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Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction
Md Shafiqul Islam1, Samuel L Junod2, Si Zhang1
1Department of Chemistry, Temple University, 1901 N. 13th Street, Philadelphia, PA, 19122, USA.
Nature Communications
|January 18, 2022
Summary
A new fluorine thiol displacement reaction (FTDR) creates stable peptide analogues with improved cancer cell inhibition. This facile macrocyclization strategy enhances peptide stability, affinity, and cellular uptake compared to traditional methods.
Area of Science:
- Medicinal Chemistry
- Peptide Chemistry
- Bioconjugation
Background:
- Peptide stapling enhances stability and cell permeability.
- Current methods like ring-closing metathesis (RCM) have limitations.
- Developing facile and efficient peptide macrocyclization is crucial for drug discovery.
Purpose of the Study:
- To develop a novel peptide macrocyclization and stapling strategy.
- To create peptide analogues with enhanced pharmacological properties.
- To investigate the mechanism of cellular uptake for stapled peptides.
Main Methods:
- Utilizing a fluorine thiol displacement reaction (FTDR) for peptide macrocyclization.
- Employing benzenedimethanethiol as a linker for stapling.
- Assessing peptide stability, affinity, and cellular uptake.
- Conducting molecular dynamics simulations to evaluate alpha helicity.
- Comparing FTDR-stapled peptides with RCM-stapled and unstapled controls.
Main Results:
- FTDR enables facile macrocyclization and stapling of unprotected peptides.
- Benzenedimethanethiol linker enhances alpha helicity and peptide stability.
- FTDR-stapled peptides show universally enhanced cellular uptake compared to RCM-stapled peptides.
- FTDR-stapled peptide analogues exhibit improved inhibition of cancer cells.
Conclusions:
- FTDR is a versatile and efficient strategy for peptide stapling.
- FTDR-stapled peptides possess superior pharmacological properties for potential therapeutic applications.
- The enhanced cellular uptake mechanism of FTDR-stapled peptides warrants further investigation.
