Stereodependent Inhibition of Plasminogen Activator Inhibitor Type 1 by Phosphorothioate Oligonucleotides: Proof of Sequence Specificity in Cell Culture and In Vivo Rat Experiments

Abstract

Hexadecadeoxyribonucleotides complementary to a fragment of human PAI-1 mRNA located upstream of the start codon and their phosphorothioate analogs were studied in cultured HUVECs as sequence-dependent inhibitors of PAI-1 expression. The activity of the random mixture of diastereomers of phosphorothioate hexadecanucleotide PS-16H has been compared with that of isosequential, stereoregular [All-S_P] and [All-R_P] isomers. The highest inhibitory effect on PAI-1 synthesis was observed with the [A11-S_P] diastereomer. Stereorandom phosphorothioate oligonucleotide PS-16R complementary to the same region of rat PAI-1 mRNA, when injected into tail vein of rats, substantially decreased the level of PAI-1 in blood plasma.