The Symmetric Tetravalent Sulfhydryl-Specific Linker NATBAFacilitates a Combinatorial “Tool Kit” Strategy for Phage DisplayBased Selection of Functionalized Bicyclic Peptides

摘要

The rigid conformation of constrained bicyclicpeptides provides a number of advantages over larger proteinbased ligands, including better chemical stability, enhancedtissue penetration, and a wider field of possible applications.Selective chemical modification strategies are able to extendthe scope of applications not only in a therapeutic manner butalso for the development of novel tools for protein capturing,bioimaging, and targeted drug delivery. Herein, we report thesynthesis of an adamantane-based, symmetrical, tetravalent,sulfhydryl-specific peptide linker. We have developed an invitro two-step modification strategy that allows the generationof differently functionalized bicyclic peptides. This “tool kit”strategy was applied to cyclize and functionalize a phage-encoded peptide library bearing the sequence CX6CX6C. After phagedisplay against a model target, isolated peptides show strong consensus sequences, indicating target-specific binding. The newlydeveloped symmetric tetravalent linker opens new avenues for the combinatorial selection and functionalization of bicyclicpeptide ligands with affinity to virtually any target.