化学
肽
部分
组合化学
药物输送
细胞内
抗菌肽
赖氨酸
靶肽
生物化学
立体化学
氨基酸
有机化学
作者
Zizhen Zeng,Jibao Zhu,Xiaoyu Deng,Huanwen Chen,Yi Jin,Emeric Miclet,Valérie Alezra,Yang Wan
摘要
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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