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

Xinyu He, Jie Li, Xinxin Liang, Wuyu Mao, Xinglong Deng, Meng Qin, Hao Su and Haoxing Wu ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47188-6

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