BINDING OF PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDES TO BASIC FIBROBLAST GROWTH-FACTOR, RECOMBINANT SOLUBLE CD4, LAMININ AND FIBRONECTIN IS P-CHIRALITY INDEPENDENT

Antisense oligodeoxynucleotides can selectively inhibit the expression of individual genes and thus have potential applications in anticancer and antiviral therapy, A critical prerequisite to their use as therapeutic agents is the understanding of their non-specific interactions with biological structures, e.g. proteins, In this study we examined the interactions of P-chiral phosphorothioate oligodeoxynucleotides with several proteins, The Rp- and Sp- diastereomers, and racemic machine-made mixtures, or M-oligodeoxynucleotides were used independently as competitors of the binding of a probe, phosphodiester oligodeoxynucleotide bearing a 5' alkylating moiety, to rsCD4, bFGF and laminin, These oligodeoxynucleotides were also used as competitors of the binding of a non-alkylating probe M-phosphorothioate oligodeoxynucleotide, 5'-P-32-SdT(18) to fibronectin, The average values of and quantitative estimates for the IC50 of competition and the constant of competition (K-c) of Rp-, Sp- and M- stereoisomers of several homo- and heteropolymer oligodeoxynucleotides were determined and compared, Surprisingly, in the proteins we studied, the values of IC50 and K-c for the Rp-, Sp- and M-oligodeoxynucleotides were essentially identical, Thus, the ability of the phosphorethioate oligodeoxynucleotides we employed, to bind to the proteins studied in this work, is virtually independent of P-chirality, Our results also imply that the role of the purine and pyrimidine bases in oligodeoxynucleotide-protein interactions, as well as the nature of the contact points (sulfur versus oxygen) between the oligomer and the protein, may be relatively unimportant.