Development of an Effective Dual Ring-Opening/Cleavage Approach for the Synthesis and Decoding of One-Bead One-Compound Cyclic Peptide Libraries

摘要

Cyclic peptides are useful tools in chemical biology and medicinal chemistry. Their great therapeutic potential has prompted their use in combinatorial chemistry. The one-bead-one-compound (OBOC) approach, in which each bead carries many copies of a unique compound, has become a powerful tool in drug discovery [1]. Such libraries have been successfully used to discover ligands for a wide variety of macromolecular targets. However, the use of the OBOC technology with cyclic peptides has been limited by difficulties in sequencing hit compounds after the screening. Lacking a free jV-terminal amine, Edman degradation sequencing cannot be used and complicated fragmentation patterns are obtained by MS/MS. In this regard, the Pei group used a one-bead-two-compound approach on topologically segregated bilayer beads in which the cyclic peptide is exposed on the surface and its linear counterpart is found inside as a tag for sequencing [2]. More recently, a ring-opening strategy on cyclic peptoids has been developed to reduce the need for encoding in OBOC libraries [3,4]. In this strategy, a cleavable residue is introduced in the cycle backbone to allow a linearization of the molecule under specific conditions and sequencing of the linear variant by MS/MS. Based on this ring-opening strategy, our objective was to develop a simple and efficient approach to prepare OBOC cyclic peptide libraries that would allow fast sequence determination after simultaneous macrocycle opening and release from the resin.