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.
Cyclative Release Strategy to Obtain Pure Cyclic Peptides Directly from the Solid Phase
Sevan Habeshian, Ganesh A. Sable, Mischa Schüttel, Manuel L. Merz, and Christian Heinis*
ACS Chem. Biol. 2022, 17, 1, 181–186