Highly efficient synthesis of peptide-oligonucleotide conjugates: Chemoselective oxime and thiazolidine formation

A convergent strategy for the synthesis of peptide-oligonucleotide conjugat es (POC) is presented. Chemoselective ligation of peptide to oligonucleotid e was accomplished by oxime and thiazolidine formation. Oxime conjugation w as performed by treating an oxyamine-containing peptide with an aldehyde-co ntaining oligonucleotide or vice versa. Ligation by thiazolidine formation was achieved by coupling a peptide, acylated with a cysteine residue, to an oligonucleotide that was derivatised by an aldehyde function. For both app roaches, the conjugates were obtained in good yield without the need for a protection strategy and under mild aqueous conditions. Moreover; the oxime ligation proved useful for directly conjugating duplex oligonucleotides. Co mbined with molecular biology tools, this methodology opens up new prospect s for post-functionalisation of high-molecular-weight DNA structures.