A Simple and Efficient Approach to Prepare One-Bead One-Compound Cyclic Peptide Libraries for Ligands Identification

摘要

The controlled interference of protein-protein interactions (PPl) with chemical compounds has great potential for the discovery of novel therapeutics. Considering the nature of the interaction, cyclic peptides represent a template of choice to mimic protein secondary structures and modulate PPL Besides increased conformational rigidity and improved proteolytic stability, they offer a great degree of molecular complexity and diversity to fully exploit this great chemical diversity, the combinatorial one-bead one-compound (OBOC) approach is a very powerful approach [1]. However, its use with cyclic peptides is limited by difficulties in sequencing hit compounds by Edman degradation or MS/MS due to the lack of free N-terminal amine and complicated fragmentation patterns, respectively. This problem has been overcome by Pei and coworkers by using a bead segregation strategy [2,3] (Figure 1). Initially introduced by Lam et ai. [4], the topological segregation offers the opportunity to synthesize two compounds per bead. Based on previous results, our objective was to study the effects of various parameters on bead segregation in order to control the exterior versus interior ratio in a reproducible manner.