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Noncanonical amino acids as doubly bio-orthogonal handles for one-pot preparation of protein multiconjugates

Author

Listed:
  • Yong Wang

    (Peking University)

  • Jingming Zhang

    (Peking University First Hospital)

  • Boyang Han

    (Peking University)

  • Linzhi Tan

    (Peking University)

  • Wenkang Cai

    (Peking University)

  • Yuxuan Li

    (Peking University)

  • Yeyu Su

    (Peking University)

  • Yutong Yu

    (Peking University)

  • Xin Wang

    (Peking University)

  • Xiaojiang Duan

    (Peking University First Hospital)

  • Haoyu Wang

    (Peking University)

  • Xiaomeng Shi

    (Peking University)

  • Jing Wang

    (Peking University)

  • Xing Yang

    (Peking University First Hospital
    Peking University Health Science Center)

  • Tao Liu

    (Peking University)

Abstract

Genetic encoding of noncanonical amino acid (ncAA) for site-specific protein modification has been widely applied for many biological and therapeutic applications. To efficiently prepare homogeneous protein multiconjugates, we design two encodable noncanonical amino acids (ncAAs), 4-(6-(3-azidopropyl)-s-tetrazin-3-yl) phenylalanine (pTAF) and 3-(6-(3-azidopropyl)-s-tetrazin-3-yl) phenylalanine (mTAF), containing mutually orthogonal and bioorthogonal azide and tetrazine reaction handles. Recombinant proteins and antibody fragments containing the TAFs can easily be functionalized in one-pot reactions with combinations of commercially available fluorophores, radioisotopes, PEGs, and drugs in a plug-and-play manner to afford protein dual conjugates to assess combinations of tumor diagnosis, image-guided surgery, and targeted therapy in mouse models. Furthermore, we demonstrate that simultaneously incorporating mTAF and a ketone-containing ncAA into one protein via two non-sense codons allows preparation of a site-specific protein triconjugate. Our results demonstrate that TAFs are doubly bio-orthogonal handles for efficient and scalable preparation of homogeneous protein multiconjugates.

Suggested Citation

  • Yong Wang & Jingming Zhang & Boyang Han & Linzhi Tan & Wenkang Cai & Yuxuan Li & Yeyu Su & Yutong Yu & Xin Wang & Xiaojiang Duan & Haoyu Wang & Xiaomeng Shi & Jing Wang & Xing Yang & Tao Liu, 2023. "Noncanonical amino acids as doubly bio-orthogonal handles for one-pot preparation of protein multiconjugates," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36658-y
    DOI: 10.1038/s41467-023-36658-y
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    1. Mengmeng Xia & Qiyue Wang & Yamin Liu & Chunyan Fang & Bo Zhang & Shengfei Yang & Fu Zhou & Peihua Lin & Mingzheng Gu & Canyu Huang & Xiaojun Zhang & Fangyuan Li & Hongying Liu & Guangfeng Wang & Dais, 2024. "Self-propelled assembly of nanoparticles with self-catalytic regulation for tumour-specific imaging and therapy," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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