Synthesis and Enzymatic Stability of Phosphodiester-Linked Peptide−Oligonucleotide Hybrids

Abstract
Nucleopeptides Ac-Tyr(p3dACGT)-Ala-Phe-Gly-NH2, Ac-Thr(p3dACGT)-Ala-Phe-Gly-OH, Ac-Ser(p3dACGT)-Ala-Phe-Gly-OH, and Phac-Hse(p3dACGT)-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.