Cyclic peptides can act as protein ligands. They can target binding pockets in proteins that are challenging targets for small-molecule ligands. Therefore, cyclic peptides are useful candidates for drug development. In this context, peptide library generation and screening procedures are the methods of choice to evaluate the (bio-)chemical properties of a large group of—often randomly synthesized—peptide ligands.
To facilitate the creation of such libraries of cyclic peptides, Christian Heinis, École Polytechnique Fédérale de Lausanne (EPFL), Switzerland, and colleagues have developed a fast synthesis approach using solid-phase peptide synthesis (SPPS) without the need for an additional purification step. The desired peptides are synthesized in a linear manner while being immobilized on a resin bead with a disulfide linker. For this strategy, it is important that the last amino acid of the chain contains a thiol function (e.g., cysteine). After the linear peptide is complete, possible protecting groups are cleaved. Then, the peptide can be released by adding a base. This deprotonates the N-terminal thiol group, which attacks the disulfide linker between the peptide and the resin in an intramolecular cyclization reaction. The result is the desired cyclic product.
Apolar polystyrene resins were found to give the best yields (54–100 %). The product purity (>93 %) was confirmed by liquid chromatography–mass spectrometry (LC–MS) analysis. The developed method can, in principle, be used for every type of molecule that contains thiol groups and can form disulfide bonds with a solid phase.
- Cyclative Release Strategy to Obtain Pure Cyclic Peptides Directly from the Solid Phase,
Sevan Habeshian, Ganesh A. Sable, Mischa Schüttel, Manuel L. Merz, Christian Heinis,
ACS Chem. Biol. 2022.