Derivatization of Mirror-Image l-Nucleic Acids with 2′-OMe Modification for Thermal and Structural Stabilization

To further expand the functionality and enhance the stability of mirror-image nucleic acids as advanced agents for basic research and therapeutic design, we have synthesized 2′-deoxy-2′-methoxy-l-uridine phosphoramidite and incorporated it into l-DNA and l-RNA by solid-phase synthesis quantitatively. We found that the thermostability of l-nucleic acids is dramatically improved after introducing the modifications. Moreover, we successfully crystallized both l-DNA and l-RNA duplexes containing the 2′-OMe modifications and sharing identical sequences. Crystal structure determination and analysis revealed the overall structures of the mirror-image nucleic acids, and for the first time it was possible to interpret the structural deviations caused by 2′-OMe and 2′-OH groups in the oligonucleotides, which are very similar. This novel chemical nucleic acid modification has the potential to be used to design nucleic acid-based therapeutics and materials in the future.