PEPTIDE-OLIGONUCLEOTIDE HYBRIDS WITH N-ACYLPHOSPHORAMIDATE LINKAGES

The preparation of a peptide-oligonucleotide hybrid with an N-acylphos phoramidate linkage has been carried out by (i) phosphitylation of the C-terminal carboxamide of a protected peptide by reaction with a chlo roalkoxy(dialkylamino)phosphine in the presence of a base, (ii) coupli ng of the resulting N-acylphosphorodiamidite onto an oligonucleotide-r esin followed by oxidation, and (iii) deprotection and cleavage under basic conditions. The synthetic method takes advantage of the unpreced ented reaction of primary carboxamides with electrophilic P-III specie s and takes place under mild conditions which are compatible with the stability of both the peptide and the oligonucleotide components.