Structural Correlations of Backbone Modifications in Antisense Oligonucleotide Duplexes

NMR Structure of an Antisense DNA·RNA Hybrid Duplex Containing a 3‘-CH2N(CH3)-O-5‘ or an MMI Backbone Linker

“…It appears that in R4, the inherent stability requirement of the MMI group outweighs the backbone conformational preferences. The analogy that a backbone modification dominates the resultant local structure has been observed in the duplexes containing the FMA and the 3′-TFMA linkers (15)(16)(17)25). The presence of the MMI linker, however, also introduces local motions that can be discerned at the T6 H2′, H2′′, and H3′ protons.…”

“…(b) Torsion Angle Comparisons with Other Antisense Duplexes. In Figure 6, the backbone torsion angles of the chemically modified sites in several antisense duplexes (25) are displayed. The figure compares RNA‚DNA hybrid duplexes and DNA‚DNA duplexes, RIII, R4, DII, and DIII.…”

“…The conformational preferences of the MMI linker in a duplex versus those in a single-stranded dimer demonstrate the influence of several inter-related factors, such as overall flexibility allowed by the molecule and the energy requirement of the local chemical moieties and overall molecules, in the determination of the local structures of oligonucleotides. The understanding of the interplay of these and several other factors (25) is an important step toward the improved design of antisense sequences.…”

“…(e) An Analysis of C3′-Modified Oligonucleotide Sequences. There has been a rapid increase in the number of structures determined for DNA‚RNA and antisense sequence‚ RNA hybrid duplexes (16,(25)(26)(27)(28)(29)(30). Several examples of C3′ modifications on the 2′-deoxyribose by a methylene group, such as C3′-CH 2 phosphonate (26) and C3′-CH 2 CH 2 NH (28), have demonstrated a 3′-endo conformation for the corresponding sugar moiety.…”