One of the first reported successful ligand encoding strategies exploited oligo-deoxyribonucleic acid (DNA) as the surrogate analyte. This DNA encoding concept had in fact been demonstrated in some of the first combinatorial library preparation methods ever reported – those utilising filamentous phage particles. In this approach, libraries of peptides are prepared biochemically from the cloning and expression of random sequence oligonucleotides. Pools of oligonucleotides encoding the peptides of interest are interested into an appropriate expression system, where upon translation the resulting peptides
are synthesised as fusion proteins. One of the common expression systems fuses these sequences to the gene III or the gene VIII coat protein of filamentous phage particles. Each viral particle contains a unique DNA sequence that encodes only a simple peptide. After screening a library in a given biological system, any viral particles displaying active peptides are isolated and the structure of the active peptides is elucidated by sequencing their encoding DNAs. A distinct disadvantage with this approach is that the molecular diversity of such systems is limited to peptides,
and amino acids that compose these peptides are restricted to the 20 encoded by genes.
DNA encoded peptide prepared in a 1:1 correspondence on a linker capable of anchoring the synthesis of both oligomers. The structure of the peptides are determined by sequencing their accompanying unique DNA sequence.