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Constructing Cyclic Peptides Using an On-Tether Sulfonium Center
Published on: September 28, 2022
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Spontaneous, co-translational peptide macrocyclization using p-cyanoacetylene-phenylalanine
H Estheban Osorio Franco1,2, Brennan T Chaloux1,2, Matthew C T Hartman1,2
1Massey Cancer Center, Virginia Commonwealth University, 401 College St, Richmond, 23219, Virginia, USA. osoriofranche@vcu.edu.
Chemical Communications (Cambridge, England)
|May 24, 2022
Summary
We developed a new amino acid, p-cyanoacetylene-L-Phe (pCAF), for creating peptide macrocycles (PMCs). This enables spontaneous, co-translational cyclization under physiological conditions, expanding inhibitor development for protein-protein interactions (PPIs).
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Molecular Biology
Background:
- Peptide macrocycles (PMCs) are crucial for developing inhibitors of protein-protein interactions (PPIs).
- Current display technologies for generating large PMC libraries are limited by macrocyclization chemistry constraints compatible with biological conditions.
- Existing methods often require harsh conditions, limiting their applicability in biological systems.
Purpose of the Study:
- To introduce a novel non-canonical amino acid (ncAA) for efficient and versatile PMC synthesis.
- To enable spontaneous, co-translational macrocyclization under physiological conditions.
- To expand the toolkit for developing novel PPI inhibitors.
Main Methods:
- Introduction of a novel ncAA, p-cyanoacetylene-L-Phe (pCAF).
- Utilizing Michael addition chemistry between pCAF and cysteine for spontaneous cyclization.
- Co-translational macrocyclization within a biological milieu.
Main Results:
- pCAF facilitates spontaneous cyclization with cysteine under physiological conditions.
- The developed chemistry is robust and compatible with biological systems.
- Stable macrocycles of various ring sizes, including bicyclic structures, can be generated.
Conclusions:
- The novel ncAA pCAF offers a powerful new method for PMC synthesis.
- This approach overcomes limitations of existing macrocyclization chemistries for display technologies.
- pCAF-mediated cyclization provides a versatile platform for generating PPI inhibitors.
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