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PreprintCited by 29Chemical Synthesis and AnalysisBiochemical and Structural CharacterizationFluorine in Organic Chemistry

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Unprotected Peptide Macrocyclization and Stapling via A Fluorine-Thiol Displacement Reaction

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Islam, Md Shafiqul, Junod, Samuel L., Zhang, Si, Buuh, Zakey Yusuf, Guan, Yifu, Kaneria, Kishan H, Lyu, Zhigang, Voelz, Vincent, Yang, Weidong, Wang, Rongsheng E.·2020·Nature Communications
DOI 10.1101/2020.09.09.290379PMC PMC8763920

Preprint — published as 10.1038/s41467-022-27995-5 · Paper page

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Abstract

Stapled peptides serve as a powerful tool for probing protein-protein interactions, but its application has been largely impeded by the limited cellular uptake. Here 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, and cell permeability. This new approach enabled selective modification of the orthogonal fluoroacetamide side chains in unprotected peptides, with the identified 1,3-benzenedimethanethiol linker promoting alpha helicity of a variety of peptide substrates, as corroborated by molecular dynamics simulations. The cellular uptake of these stapled peptides was 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. Consistent with the improved cell permeability, the FTDR-stapled lead Axin analogues demonstrated better inhibition of cancer cell growth than the RCM-stapled analogues. Graphical Abstract:

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Metadata

Authors
Islam, M. S., Junod, S. L., Zhang, S., Buuh, Z. Y., Guan, Y., Kaneria, K. H., Lyu, Z., Voelz, V., Yang, W., & Wang, R. E.
Affiliations
Temple University (US)
Corresponding author
Wang, Rongsheng E.
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2020-09-09
Volume
13
Issue
1
Pages
350-350
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2020.09.09.290379
PMC
PMC8763920
OpenAlex
W4225767184
Cited by
29
References
1
Citations by year
2026: 2 · 2025: 5 · 2024: 12 · 2023: 6 · 2022: 4
FWCI
2.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • TUScholarShare (Temple University) (submittedVersion, cc-by)
Funders
  • National Science Foundation (W911NF-16-2-0189, 1625061, R01GM123296)
  • U.S. Department of Health and Human Services (R01GM123296, R35GM22552, R01GM116204, R35GM133468)
  • Pennsylvania Department of Health
  • University of Pennsylvania
  • Pennsylvania State University
  • Temple University (W911NF-16-2-0189, 1625061)
  • National Institutes of Health (1s10od020095-01, CNS-1625061, W911NF-16-2-0189, 1625061, R35GM22552)
  • National Institute of General Medical Sciences (R01GM116204, R35GM133468, R01GM123296, R35GM122552)
  • Army Research Laboratory (W911NF-16-2-0189, 1625061, CNS-1625061, W911NF, R01GM123296)
Topics
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
  • Physical Sciences › Chemistry › Organic Chemistry › Fluorine in Organic Chemistry
Keywords
peptide macrocyclization, peptide stapling, orthogonal protecting groups, cellular uptake, endocytic pathway, cancer cell inhibition, peptide stability
MeSH terms
Amino Acid Sequence, Cell Membrane Permeability, Cross-Linking Reagents, Cyclization, Fluorine, Humans, Models, Molecular, Magnetic Resonance Spectroscopy, Peptides, Sulfhydryl Compounds, Thermodynamics, Tumor Suppressor Protein p53, Macrocyclic Compounds, Molecular Dynamics Simulation, HEK293 Cells, Cell-Penetrating Peptides, Axin Protein

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