Cyclic peptides, due to their conformational rigidity, possess high target affinity and biochemical stability. Combinatorial libraries of cyclic peptides are powerful tools in discovering novel ligands and drugs. The process of lead discovery, however, is bottlenecked at the sequence identification step, mainly performed via multiple stages of MS/MS. While the determination of linear sequences is straightforward, the sequencing of cyclic peptides is much more challenging. We therefore propose a method for the synthesis of a combinatorial library of reversible cyclic peptides. Our strategy includes the insertion of a cleavable linker within the peptide sequence before cyclization. The cleavable linker allows to open the cyclic peptide in a predetermined position upon treatment with a cleaving agent. The linearized peptide is released from the solid support to the liquid phase and finally sequenced by single stage MS/MS. This library is a very promising tool for the discovery of affinity ligands and drugs.

Novel reversible cyclic peptides for the identification of affinity ligands

243rd National Meeting (2012)

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