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Synthesis of Disulfide Surrogate Peptides Incorporating Large-Span Surrogate Bridges Through a
Qian Qu1, Shuai Gao1, Fangming Wu2
1Tsinghua-Peking Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus, Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, China.
Angewandte Chemie (International Ed. in English)
|February 16, 2020
Summary
Synthetic bridges can replace unstable disulfide bonds in peptides. A new native chemical ligation-assisted diaminodiacid (NCL-DADA) strategy enables robust generation of large-span disulfide surrogate peptides up to 50 amino acids.
Area of Science:
- Peptide Chemistry
- Biotechnology
- Medicinal Chemistry
Background:
- Disulfide bonds are crucial for peptide structure and function.
- Poor stability of disulfide bonds limits therapeutic applications of many peptides.
- Existing methods struggle to create peptides with large-span synthetic disulfide bond surrogates.
Purpose of the Study:
- To develop a robust method for generating disulfide surrogate peptides with large-span synthetic bridges.
- To overcome limitations of current peptide synthesis techniques for complex disulfide mimetics.
- To enable access to previously unattainable bioactive peptide disulfide surrogates.
Main Methods:
- Development of a native chemical ligation (NCL)-assisted diaminodiacid (DADA) strategy.
- Synthesis of disulfide surrogate peptides incorporating large-span bridges (up to 50 amino acids).
- Verification of bioactivity, structure, and stability of synthesized peptides.
Main Results:
- The NCL-DADA strategy successfully generated disulfide surrogate peptides with bridges up to 50 amino acids.
- Synthesized surrogates demonstrated preserved bioactivities and defined structures (NMR, X-ray crystallography).
- Disulfide replacements effectively prevented disulfide reduction and scrambling, enhancing peptide stability.
Conclusions:
- The NCL-DADA strategy is a powerful tool for creating stable, large-span disulfide surrogate peptides.
- This method significantly expands the scope of peptide engineering for therapeutic development.
- Disulfide surrogate peptides offer improved stability and overcome limitations of natural disulfide bonds in pharmacologically important peptides.
