STRUCTURAL BASIS FOR THE RNA-BINDING SELECTIVITY OF OLIGONUCLEOTIDE ANALOGS CONTAINING ALKYLSULFIDE INTERNUCLEOSIDE LINKAGES AND 2'-SUBSTITUTED 3'-DEOXYRIBONUCLEOSIDES

In this report we describe the synthesis of oligonucleotides containin g sulfide-linked dinucleoside units, namely rT((2'OH))(s)dT, rT((2'OMe ))(s)dT, dT(s)rU((2'OMe)) and dT((2'OMe))(s)rU((2'OMe)). We also descr ibe the interactions of such oligomers with complementary DNA and RNA targets, and provide the structural basis for their remarkable RNA bin ding selectivity. In all cases, the T-m values of the S/P-chimera dupl exes were lower than those of the corresponding unmodified duplexes. W e attribute this to steric interactions between the 5' sulfur and the atoms of the nearby base/sugar residues, The 2'-substituents (i.e., 2' OH or 2'OMe) vicinal to the alkylsulfide internucleoside linkage signi ficantly perturb the structure and stability of the duplexes formed wi th DNA, and more so than with RNA. The introduction of three rT((2'OH) )(s)dT(p) (or rT((2'OMe))(s)dT(p)) units into an oligodeoxynucleotide sequence was sufficient to abolish binding to complementary DNA but no t RNA. The same three substitutions with dT(s)rU((2'OMe))p and dT((2'O Me))(s)rU((2'OMe))(p) did not abolish binding to DNA but the resulting complexes had poor thermal stability. The RNA-binding 'selectivity' e xhibited by these oligomers is attributed to the tendency of the 2'-su bstituted (branched) furanoses to adopt the C3'-endo pucker, a conform ation that is inconsistent with the B-form structure of helical DNA. T he preference of these sugars to exist often exclusively in the C3'-en do form is attributed to stereoelectronic effects, namely gauche and a nomeric effects. Our findings support the hypothesis that nucleoside a nalogues puckered exclusively in the C3'-endo form may result in them being especially good binders of targeted mRNA [S.H. Kawai (1991), Ph. D. Thesis, McGill University; Kawasaki et al. (1993) J. Med. Chem. 36, 831-841].