Polymer-scaffolded dynamic combinatorial libraries

Abstract

Through billions of years of evolution, nature has assembled a multitude of polymeric macromolecules capable of exquisite molecular recognition. This functionality is achieved by the precise control of amino acid sequence during the assembly of proteins, producing three-dimensional macromolecules with key residues anchored in the correct positions to interact with their targets. Developing ‘wholly-synthetic’ macromolecular analogues which mimic this function presents a considerable challenge to chemists, who lack the ‘biological machinery’ used by nature in the precision-assembly of polymers. In addressing this challenge, familiar chemical concepts, such as combinatorial methods and supramolecular interactions, have been adapted for application in the macromolecular arena. Working from a limited set of residues, synthetic macromolecules have been produced which display surprisingly high binding affinities towards target proteins, even possessing useful in vivo activities. These observations are all the more surprising when one considers the heterogeneity inherent within these synthetic macromolecular receptors, and provoke intriguing questions regarding our assumptions about the design of receptors.