Optimisation of a Peptide Library for Screening Specific RNA Ligands by Flow-Injection NMR

Flow-injection NMR is a very attractive technique for identifying weak but specific ligandmacromolecule interactions. The low-sensitivity of this method is, however, a major concern which hinders its widespread application to large-scale screening. Focussing on RNA-targeting ligands, we have shown in this report that it is possible to design a peptide library that will simultaneously satisfy a number of physicochemical restraints and sample the sequence space in an “optimal” fashion. This library, which contains less than 200 peptides, covers most of the allowable tripeptide sequences in a non-redundant fashion. In addition, for almost any allowable tetrapeptide sequences, the library contains a close neighbor that will differ at the most by a single conservative replacement. A subset of this library was actually synthesised and used in a preliminary screen against human tRNALys3, the primer of HIV-1 reverse transcriptase.