Stability of stereoregular oligo(nucleoside phosphorothioate)s in human plasma: Diastereoselectivity of plasma 3'-exonuclease

The stability of stereoregular oligo(nucleoside phosphorothioate)s (PS-oligos) in human plasma has been studied. 3'-Exonuclease present in human plasma appeared to be R(p) specific, that is, it cleaves internucleotide phosphorothioate linkages of [R(p)]-configuration and not those of [S-p]-configuration. Therefore, PS-oligos containing all phosphorothioate internucleotide linkages of [R(p)]-configuration [R(p)-PS-oligos]) are more effectively degraded by the enzyme than PS-oligos prepared via nonstereocontrolled methods (so-called random mixture of diastereomers [Mix-PS-oligos]), whereas oligo(nucleoside phosphorothioate)s of [S-p]-configuration remain intact. The enzyme activity depends on the sequence of nucleobases. The presence of deoxycytidine units (three or more residues) at the 3'-end of PS-oligo substrate significantly inhibits the enzyme activity.