The synthesis of large numbers of cyclic peptides─required, for example, in screens for drug development─is currently limited by the need of chromatographic purification of individual peptides.

Herein, researchers have developed a strategy in which cyclic peptides are released from the solid phase in the pure form and do not need purification. Peptides with an N-terminal thiol group are synthesized on the solid phase via a C-terminal disulfide linker, their sidechain-protecting groups are removed while the peptides remain on the solid phase, and the peptides are finally released via a cyclative mechanism by the addition of a base that deprotonates the N-terminal thiol group and triggers an intramolecular disulfide-exchange reaction.

The method yields disulfide-cyclized peptides, a format on which many important peptide drugs such as oxytocin, vasopressin, and octreotide are based. We demonstrate that the method is applicable for facile synthesis in 96-well plates and allows for synthesis and screening of hundreds of cyclic peptides.

Title:
Cyclative Release Strategy to Obtain Pure Cyclic Peptides Directly from the Solid Phase
Authors:
Sevan Habeshian, Ganesh A. Sable, Mischa Schüttel, Manuel L. Merz, and Christian Heinis*
Citation:
ACS Chem. Biol. 2022, 17, 1, 181–186
URL:
https://pubs.acs.org/doi/abs/10.1021/acschembio.1c00843