Cellular Pharmacology and Protein Binding of Phosphoromonothioate and Phosphorodithioate Oligodeoxynucleotides: A Comparative Study

Phosphorodithioate (PS₂) oligodeoxynucleotides (oligos) represent a relatively new class of backbone-modified oligo that have potential use as antisense agents. PS₂ oligos are isoelectronic with phosphodiester (PO) and phosphoromonothioate (PS) oligos, and are nuclease resistant. However, unlike their PS congeners, PS₂ oligos do not contain chiral centers. Little is known about the manner in which PS₂ oligos interact with biological systems. In this study, we compare the cellular pharmacology of PS and PS_, oligos in HL60 cells. Cell surface binding, internalization, and compartmentalization are examined. Furthermore, the ability of PS and PS₂ oligos to bind to rsCD4 and bFGF and to inhibit the activity of protein kinase C (PKC) is examined. Although the behavior of PS₂ oligos closely parallels that of PS oligos, PS₂ oligos appear to interact with some biological systems in a slightly different manner than PS oligos. These results indicate that PS₂ oligos may have therapeutic potential other than as antisense agents.