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An all-in-one tetrazine reagent for cysteine-selective labeling and bioorthogonal activable prodrug construction

Author

Listed:
  • Xinyu He

    (Sichuan University)

  • Jie Li

    (Sichuan University)

  • Xinxin Liang

    (Sichuan University)

  • Wuyu Mao

    (Sichuan University)

  • Xinglong Deng

    (Sichuan University)

  • Meng Qin

    (Sichuan University)

  • Hao Su

    (Sichuan University)

  • Haoxing Wu

    (Sichuan University
    Sichuan University)

Abstract

The prodrug design strategy offers a potent solution for improving therapeutic index and expanding drug targets. However, current prodrug activation designs are mainly responsive to endogenous stimuli, resulting in unintended drug release and systemic toxicity. In this study, we introduce 3-vinyl-6-oxymethyl-tetrazine (voTz) as an all-in-one reagent for modular preparation of tetrazine-caged prodrugs and chemoselective labeling peptides to produce bioorthogonal activable peptide-prodrug conjugates. These stable prodrugs can selectively bind to target cells, facilitating cellular uptake. Subsequent bioorthogonal cleavage reactions trigger prodrug activation, significantly boosting potency against tumor cells while maintaining exceptional off-target safety for normal cells. In vivo studies demonstrate the therapeutic efficacy and safety of this prodrug design approach. Given the broad applicability of functional groups and labeling versatility with voTz, we foresee that this strategy will offer a versatile solution to enhance the therapeutic range of cytotoxic agents and facilitate the development of bioorthogonal activatable biopharmaceuticals and biomaterials.

Suggested Citation

  • Xinyu He & Jie Li & Xinxin Liang & Wuyu Mao & Xinglong Deng & Meng Qin & Hao Su & Haoxing Wu, 2024. "An all-in-one tetrazine reagent for cysteine-selective labeling and bioorthogonal activable prodrug construction," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47188-6
    DOI: 10.1038/s41467-024-47188-6
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    References listed on IDEAS

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    1. Qingxin Yao & Feng Lin & Xinyuan Fan & Yanpu Wang & Ye Liu & Zhaofei Liu & Xingyu Jiang & Peng R. Chen & Yuan Gao, 2018. "Synergistic enzymatic and bioorthogonal reactions for selective prodrug activation in living systems," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
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