thank Prof. Bert Vogelstein of Johns Hopkins University for providing isogenic HCT116 cell lines. XL was supported by China Scholarship Council. This work was partially supported by the National Institutes of Health Grants CA167296 and CA219150 (to W. L.).
    Keyword
    side chain stapling chemistry
    dithiocarbamates
    peptide therapeutics
    peptide stapling strategy
    Peptides
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85060871828&doi=10.1039%2fc8sc03275k&partnerID=40&md5=a6a4b197fcf5bf73fb8865b4725cc19c; http://hdl.handle.net/10713/8665
    ae974a485f413a2113503eed53cd6c53
    10.1039/c8sc03275k
    Scopus Count
    Collections
    UMB Open Access Articles 2019

    entitlement

     
    DSpace software (copyright © 2002 - 2021)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.