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

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 and Rongsheng E. Wang ()
Additional contact information
Md Shafiqul Islam: Temple University
Samuel L. Junod: Temple University
Si Zhang: Temple University
Zakey Yusuf Buuh: Temple University
Yifu Guan: Temple University
Mi Zhao: Temple University
Kishan H. Kaneria: Temple University
Parmila Kafley: Temple University
Carson Cohen: Temple University
Robert Maloney: Temple University
Zhigang Lyu: Temple University
Vincent A. Voelz: Temple University
Weidong Yang: Temple University
Rongsheng E. Wang: Temple University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-27995-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-27995-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-27995-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().