Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction

February 1, 2022

Title

Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction

Author

Md Shafiqul Islam, Samuel L. Junod, Si Zhang, Zakey Yusuf Buuh, Yifu Guan, Mi Zhao, Kishan H. Kaneria, Parmila Kafley, Carson Cohen, Robert Maloney, Zhigang Lyu, Vincent A. Voelz, Weidong Yang & Rongsheng E. Wang

Year

2022

Journal

Nature Communications

Abstract

We report the discovery of a facile peptide macrocyclization and stapling strategy based on a fluorine thiol displacement reaction (FTDR), which renders a class of peptide analogues with enhanced stability, affinity, cellular uptake, and inhibition of cancer cells. This approach enabled selective modification of the orthogonal fluoroacetamide side chains in unprotected peptides in the presence of intrinsic cysteines. The identified benzenedimethanethiol linker greatly promoted the alpha helicity of a variety of peptide substrates, as corroborated by molecular dynamics simulations. The cellular uptake of benzenedimethanethiol stapled peptides appeared to be universally enhanced compared to the classic ring-closing metathesis (RCM) stapled peptides. Pilot mechanism studies suggested that the uptake of FTDR-stapled peptides may involve multiple endocytosis pathways in a distinct pattern in comparison to peptides stapled by RCM. Consistent with the improved cell permeability, the FTDR-stapled lead Axin and p53 peptide analogues demonstrated enhanced inhibition of cancer cells over the RCM-stapled analogues and the unstapled peptides.

Instrument

J-815

Keywords

peptide, FTDR, RCM