Zuckermann et al. at Chiron recognised that peptides could be employed as tag since their information content could be extracted with high sensitivity via Edman degradation and sequencing. Since the Edman degradation requires a free N-terminus, this peptide as code strategy could also be used to encode other peptide by acylating the N-terminus of the binding peptide strand, and leaving a free amine at the coding peptide terminus. To accommodate the parallel synthesis of both binding and coding peptides, an orthogonally protected bifunctional linker was employed that contained both acid and base
sensitive protecting groups. This bifunctional linker resided on the cleavable Rink amide linker, such that peptide-encoded peptide conjugates would be released into solution upon treatment of the Rink linker with 95% TFA.
The ligand and its associated tag are synthesised on a 1:1 correspondence on a cleavable linker and realised into free solution. Affinity selection techniques are employed to isolate conjugates that bind to the receptor, enzyme, or antibody target of interest.
The above peptide and DNA encoding techniques are not ideal because of the chemical lability of these oligomers. This places a severe restriction on the scope of the synthetic techniques that may be applied during library synthesis, and restricts the synthesis of more pharmaceutically attractive small organic molecules.