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Copper assisted sequence-specific chemical protein conjugation at a single backbone amide

Author

Listed:
  • Mengzhun Guo

    (Fudan University
    Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Kai Zhao

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Liang Guo

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Rui Zhou

    (The Second Affiliated Hospital of Zhejiang University School of Medicine)

  • Qiuju He

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Kuan Lu

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Tian Li

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Dandan Liu

    (Zhejiang University)

  • Jinfeng Chen

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Jing Tang

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Xin Fu

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Jinyun Zhou

    (The Second Affiliated Hospital of Zhejiang University School of Medicine)

  • Bei Zheng

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Samuel I. Mann

    (University of California at San Francisco)

  • Yongdeng Zhang

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Jing Huang

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Bing Yang

    (Zhejiang University)

  • Ting Zhou

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Yingjie Lei

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

  • Bobo Dang

    (Fudan University
    Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University
    Westlake Institute for Advanced Study)

Abstract

Direct, site-specific methods of protein functionalization are highly desirable for biotechnology. However, such methods are challenging due to the difficulty of chemically differentiating a single site within a large protein. Herein, we propose “metal binding targeting” strategy and develop a Copper Assisted Sequence-specific conjugation Tag (CAST) method to achieve rapid (second order rate 8.1 M−1 s−1), site-specific protein backbone chemical modification with pinpoint accuracy. We demonstrate the versatility of CAST conjugation by preparing various on-demand modified recombinant proteins, including a homogeneous antibody-drug conjugate with high plasma stability and potent efficacy in vitro and in vivo. Thus, CAST provides an efficient and quantitative method to site-specifically attach payloads on large, native proteins.

Suggested Citation

  • Mengzhun Guo & Kai Zhao & Liang Guo & Rui Zhou & Qiuju He & Kuan Lu & Tian Li & Dandan Liu & Jinfeng Chen & Jing Tang & Xin Fu & Jinyun Zhou & Bei Zheng & Samuel I. Mann & Yongdeng Zhang & Jing Huang , 2023. "Copper assisted sequence-specific chemical protein conjugation at a single backbone amide," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43753-7
    DOI: 10.1038/s41467-023-43753-7
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    References listed on IDEAS

    as
    1. Michael T. Taylor & Jennifer E. Nelson & Marcos G. Suero & Matthew J. Gaunt, 2018. "A protein functionalization platform based on selective reactions at methionine residues," Nature, Nature, vol. 562(7728), pages 563-568, October.
    2. Ekaterina V. Vinogradova & Chi Zhang & Alexander M. Spokoyny & Bradley L. Pentelute & Stephen L. Buchwald, 2015. "Organometallic palladium reagents for cysteine bioconjugation," Nature, Nature, vol. 526(7575), pages 687-691, October.
    3. Yasuaki Anami & Chisato M. Yamazaki & Wei Xiong & Xun Gui & Ningyan Zhang & Zhiqiang An & Kyoji Tsuchikama, 2018. "Glutamic acid–valine–citrulline linkers ensure stability and efficacy of antibody–drug conjugates in mice," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    4. Chisato M. Yamazaki & Aiko Yamaguchi & Yasuaki Anami & Wei Xiong & Yoshihiro Otani & Jangsoon Lee & Naoto T. Ueno & Ningyan Zhang & Zhiqiang An & Kyoji Tsuchikama, 2021. "Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    Full references (including those not matched with items on IDEAS)

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