Customized Reversible Stapling for Selective Delivery of Bioactive Peptides

Zizhen Zeng (1) , Jibao Zhu (1) , Xiaoyu Deng (2, 1) , Huanwen Chen (1) , Yi Jin (3, 1) , Emeric Miclet (4, 5, 6, 7) , Valérie Alezra (8) , Yang Wan (9, 1)

1 Jiangxi University of Chinese Medicine
2 RU - Rutgers, The State University of New Jersey [New Brunswick]
3 TUFE - Tianjin University of Finance and Economics
4 LBM UMR 7203 - Laboratoire des biomolécules
5 LBM-E3 - Structure et Dynamique des Biomolécules
6 SU - Sorbonne Université
7 UPMC - Université Pierre et Marie Curie - Paris 6
8 ICMMO - Institut de Chimie Moléculaire et des Matériaux d'Orsay
9 Department of Physics of Complex Systems

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.

Domains: Chemical Sciences

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⟩