Citation: Shu Li, Yuanyuan Tang, Xiaojing Liu, Shibo Song, Baokang Zhu, Min Chang, Yali Peng. Achieving enhancing endosome escape of Tat47-57-derived stapled peptides through decafluorobiphenyl bridge[J]. Chinese Chemical Letters, ;2026, 37(4): 111278. doi: 10.1016/j.cclet.2025.111278 shu

Achieving enhancing endosome escape of Tat47-57-derived stapled peptides through decafluorobiphenyl bridge

Shu Li ^{a, b, 1} ,
Yuanyuan Tang ^{a, 1} ,
Xiaojing Liu ^a ,
Shibo Song ^a ,
Baokang Zhu ^b ,
Min Chang ^{a, *,} ,
Yali Peng ^{a, *,}

a.
Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China
b.
Pharmacy College of Shihezi University/Key Laborataty of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education/Collaborative Innovation Center for Efficient Safflower Production and Resource Utilization of XPCC/Institute for Safflower Industry Research, Shihezi University, Shihezi 832003, China

changmin@lzu.edu.cn

pengyali@lzu.edu.cn

Received Date: 8 January 2025
Revised Date: 17 April 2025
Accepted Date: 29 April 2025
Available Online: 1 May 2025

Figures(4)

Cell-penetrating peptides (CPPs) hold great potential as a tool using non-invasive delivery of therapeutic or diagnostic molecules into mammalian cells, but their broad application has been limited by poor endosomal escape. Thus, the rational design and selection of CPPs remains a challenge and calls for deeper mechanistic understandings. Here, we developed novel stapled cell-penetrating peptides based on the highly positively charged HIV Tat47-57 peptide using decafluorobiphenyl-cysteine S_NAr chemistry which selectively disrupt endosomal membranes. A series of stapled peptides with a cross-linked structure were synthesized and investigated their cellular uptake, endosomal escape and intracellular delivery of cargoes. Among these peptides, analogues P3 and P6 demonstrated the highest cellular uptake and endosomal escape activities with efficiencies 3.5−9-fold higher than that of Tat47-57. Notably, the results demonstrated that the decafluorobiphenyl bridge of stapled peptides exhibited significant ability for cellular uptake and endosomal escape. Moreover, we found that fluorine atoms of decafluorobiphenyl bridge played a key role for disrupting endosomal membranes. Finally, the utility of this strategy has been demonstrated by the intracellular delivery of biomacromolecules (avidin and negatively charged phosphopeptides). Together, these results suggest that the decafluorobiphenyl-cysteine S_NAr chemistry may be an efficient strategy for the development of novel stapled CPPs.
- Cell-penetrating peptides,
- Endosomal escape,
- Decafluorobiphenyl bridge,
- Stapled peptides,
- Intracellular delivery
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