IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v9y2018i1d10.1038_s41467-018-04343-0.html
   My bibliography  Save this article

Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide

Author

Listed:
  • Tomonori Tamura

    (Kyoto University, Katsura, Nishikyo-ku)

  • Tsuyoshi Ueda

    (Kyoto University, Katsura, Nishikyo-ku)

  • Taiki Goto

    (Kyoto University, Katsura, Nishikyo-ku)

  • Taku Tsukidate

    (Kyoto University, Katsura, Nishikyo-ku)

  • Yonatan Shapira

    (Weizmann Institute of Science)

  • Yuki Nishikawa

    (Kyoto University, Katsura, Nishikyo-ku)

  • Alma Fujisawa

    (Kyoto University, Katsura, Nishikyo-ku)

  • Itaru Hamachi

    (Kyoto University, Katsura, Nishikyo-ku
    CREST (Core Research for Evolutional Science and Technology, JST), Sanbancho, Chiyodaku)

Abstract

Selective modification of native proteins in live cells is one of the central challenges in recent chemical biology. As a unique bioorthogonal approach, ligand-directed chemistry recently emerged, but the slow kinetics limits its scope. Here we successfully overcome this obstacle using N-acyl-N-alkyl sulfonamide as a reactive group. Quantitative kinetic analyses reveal that ligand-directed N-acyl-N-alkyl sulfonamide chemistry allows for rapid modification of a lysine residue proximal to the ligand binding site of a target protein, with a rate constant of ~104 M−1 s−1, comparable to the fastest bioorthogonal chemistry. Despite some off-target reactions, this method can selectively label both intracellular and membrane-bound endogenous proteins. Moreover, the unique reactivity of N-acyl-N-alkyl sulfonamide enables the rational design of a lysine-targeted covalent inhibitor that shows durable suppression of the activity of Hsp90 in cancer cells. This work provides possibilities to extend the covalent inhibition approach that is currently being reassessed in drug discovery.

Suggested Citation

  • Tomonori Tamura & Tsuyoshi Ueda & Taiki Goto & Taku Tsukidate & Yonatan Shapira & Yuki Nishikawa & Alma Fujisawa & Itaru Hamachi, 2018. "Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04343-0
    DOI: 10.1038/s41467-018-04343-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-04343-0
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-018-04343-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Jun-ichi Kishikawa & Moe Ishikawa & Takahiro Masuya & Masatoshi Murai & Yuki Kitazumi & Nicole L. Butler & Takayuki Kato & Blanca Barquera & Hideto Miyoshi, 2022. "Cryo-EM structures of Na+-pumping NADH-ubiquinone oxidoreductase from Vibrio cholerae," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04343-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.