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Pure Appl. Chem., 2006, Vol. 78, No. 5, pp. 993-1002

Enhanced P-stereodependent stability of complexes formed by phosphorothioate oligonucleotides due to involvement of sulfur as strong hydrogen bond acceptor

Piotr Guga, Małgorzata Boczkowska, Magdalena Janicka, Anna Maciaszek, Barbara Nawrot, Sławomir Antoszczyk and Wojciech J. Stec

Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Bioorganic Chemistry, Sienkiewicza 112, 90-363 Lódź, Poland

Abstract: The antisense or antigene properties are exerted not only by natural oligonucleotides, but also by their different analogs. Among them, phosphorothioate oligonucleotides (PS-DNA), in which the sugar-phosphate backbone is modified due to substitution of the sulfur atom for one of the nonbridging oxygens, are much more resistant toward nucleases and, simultaneously, maintain good hybridization properties. However, the substitution induces the P-chirality of dinucleoside phosphorothioate moiety and even short PS-DNA synthesized using standard chemical methods exist as a mixture of hundreds or thousands of diastereoisomers. Diastereomerically pure oligomers of [PS]-d(CG)4 and [PS]-d(GC)4 series, obtained using the oxathiaphospholane method, were investigated with respect to their ability to adopt the left-handed conformation at high sodium chloride concentration. Obtained data allow us to postulate the formation of a strong intramolecular hydrogen bond with anionic sulfur atom as an acceptor. Homopurine [All-RP-PS]-oligos, but not [All-SP-PS]-oligos, form with the RNA templates extremely stable triplex structures, so far not described in the literature. Most likely, the triplexes are stabilized by hydrogen bonds or water bridges with the participation of sulfur atoms of internucleotide linkage. Notably, target RNA molecules are "arrested" by properly designed [All-RP-PS]-DNA probes at submicromolar concentration, and as the result, they are not recognized by reverse transcriptase.