Encoded self-assembling chemical libraries

Abstract

The isolation of molecules capable of high-affinity and specific binding to biological targets is a central problem in chemistry, biology and pharmaceutical sciences. Here we describe the use of encoded self-assembling chemical (ESAC) libraries for the facile identification of molecules that bind macromolecular targets. ESAC technology uses libraries of organic molecules linked to individual oligonucleotides that mediate the self-assembly of the library and provide a code associated with each organic molecule. After panning ESAC libraries on the biomolecular target of interest, the 'binding code' of the selected compounds can be 'decoded' by a number of experimental techniques (e.g., hybridization on oligonucleotide microarrays). The potential of this technology was demonstrated by the affinity maturation (>40-fold) of binding molecules to human serum albumin and bovine carbonic anhydrase, leading to binders with dissociation constants in the nanomolar range.

Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand Binding

“…546 DNA-based libraries have been useful in identifying inhibitors of BCA. 414,547 Doyon et al reported a technique for using BCA to enrich the concentration of their target inhibitors within a small library of inhibitors. 547 They linked each inhibitor to a unique sequence of DNA, which served as a means to amplify and identify the enriched species.…”

Isolation of High‐Affinity Trypsin Inhibitors from a DNA‐Encoded Chemical Library

“…[4] Such DNAencoded chemical libraries may be constructed as singlepharmacophore libraries (in which suitable chemical moieties are added in a stepwise fashion to molecular scaffolds [5][6][7][8] ) or as dual-pharmacophore chemical libraries (also termed encoded self-assembling chemical (ESAC) libraries [9,10] ). This second methodology is particularly suited for the improvement of binding affinity and specificity, starting from lead compounds of modest potency.…”

Nucleic Acid-programmed Assemblies: Translating Instruction into Function in Chemical Biology

“…Both DNA and PNA platforms have been used successfully to encode small molecule libraries with the first libraries reported in 2004. [25][26][27][28][29][30] PNA encoded synthesis (PES) is facilitated by the fact that it can be carried out using conventional solid phase synthesis. [31] Starting with a resin loaded with a bifunctional linker (such as lysine) bearing orthogonal protecting groups, the synthesis of the small molecule can be carried out alongside the PNA synthesis ( Fig.…”

“…The strategy was used first to pair a small library of drug fragments with a known pharmacophore to increase affinity. [30] Displaying ligands on a DNA template rather than through selfcomplementation offers the advantage that the pairing and distances are controlled through the instructions in the template. Thus, the same nucleic acid-tagged molecules can be arranged in a variety of controlled pairing and distance using a library of templates.…”