Application Of Thiol Cyclization Strategies In Peptide Library

Combinatorial chemistry is regarded as one of the most important advances in medicinal chemistry in the past ten years. One of the most significant respects is to generate a peptide library for identifying the antigen epitopes, enzyme-substrate/inhibitor as well as receptor antagonists/agonists. Generally, the diversity of a peptide library is achieved by altering the building blocks of a parent peptide or template. This method aims at creating a collection of building-block-based diversity with the same scaffold. How to create a collection of structure-based diversity with a large number of different scaffolds is challengeable.Constraining peptides to a discrete set of conformers has been shown to be useful in designing peptidyl drugs with enhanced receptor-binding affinity and selectivity. End-to-end lactamization forming cyclic peptides is a conformational constraint commonly found in both nature and synthetic design. This constraint has the additional advantages of improving bioavailability and metabolic stability. Conventinal methods for peptide cyclization involve partially or fully protected/deprotected strategies and the ring closure is achieved with a coupling reagent. Recently, Tam and co-workers developed a cyclization strategy using unprotected linear peptide precursors based on the intermolecular thioester ligation strategy. This cyclization strategy is achieved through an intramolecular transthioesterification of an unprotected cysteinyl peptide thioester to form a reversible intramolecular thioester and then through a proximity-driven S- to N-acyl transfer of the 1,2-amino thiol of the N~α-Cys to form an end-to-end cyclic peptide. A free thiol group is obtained after cyclization. Subsequently further modifications on thiol groups can be carried out. Based on this thiol cyclization method we designed a strategy to increase the structure diversity. Generally, our strategy has three steps: (1) synthesis of linear peptide precursors using Boc/Bzl chemistry based on a previously developed thiol resin; (2) cyclization of the linear precursors through an intramolecular thioester ligation; (3) modification on thiol groups by oxidation and alkylation.