Combinatorial Library Screening Coupled to Mass Spectrometry toIdentify Valuable Cyclic Peptides

Abstract

Combinatorial library screening coupled to mass spectrometry (MS) analysis isa practical approach to identify useful peptides. Cyclic peptides can have highbiological activity, selectivity, and affinity for target proteins, and high stabilityagainst proteolytic degradation. Here we describe two strategies to preparecombinatorial libraries suitable for MS analysis to accelerate the discoveryof cyclic peptide structures. Both approaches use ChemMatrix resin and thelinker 4-hydroxymethylbenzoic acid. One strategy involves the synthesis ofa one-bead?two-peptides library in which each bead contains both the cyclicpeptide and its linear counterpart to facilitate MS analysis. The other protocol isbased on the synthesis of a cyclic depsipeptide library in which a glycolamidicester group is incorporated by adding glycolic acid. After library screening, thering is opened and the peptide is released simultaneously for subsequent MSanalysis.