De novo design of functional oligonucleotides with acyclic scaffolds

In this account, we demonstrate a new methodology for the de novo design of functional oligonucleotides with the acyclic scaffolds threoninol and serinol. Four functional motifs-wedge, interstrand-wedge, dimer, and cluster-have been prepared from natural DNA or RNA and functional base surrogates prepared from d-threoninol. The following applications of these motifs are described: (1) photoregulation of formation and dissociation of a DNA duplex modified with azobenzene, (2) sequence-specific detection of DNA using a fluorescent probe, (3) formation of fluorophore assemblies that mimic quantum dots, (4) improved strand selectivity of siRNA modified with a base surrogate, and (5) in vivo tracing of the RNAi pathway. Finally, we introduce artificial nucleic acids (XNAs) prepared from d-threoninol and serinol functionalized with each of the four nucleobases, which have unique properties compared with other acyclic XNAs. Functional oligonucleotides designed from acyclic scaffolds will be powerful tools for both DNA nanotechnology and biotechnology.