Habeshian, SevanSable, Ganesh A.Schuettel, MischaMerz, Manuel L.Heinis, Christian2022-01-312022-01-312022-01-312022-01-1110.1021/acschembio.1c00843https://infoscience.epfl.ch/handle/20.500.14299/184888WOS:000743168400001The 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, we 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 o 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.Biochemistry & Molecular Biologydisulfidestext::journal::journal article::research article