Customized Reversible Stapling for Selective Delivery of Bioactive Peptides - Structure et Dynamique des Biomolécules
Article Dans Une Revue Journal of the American Chemical Society Année : 2022

Customized Reversible Stapling for Selective Delivery of Bioactive Peptides

Résumé

We have developed a new concept for reversible peptide stapling that involves macrocyclization between two amino groups and decyclization promoted via dual 1,4-elimination. Depending on the trigger moiety, this strategy could be employed to selectively deliver peptides to either intracellular or extracellular targets. As a proof of concept, a peptide inhibitor targeting a lysine-specific demethylase 1 (LSD1) was temporarily cyclized to enhance its stability and ability to cross the cell membrane. Once inside the cells, the biologically active linear peptide was released under reducing environment. Moreover, we have developed reversibly stapled peptides using antimicrobial peptides (RStAMPs) whose bioactive helical conformation can be temporarily destabilized by stapling the peptide backbone. The resulting helix-distorted RStAMPs are nontoxic and highly resistant to protease hydrolysis, while at the infection site, RStAMPs can be rapidly activated by the overproduced H2O2 through the dual 1,4-elimination. The latter restored the helical structure of the native peptide and its antimicrobial activity. This work illustrates a highly valuable macrocyclization strategy for the peptide community and should greatly benefit the field of peptide delivery.

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Chimie
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Dates et versions

hal-03988530 , version 1 (14-02-2023)

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Zizhen Zeng, Jibao Zhu, Xiaoyu Deng, Huanwen Chen, Yi Jin, et al.. Customized Reversible Stapling for Selective Delivery of Bioactive Peptides. Journal of the American Chemical Society, 2022, 144 (51), pp.23614-23621. ⟨10.1021/jacs.2c10949⟩. ⟨hal-03988530⟩
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