NEW TWISTS ON NUCLEIC-ACIDS - STRUCTURAL-PROPERTIES OF MODIFIED NUCLEOSIDES INCORPORATED INTO OLIGONUCLEOTIDES

The structures and physical properties of oligonucleotide duplexes depend strongly on the limited conformational flexibility of (deoxy)ribose-phosphodiester linkages and the sugar. Molecular mechanics and NMR spectroscopy have been employed to understand and predict alterations in sugar pucker and conformation resulting from replacement of oxygen, hydrogen, and carbon in the sugar with other heteroatoms. Studies on model monomer, dimer, and longer single stranded nucleosides are correlated with data on duplex stability obtained from oligomers incorporating 2', 3', and 4'-modified sugars to establish a set of guidelines for the types of alterations that can be tolerated within oligonucleotide duplexes. The results suggest that increased affinity of an antisense oligomer for a complementary RNA target can be achieved by decreasing the entropic motion of the sugar while maintaining a preorganized structure with an RNA-like conformation.