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Nucleic Acids Research, 1993, Vol. 21, No. 24 5761-5766
© 1993

CHEMISTRY

Evaluation of some properties of a phosphorodithioate oligodeoxyribonucleotide for antisense application

Mridul K. Ghosh, Krishnakali Ghosh, Otto Dahl1 and Jack S. Cohen*

Pharmacology Department, Georgetown University Medical Center Washington, DC 20007, USA 1nstitute of Chemistry, The H.C.Orsted Institute Copenhagen DK-2100, Denmark

*To whom correspondence should be addressed

Received July 20, 1993. Revised August 15, 1993. Accepted August 15, 1993.

An all phosphorodithioate oligodeoxyribonucleotide (PS2; 17-mer) complementary to the coding region of the rabbit ß-globin mRNA was compared with the normal (PO2) and phosphorothioate (POS) oligonucleotide of the same size and sequence with respect to physicochemical properties and antisense activity in cell-free systems. The melting temperature (Tm) of the PS2-cDNA duplex was reduced by 17{ring}C relative to the PO2 - cDNA duplex, compared to 11{ring}C for the POS-cDNA duplex, suggesting a decreased stability of the duplex with an increasing sulfur substitution.Like the POS-derivative, the PS2 oligonucleotide is quite stable against exonucleases, but these modified oligonucleotides showed different stability towards endonucleases and also towards different sub-cellular fractions of MCF-7 cells. During in vitro protein binding studies, the PS2 oligonucleotide showed similar binding (10-20%) to that of the PO2 oligonucleotide, while the POS oligonucleotide bound 60%. In cell-free translation, the PS2 oligonucleotide produced slightly higher specific translation inhibition of rabbit ß-globin mRNA compared to that of the PO2 oligonucleotide, and this was true only at concentration below 2 mM. The POS-derivative, except at 10 mM concentration, always showed higher translation arrest of the rabbit ß-globin mRNA compared to that of the other two oligonucleotides. The present study suggests that the PS2 oligonucleotide offers very little advantage over the POS oligonucleotide for use as an antisense analog.


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