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Constructing Thioether/Vinyl Sulfide-tethered Helical Peptides Via Photo-induced Thiol-ene/yne Hydrothiolation
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Cyclobutane-bearing restricted anchoring residues enabled geometry-specific hydrocarbon peptide stapling
Baobao Chen1, Chao Liu1, Wei Cong1
1School of Medicine or Institute of Translational Medicine, Shanghai University Shanghai 200444 China hhu66@shu.edu.cn.
Chemical Science
|October 27, 2023
Summary
This study introduces novel cyclobutane-based amino acids for hydrocarbon peptide stapling, enhancing therapeutic potential. The E7-E7 combination optimizes stapled peptides, showing increased helicity and stronger biological activity against SARS-CoV-2 spike protein.
Area of Science:
- Medicinal Chemistry
- Organic Chemistry
- Biochemistry
Background:
- Stapled peptides offer improved therapeutic properties over linear peptides.
- Hydrocarbon stapling via ring-closing metathesis (RCM) is a key technique.
- Existing methods can be expanded to enhance peptide structure and function.
Purpose of the Study:
- To design and synthesize novel cyclobutane-based amino acids for peptide stapling.
- To investigate the utility of these new amino acids in RCM-mediated stapling.
- To evaluate the impact of cyclobutane stapling on peptide helicity and biological activity.
Main Methods:
- Synthesis of cyclobutane-based amino acids: (E)-1-amino-3-(but-3-en-1-yl)cyclobutane-1-carboxylic acid (E7) and (Z)-1-amino-3-(but-3-en-1-yl)cyclobutane-1-carboxylic acid (Z7).
- Application of E7 and Z7 in RCM-mediated peptide stapling with all four stereoisomeric combinations.
- Computational analysis (quantum and molecular mechanics) to determine optimal E7-E7 combination for RCM and helical stabilization.
- Biological evaluation of cyclobutane-stapled peptides targeting the SARS-CoV-2 spike protein.
Main Results:
- Successful synthesis of E7 and Z7 amino acids.
- Demonstrated applicability of all four E7/Z7 combinations in RCM peptide stapling, yielding geometry-specific stapled peptides.
- Identified E7-E7 as the optimal combination for RCM efficiency and helical stabilization.
- Cyclobutane-bearing stapled peptides, particularly E7-E7, showed higher alpha-helicity and enhanced biological activity compared to conventional stapled peptides.
- Targeted SARS-CoV-2 spike protein with promising results.
Conclusions:
- Cyclobutane-based amino acids are effective building blocks for expanding hydrocarbon peptide stapling strategies.
- The E7-E7 geometry-specific stapled peptides offer superior helicity and biological activity.
- This novel stapling methodology holds significant potential for developing next-generation peptide therapeutics.
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