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

Abstract

AbstractTo 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.