Synthesis and enzymatic stability of phosphodiester-linked peptide-oligonucleotide hybrids

Nucleopeptides Ac-Tyr(p3' dACGT)-Ala-Phe-Gly-NH2, Ac-Thr(p3'dACGT)-Ala-Phe-Gly-OH, Ac-Ser(p3'dACGT)-Ala-Phe-Gly-OH, and Phac-Hse(p3'dACGT)-Ala-Phe-Gly-OH, in which the 3'-end of a tetradeoxyribonucleotide is linked by a phosphodiester bond to a hydroxylated amino acid, were synthesized using a stepwise solid-phase methodology to study the influence of the linking amino acid on their stability to 3'-exonucleases. HPLC analysis of the reaction crudes after treatment of each nucleopeptide with snake venom phosphodiesterase showed that the lability of the amino acid-nucleoside linkage increases in the order Thr < Ser < Hse < Tyr.