Xylo- and lyxo-type phosphonate nucleic acids: Synthesis and structural analysis

The exploration of the chemical space of nucleic acids is important to identify modified structural analogues with desirable properties for applications in therapy and synthetic biology. Diastereoisomeric DNA and RNA analogues such as deoxyxylo- and xylonucleic acids (dXyloNA and XyloNA) have been demonstrated to be strong-self pairing systems with a flexible backbone that can adopt unique helical geometries, which might play a role in their lack of cross-pairing with natural nucleic acids. In order to broaden our knowledge on the structure-function relationship of unnatural nucleic acids, we wish to investigate structurally related analogues by further replacing the phosphodiester bond in their backbone with an isosteric phosphonomethoxy linkage. The initial phase of this project will involve the synthesis of both xylo- and lyxo-nucleoside phosphonates as well as their corresponding activated monomers, which will then be subjected to theoretical and experimental structure analyses. Within the project, we plan to use solid-phase synthesis approaches to generate specific oligonucleotidic sequences containing the abovementioned monomers. The study of the physicochemical properties and helical structural characterization of such oligomers will then be performed using solution NMR spectroscopy and circular dichroism (CD) experiments.