Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction
Open accessPublished version of a preprint
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.
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- Authors
- Islam, M. S., Junod, S. L., Zhang, S., Buuh, Z. Y., Guan, Y., Zhao, M., Kaneria, K. H., Kafley, P., Cohen, C., Maloney, R., Lyu, Z., Voelz, V. A., Yang, W., & Wang, R. E.
- Affiliations
- Temple University (US)
- Corresponding author
- Wang, Rongsheng E.
- ORCID
- Venue
- Nature Communications
- Published
- 2022-01-17
- Volume
- 13
- Issue
- 1
- Pages
- 350-350
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8763920
- OpenAlex
- W4225767184
- Cited by
- 28
- References
- 10
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 12 · 2023: 6 · 2022: 4
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- 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
- U.S. Department of Health & Human Services | National Institutes of Health (R35GM133468, R01GM116204, R35GM22552, R01GM123296)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › 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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